The Complementary and Alternative Medicine Fact Book Resource List
Here are all 1,796 citations from the book, covering 67 categories.
Mediterranean Diet References
16 references
Depression
1. Cabrera-Suárez BM, Hernández-Fleta JL, Molero P, González-Pinto A, Lahortiga F, Cabrera C, Chiclana-Actis C, Sánchez-Villegas A; PREDI-DEP investigators. Mediterranean diet-based intervention to improve depressive symptoms: Analysis of the PREDIDEP randomized trial. Nutr Neurosci. 2024 Sep;27(9):951–961. doi: 10.1080/1028415X.2023.2283290. Epub 2023 Nov 22. PMID: 37990906.
2. Jacka FN, O'Neil A, Opie R, Itsiopoulos C, Cotton S, Mohebbi M, Castle D, Dash S, Mihalopoulos C, Chatterton ML, Brazionis L, Dean OM, Hodge AM, Berk M. A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial). BMC Med. 2017 Jan 30;15(1):23. doi: 10.1186/s12916-017-0791-y. Erratum in: BMC Med. 2018 Dec 28;16(1):236. doi: 10.1186/s12916-018-1220-6. PMID: 28137247; PMCID: PMC5282719.
3. Parletta N, Zarnowiecki D, Cho J, Wilson A, Bogomolova S, Villani A, Itsiopoulos C, Niyonsenga T, Blunden S, Meyer B, Segal L, Baune BT, O'Dea K. A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED). Nutr Neurosci. 2019 Jul;22(7):474–487. doi: 10.1080/1028415X.2017.1411320. Epub 2017 Dec 7. PMID: 29215971.
4. Francis HM, Stevenson RJ, Chambers JR, Gupta D, Newey B, Lim CK. A brief diet intervention can reduce symptoms of depression in young adults - A randomised controlled trial. PLoS One. 2019 Oct 9;14(10):e0222768. doi: 10.1371/journal.pone.0222768. PMID: 31596866; PMCID: PMC6784975.
5. Bayes J, Schloss J, Sibbritt D. The effect of a Mediterranean diet on the symptoms of depression in young males (the "AMMEND: A Mediterranean Diet in MEN with Depression" study): A randomized controlled trial. Am J Clin Nutr. 2022 Aug 4;116(2):572–580. doi: 10.1093/ajcn/nqac106. PMID: 35441666.
ADHD
6. Khoshbakht Y, Moghtaderi F, Bidaki R, Hosseinzadeh M, Salehi-Abargouei A. The effect of dietary approaches to stop hypertension (DASH) diet on attention-deficit hyperactivity disorder (ADHD) symptoms: A randomized controlled clinical trial. Eur J Nutr. 2021 Oct;60(7):3647–3658. doi: 10.1007/s00394-021-02527-x. Epub 2021 Mar 14. PMID: 33715085.
Generalized anxiety disorder
7. Aucoin M, LaChance L, van der Wurff I, McLaren M, Monteiro S, Miller S, Jenkins A, Sabri E, Cooley K. Dietary counseling plus omega-3 supplementation in the treatment of generalized anxiety disorder: Results of a randomized wait-list controlled pilot trial (the 'EASe-GAD Trial'). Nutr Neurosci. 2025 Jun;28(6):635–648. doi: 10.1080/1028415X.2024.2403901. Epub 2024 Sep 24. PMID: 39316026.
Prevention of cognitive decline in older adults
8. Wardle J, Rogers P, Judd P, Taylor MA, Rapoport L, Green M, Nicholson Perry K. Randomized trial of the effects of cholesterol-lowering dietary treatment on psychological function. Am J Med. 2000 May;108(7):547–553. doi: 10.1016/s0002-9343(00)00330-2. PMID: 10806283.
9. Chou CC, Li YJ, Wang CJ, Lyu LC. A mini-flipped, game-based Mediterranean diet learning program on dietary behavior and cognitive function among community-dwelling older adults in Taiwan: A cluster-randomized controlled trial. Geriatr Nurs. 2022 May-Jun;45:160–168. doi: 10.1016/j.gerinurse.2022.03.009. Epub 2022 Apr 27. PMID: 35489112.
10. Knight A, Bryan J, Wilson C, Hodgson JM, Davis CR, Murphy KJ. The Mediterranean diet and cognitive function among healthy older adults in a 6-month randomised controlled trial: The MedLey study. Nutrients. 2016 Sep 20;8(9):579. doi: 10.3390/nu8090579. PMID: 27657119; PMCID: PMC5037563.
11. Martínez-Lapiscina EH, Clavero P, Toledo E, Estruch R, Salas-Salvadó J, San Julián B, Sanchez-Tainta A, Ros E, Valls-Pedret C, Martinez-Gonzalez MÁ. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry. 2013 Dec;84(12):1318–1325. doi: 10.1136/jnnp-2012-304792. Epub 2013 May 13. PMID: 23670794.
12. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó J, Estruch R, Ros E. Mediterranean diet and age-related cognitive decline: A randomized clinical trial. JAMA Intern Med. 2015 Jul;175(7):1094–1103. doi: 10.1001/jamainternmed.2015.1668. Erratum in: JAMA Intern Med. 2018 Dec 1;178(12):1731–1732. doi: 10.1001/jamainternmed.2018.6460. PMID: 25961184.
13. Barnes LL, Dhana K, Liu X, Carey VJ, Ventrelle J, Johnson K, Hollings CS, Bishop L, Laranjo N, Stubbs BJ, Reilly X, Agarwal P, Zhang S, Grodstein F, Tangney CC, Holland TM, Aggarwal NT, Arfanakis K, Morris MC, Sacks FM. Trial of the MIND diet for prevention of cognitive decline in older persons. N Engl J Med. 2023 Aug 17;389(7):602–611. doi: 10.1056/NEJMoa2302368. Epub 2023 Jul 18. PMID: 37466280; PMCID: PMC10513737.
14. Paknahad Z, Sheklabadi E, Derakhshan Y, Bagherniya M, Chitsaz A. The effect of the Mediterranean diet on cognitive function in patients with Parkinson's disease: A randomized clinical controlled trial. Complement Ther Med. 2020 May;50:102366. doi: 10.1016/j.ctim.2020.102366. Epub 2020 Mar 4. PMID: 32444045.
Sleep quality
15. Arab A, Lempesis IG, Garaulet M, Scheer FAJL. Sleep and the Mediterranean diet: A systematic review and meta-analysis. Sleep Med Rev. 2025 Apr;80:102071. doi: 10.1016/j.smrv.2025.102071. Epub 2025 Feb 7. PMID: 40081182; PMCID: PMC12110763.
Relevant meta-analyses
16. Abukmail E, Pradeep NK, Ahmed S, Albarqouni L. Moderate- to long-term effect of dietary interventions for depression and anxiety: A systematic review and meta-analysis. Ann Intern Med. 2025 Jul;178(7):987–999. doi: 10.7326/ANNALS-24-03016. Epub 2025 May 20. PMID: 40388814.
Exercise References
25 references
ADHD
1. Xu S, Zhao C, Hu L. The effects of acute and chronic exercise on executive functions and core symptoms in adults with ADHD: A systematic review and meta-analysis. Psychol Sport Exerc. 2026 May;84:103088. doi: 10.1016/j.psychsport.2026.103088. Epub 2026 Feb 2. PMID: 41638541.
2. Sun W, Yu M, Zhou X. Effects of physical exercise on attention deficit and other major symptoms in children with ADHD: A meta-analysis. Psychiatry Res. 2022 May;311:114509. doi: 10.1016/j.psychres.2022.114509. Epub 2022 Mar 14. PMID: 35305344.
Anxiety
3. Su H, Liang Y, Zhou R, Lv Y, He L, Yu L. The anxiolytic effects of exercise: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2026 May;97:103328. doi: 10.1016/j.ctim.2026.103328. Epub 2026 Feb 19. PMID: 41722711.
Cognition
4. Singh B, Bennett H, Miatke A, Dumuid D, Curtis R, Ferguson T, Brinsley J, Szeto K, Petersen JM, Gough C, Eglitis E, Simpson CE, Ekegren CL, Smith AE, Erickson KI, Maher C. Effectiveness of exercise for improving cognition, memory and executive function: A systematic umbrella review and meta-meta-analysis. Br J Sports Med. 2025 Jun 3;59(12):866–876. doi: 10.1136/bjsports-2024-108589. PMID: 40049759; PMCID: PMC12229068.
Major depressive disorder
5. Noetel M, Sanders T, Gallardo-Gómez D, Taylor P, Del Pozo Cruz B, van den Hoek D, Smith JJ, Mahoney J, Spathis J, Moresi M, Pagano R, Pagano L, Vasconcellos R, Arnott H, Varley B, Parker P, Biddle S, Lonsdale C. Effect of exercise for depression: Systematic review and network meta-analysis of randomised controlled trials. BMJ. 2024 Feb 14;384:e075847. doi: 10.1136/bmj-2023-075847. Erratum in: BMJ. 2024 May 28;385:q1024. doi: 10.1136/bmj.q1024. PMID: 38355154; PMCID: PMC10870815.
6. Tous-Espelosin M, Pavón-Navajas C, Etxaniz-Oses J, Cañas-García MT, Maldonado-Martin S, Orruño-Vivar J, Corres P, Iriarte-Yoller N. Effects of combined exercise training for adults with resistant major depression: A pilot study from the TRACE-RMD project. PeerJ. 2025 Nov 17;13:e20356. doi: 10.7717/peerj.20356. PMID: 41282982; PMCID: PMC12633128.
7. Mota-Pereira J, Silverio J, Carvalho S, Ribeiro JC, Fonte D, Ramos J. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Psychiatr Res. 2011 Aug;45(8):1005–1011. doi: 10.1016/j.jpsychires.2011.02.005. Epub 2011 Mar 5. PMID: 21377690.
Substance use disorders
8. Wang D, Wang Y, Wang Y, Li R, Zhou C. Impact of physical exercise on substance use disorders: A meta-analysis. PLoS One. 2014 Oct 16;9(10):e110728. doi: 10.1371/journal.pone.0110728. PMID: 25330437; PMCID: PMC4199732.
Binge eating disorder
9. Raisi A, Zerbini V, Piva T, Belvederi Murri M, Menegatti E, Caruso L, Masotti S, Grazzi G, Mazzoni G, Mandini S. Treating binge eating disorder with physical exercise: A systematic review and meta-analysis. J Nutr Educ Behav. 2023 Jul;55(7):523–530. doi: 10.1016/j.jneb.2023.03.010. Epub 2023 May 26. PMID: 37245147.
Bipolar disorder
10. Li X, Liu F, Ding F, Ma X, Zhu Y. Exercise interventions for depressive, manic, and anxiety symptoms in bipolar disorder: A systematic review and meta-analysis. Front Psychiatry. 2025 Sep 22;16:1648008. doi: 10.3389/fpsyt.2025.1648008. PMID: 41058644; PMCID: PMC12497790.
Internet addiction
11. Jia S, Wang H, Chu D, Yao J, Wang H, Chen W, Zhang D, Zhang W. The intervention effect of physical and mental exercise on young adults internet addiction disorder: A systematic review and Bayesian model analysis. Front Public Health. 2025 Oct 2;13:1670168. doi: 10.3389/fpubh.2025.1670168. PMID: 41112661; PMCID: PMC12528216.
Long COVID
12. Cheng X, Cao M, Yeung WF, Cheung DST. The effectiveness of exercise in alleviating long COVID symptoms: A systematic review and meta-analysis. Worldviews Evid Based Nurs. 2024 Oct;21(5):561–574. doi: 10.1111/wvn.12743. Epub 2024 Sep 1. PMID: 39218998.
Panic disorder
13. Broocks A, Bandelow B, Pekrun G, George A, Meyer T, Bartmann U, Hillmer-Vogel U, Rüther E. Comparison of aerobic exercise, clomipramine, and placebo in the treatment of panic disorder. Am J Psychiatry. 1998 May;155(5):603–609. doi: 10.1176/ajp.155.5.603. PMID: 9585709.
14. Bischoff S, Wieder G, Einsle F, Petzold MB, Janßen C, Mumm JLM, Wittchen HU, Fydrich T, Plag J, Ströhle A. Running for extinction? Aerobic exercise as an augmentation of exposure therapy in panic disorder with agoraphobia. J Psychiatr Res. 2018 Jun;101:34–41. doi: 10.1016/j.jpsychires.2018.03.001. Epub 2018 Mar 5. PMID: 29539585.
15. Gaudlitz K, Plag J, Dimeo F, Ströhle A. Aerobic exercise training facilitates the effectiveness of cognitive behavioral therapy in panic disorder. Depress Anxiety. 2015 Mar;32(3):221–228. doi: 10.1002/da.22337. Epub 2014 Dec 17. PMID: 25515221.
16. Wedekind D, Broocks A, Weiss N, Engel K, Neubert K, Bandelow B. A randomized, controlled trial of aerobic exercise in combination with paroxetine in the treatment of panic disorder. World J Biol Psychiatry. 2010 Oct;11(7):904–913. doi: 10.3109/15622975.2010.489620. PMID: 20602575.
17. Hovland A, Nordhus IH, Sjøbø T, Gjestad BA, Birknes B, Martinsen EW, Torsheim T, Pallesen S. Comparing physical exercise in groups to group cognitive behaviour therapy for the treatment of panic disorder in a randomized controlled trial. Behav Cogn Psychother. 2013 Jul;41(4):408–432. doi: 10.1017/S1352465812000446. Epub 2012 Jul 5. PMID: 22874661; PMCID: PMC3675676.
PTSD
18. Fang Y, Zhang Q, Lin Z. Assessment of the effectiveness of exercise interventions in the treatment of PTSD: Based on a systematic evaluation and meta-analysis. Front Psychol. 2026 Jan 7;16:1702199. doi: 10.3389/fpsyg.2025.1702199. PMID: 41574081; PMCID: PMC12819760.
19. Fetzner MG, Asmundson GJ. Aerobic exercise reduces symptoms of posttraumatic stress disorder: A randomized controlled trial. Cogn Behav Ther. 2015;44(4):301–313. doi: 10.1080/16506073.2014.916745. Epub 2014 Jun 9. PMID: 24911173.
20. Rosenbaum S, Sherrington C, Tiedemann A. Exercise augmentation compared with usual care for post-traumatic stress disorder: A randomized controlled trial. Acta Psychiatr Scand. 2015 May;131(5):350–359. doi: 10.1111/acps.12371. Epub 2014 Dec 1. PMID: 25443996.
21. Bryant RA, Dawson KS, Azevedo S, Yadav S, Cahill C, Kenny L, Maccallum F, Tran J, Rawson N, Tockar J, Garber B, Keyan D. Augmenting trauma-focused psychotherapy for post-traumatic stress disorder with brief aerobic exercise in Australia: A randomised clinical trial. Lancet Psychiatry. 2023 Jan;10(1):21–29. doi: 10.1016/S2215-0366(22)00368-6. Epub 2022 Nov 24. PMID: 36436532.
22. Neylan TC, Muratore LA, Williams CL, Schmitz M, Valdez CV, Maguen S, O’Donovan A, Kelley DP, Metzler TJ, Cohen BE, West AC, Phan JDV, Antonetti V, Mayzel O, Hlavin JA, Chesney MA, Mehling WE. Group integrated exercise versus recovery class for veterans with posttraumatic stress disorder: A randomized clinical trial. BMC Psychiatry. 2025 Feb 28;25(1):185. doi: 10.1186/s12888-025-06638-1. PMID: 40021975; PMCID: PMC11871828.
23. Crombie KM, Sartin-Tarm A, Sellnow K, Ahrenholtz R, Lee S, Matalamaki M, Adams TG, Cisler JM. Aerobic exercise and consolidation of fear extinction learning among women with posttraumatic stress disorder. Behav Res Ther. 2021 Jul;142:103867. doi: 10.1016/j.brat.2021.103867. Epub 2021 Apr 27. PMID: 34020153.
OCD
24. Bottoms L, Prat Pons M, Fineberg NA, Pellegrini L, Fox O, Wellsted D, Drummond LM, Reid J, Baldwin DS, Hou R, Chamberlain S, Sireau N, Grohmann D, Laws KR. Effects of exercise on obsessive-compulsive disorder symptoms: A systematic review and meta-analysis. Int J Psychiatry Clin Pract. 2023 Sep;27(3):232–242. doi: 10.1080/13651501.2022.2151474. Epub 2022 Dec 21. PMID: 36541901.
Metabolic syndrome in schizophrenia
25. Ancín-Osés A, Izquierdo M, Cuesta MJ, Sáez de Asteasu ML. Effects of physical exercise on metabolic syndrome in psychotic disorders: A systematic review with meta-analysis of randomized controlled trials. Eur Psychiatry. 2025 Jul 18;68(1):e101. doi: 10.1192/j.eurpsy.2025.10064. PMID: 40677207; PMCID: PMC12344471.
Forest Therapy References
48 references
Cognition
1. Bourdon E, Belmin J. Enriched gardens improve cognition and independence of nursing home residents with dementia: A pilot controlled trial. Alzheimers Res Ther. 2021 Jun 16;13(1):116. doi: 10.1186/s13195-021-00849-w. PMID: 34134758; PMCID: PMC8207740.
2. Daniels S, Clemente DBP, Desart S, Saenen N, Sleurs H, Nawrot TS, Malina R, Plusquin M. Introducing nature at the work floor: A nature-based intervention to reduce stress and improve cognitive performance. Int J Hyg Environ Health. 2022 Mar;240:113884. doi: 10.1016/j.ijheh.2021.113884. Epub 2021 Nov 27. PMID: 34847453.
4. McDonnell AS, Strayer DL. Immersion in nature enhances neural indices of executive attention. Sci Rep. 2024 Jan 22;14(1):1845. doi: 10.1038/s41598-024-52205-1. PMID: 38253734; PMCID: PMC10803324.
5. Pedrinolla A, Tamburin S, Brasioli A, Sollima A, Fonte C, Muti E, Smania N, Schena F, Venturelli M. An indoor therapeutic garden for behavioral symptoms in alzheimer’s disease: A randomized controlled trial. J Alzheimers Dis. 2019;71(3):813–823. doi: 10.3233/JAD-190394. PMID: 31424399.
Cognition / Major depressive disorder
3. Kim S, Choi J. The effect of a forest healing program on cognitive function, depression, anxiety, and cortisol levels in elderly people. Journal of Forest and Environmental Science. 2022;38(4):290–301.
Major depressive disorder
6. Berman MG, Kross E, Krpan KM, Askren MK, Burson A, Deldin PJ, Kaplan S, Sherdell L, Gotlib IH, Jonides J. Interacting with nature improves cognition and affect for individuals with depression. J Affect Disord. 2012 Nov;140(3):300–305. doi: 10.1016/j.jad.2012.03.012. Epub 2012 Mar 31. PMID: 22464936; PMCID: PMC3393816.
7. Chun MH, Chang MC, Lee SJ. The effects of forest therapy on depression and anxiety in patients with chronic stroke. Int J Neurosci. 2017 Mar;127(3):199–203. doi: 10.3109/00207454.2016.1170015. Epub 2016 Apr 10. PMID: 27033879.
8. Gao C, Wu RY, Dong XM, Li L, Tan YX, Liu CL, Chen J. The effect of virtual immersion in nature on hospitalization stress in psychiatric patients: A randomized controlled trial. J Affect Disord. 2025 Dec 15;391:119942. doi: 10.1016/j.jad.2025.119942. Epub 2025 Jul 16. PMID: 40681000.
9. Hyvönen K, Salonen K, Paakkolanvaara J-V, Väkeväinen P, Korpela K. Effects of nature-based intervention in the treatment of depression: A multi-center, randomized controlled trial. J Environ Psychol. 2023;85:101950. doi: 10.1016/j.jenvp.2022.101950.
10. Keenan R, Lumber R, Richardson M, Sheffield D. Three good things in nature: A nature-based positive psychological intervention to improve mood and well-being for depression and anxiety. JPMH. 2021 Aug 30;20(4):243–250. doi: 10.1108/JPMH-02-2021-0029.
11. Kim G, Kang S, Paek K, Seo Y, Park S, Choi H, Min G, Lee N, Park S, Choi S, Yeon P. The effect of personalized forest therapy programs on stress and obsessive-compulsive symptoms in patients with depression. Front Public Health. 2026 Jan 12;13:1735731. doi: 10.3389/fpubh.2025.1735731. PMID: 41602044; PMCID: PMC12832841.
12. Kim W, Lim SK, Chung EJ, Woo JM. The effect of cognitive behavior therapy-based psychotherapy applied in a forest environment on physiological changes and remission of major depressive disorder. Psychiatry Investig. 2009 Dec;6(4):245–254. doi: 10.4306/pi.2009.6.4.245. Epub 2009 Nov 17. PMID: 20140122; PMCID: PMC2808793.
13. Korpela KM, Stengård E, Jussila P. Nature walks as a part of therapeutic intervention for depression. Ecopsychology. 2016;8:8–15. doi: 10.1089/eco.2015.0070.
14. Shin WS, Shin CS, Yeoun PS. The influence of forest therapy camp on depression in alcoholics. Environ Health Prev Med. 2012 Jan;17(1):73–76. doi: 10.1007/s12199-011-0215-0. Epub 2011 Apr 19. PMID: 21503628; PMCID: PMC3258312.
15. Watkins-Martin K, Bolanis D, Richard-Devantoy S, Pennestri MH, Malboeuf-Hurtubise C, Philippe F, Guindon J, Gouin JP, Ouellet-Morin I, Geoffroy MC. The effects of walking in nature on negative and positive affect in adult psychiatric outpatients with major depressive disorder: A randomized-controlled study. J Affect Disord. 2022 Dec 1;318:291–298. doi: 10.1016/j.jad.2022.08.121. Epub 2022 Sep 1. PMID: 36058362.
16. Yeon PS, Kim IO, Kang SN, Lee NE, Kim GY, Min GM, Chung CY, Lee JS, Kim JG, Shin WS. Effects of urban forest therapy program on depression patients. Int J Environ Res Public Health. 2022 Dec 28;20(1):507. doi: 10.3390/ijerph20010507. PMID: 36612825; PMCID: PMC9819035.
Stress
17. Bagereka P, Ameli R, Sinaii N, Vocci MC, Coulter AM, Neustedter M, Berger A. Effects of a combined nature-based and audio-based virtual mindfulness intervention on stress and wellbeing of COVID-19 healthcare workers: A randomized controlled trial. PeerJ. 2025 May 23;13:e19109. doi: 10.7717/peerj.19109. PMID: 40421373; PMCID: PMC12105617.
18. Bang KS, Lee IS, Kim SJ, Song MK, Park SE. The effects of urban forest-walking program on health promotion behavior, physical health, depression, and quality of life: A randomized controlled trial of office workers. J Korean Acad Nurs. 2016 Feb;46(1):140–148. doi: 10.4040/jkan.2016.46.1.140. PMID: 26963423.
19. Beukeboom CJ, Langeveld D, Tanja-Dijkstra K. Stress-reducing effects of real and artificial nature in a hospital waiting room. J Altern Complement Med. 2012 Apr;18(4):329–333. doi: 10.1089/acm.2011.0488. Epub 2012 Apr 10. PMID: 22489806.
20. Bielinis E, Simkin J, Puttonen P, Tyrväinen L. Effect of viewing video representation of the urban environment and forest environment on mood and level of procrastination. Int J Environ Res Public Health. 2020 Jul 15;17(14):5109. doi: 10.3390/ijerph17145109. PMID: 32679839; PMCID: PMC7400642.
21. Bratman GN, Hamilton JP, Hahn KS, Daily GC, Gross JJ. Nature experience reduces rumination and subgenual prefrontal cortex activation. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8567–8572. doi: 10.1073/pnas.1510459112. Epub 2015 Jun 29. PMID: 26124129; PMCID: PMC4507237.
22. Cho YM, Shin WS, Yeon PS, Lee HE. The influence of forest experience program on children from low income families, sociality and depression. J. Korean Inst. For. Recreat. 2011;15(2):69–75. doi: 10.34272/forest.2011.15.2.008.
23. Kim DJ, Lee SS. Effects of forest therapy program in school forest on employment stress and anxiety of university students. J. Korean Soc. People Plants Environ. 2014;17(2):107–115. doi: 10.11628/ksppe.2014.17.2.107.
24. Kim JG, Khil TG, Lim Y, Park K, Shin M, Shin WS. The psychological effects of a campus forest therapy program. Int. J. Environ. Res. Public Health. 2020 May 14;17(10):3409. doi: 10.3390/ijerph17103409. PMID: 32422871; PMCID: PMC7277815.
25. Lau SSS, Leung SSK, Wong JWC, Lee TCP, Cartwright SR, Wong JTC, Man J, Cheung E, Choi RPW. Brief repeated virtual nature contact for three weeks boosts university students’ nature connectedness and psychological and physiological health during the COVID-19 pandemic: A pilot study. Front Public Health. 2023 Jan 12;10:1057020. doi: 10.3389/fpubh.2022.1057020. PMID: 36711407; PMCID: PMC9878182.
26. Lim YS, Kim DJ, Yeoun PS. Changes in depression degree and self esteem of senior citizens in a nursing home according to forest therapy program. J. Korean Inst. For. Recreat. 2014 March;18:1–11. doi: 10.34272/forest.2014.18.1.001.
27. Loose T, Fuoco J, Malboeuf-Hurtubise C, Ayotte-Beaudet JP, Gauvin L, Chadi N, Ouellet-Morin I, Mâsse B, Côté SM, Geoffroy MC. A nature-based intervention and mental health of schoolchildren: A cluster randomized clinical trial. JAMA Netw Open. 2024 Nov 4;7(11):e2444824. doi: 10.1001/jamanetworkopen.2024.44824. PMID: 39546315; PMCID: PMC11568460.
28. Noushad S, Ahmed S, Saleem Y, Aziz SA. The effects of nature walk therapy on post-traumatic growth in breast cancer survivors: A comparative study. Eur J Oncol Nurs. 2025 Dec;79:102994. doi: 10.1016/j.ejon.2025.102994. Epub 2025 Oct 1. PMID: 41092524.
29. Owens M, Bunce H. The effect of brief exposure to virtual nature on mental wellbeing in adolescents. Sci Rep. 2023 Oct 18;13(1):17769. doi: 10.1038/s41598-023-44717-z. PMID: 37853074; PMCID: PMC10584913.
30. Sadowski I, Meilleur-Bédard M, Khoury B. A novel virtual reality-based nature meditation program for older adults’ mental health: Results from a pilot randomized controlled trial. Clin Gerontol. 2025 Jul–Sep;48(4):663–683. doi: 10.1080/07317115.2025.2482089. Epub 2025 Mar 28. PMID: 40152067.
31. Sjölander A, Jakobsson Ung E, Theorell T, Nilsson Å, Ung KA. Hospital design with nature films reduces stress-related variables in patients undergoing colonoscopy. HERD. 2019 Oct;12(4):186–196. doi: 10.1177/1937586719837754. Epub 2019 Mar 26. PMID: 30913926.
32. Stigsdotter UK, Corazon SS, Sidenius U, Nyed PK, Larsen HB, Fjorback LO. Efficacy of nature-based therapy for individuals with stress-related illnesses: Randomised controlled trial. Br J Psychiatry. 2018;213:404–411. doi: 10.1192/bjp.2018.2. Epub 2018 May 25. PMID: 29793558.
33. Vujcic M, Tomicevic-Dubljevic J, Grbic M, Lecic-Tosevski D, Vukovic O, Toskovic O. Nature based solution for improving mental health and well-being in urban areas. Environ Res. 2017 Oct;158:385–392. doi: 10.1016/j.envres.2017.06.030. Epub 2017 Jul 5. PMID: 28688269.
34. Yau KY, Law PS, Wong CN. Cardiac and mental benefits of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet plus forest bathing (FB) versus MIND diet among older chinese adults: A randomized controlled pilot study. Int J Environ Res Public Health. 2022 Nov 8;19(22):14665. doi: 10.3390/ijerph192214665. PMID: 36429384; PMCID: PMC9690744.
35. Zabini F, Albanese L, Becheri FR, Gavazzi G, Giganti F, Giovanelli F, Gronchi G, Guazzini A, Laurino M, Li Q, Marzi T, Mastorci F, Meneguzzo F, Righi S, Viggiano MP. Comparative study of the restorative effects of forest and urban videos during COVID-19 lockdown: Intrinsic and benchmark values. Int J Environ Res Public Health. 2020 Oct 30;17(21):8011. doi: 10.3390/ijerph17218011. PMID: 33143327; PMCID: PMC7672570.
ADHD
36. Taylor AF, Kuo FE. Children with attention deficits concentrate better after walk in the park. J Atten Disord. 2009 Mar;12(5):402–409. doi: 10.1177/1087054708323000. Epub 2008 Aug 25. PMID: 18725656.
37. Hood M, Baumann O. Could nature contribute to the management of ADHD in children? A systematic review. Int J Environ Res Public Health. 2024 Jun 5;21(6):736. doi: 10.3390/ijerph21060736. PMID: 38928982; PMCID: PMC11203786.
Insomnia
38. Kolster A, Heikkinen M, Pajunen A, Mickos A, Wennman H, Partonen T. Targeted health promotion with guided nature walks or group exercise: A controlled trial in primary care. Front Public Health. 2023 Aug 24;11:1208858. doi: 10.3389/fpubh.2023.1208858. PMID: 37766747; PMCID: PMC10520711.
39. Li Q, Takayama N, Kimura Y, Takayama H, Kumeda S, Miura T, Kitagawa T, Aoyagi Y, Imai M. Forest bathing improves inflammatory markers, SpO2, and subjective symptoms related to chronic obstructive pulmonary disease (COPD) in male subjects at risk of developing COPD. J Occup Health. 2025 Jan 7;67(1):uiaf041. doi: 10.1093/joccuh/uiaf041. PMID: 40673365; PMCID: PMC12353587.
40. Ma J, Williams JM, Morris PG, Chan SWY. Effectiveness of a mindful nature walking intervention on sleep quality and mood in university students during Covid-19: A randomised control study. Explore (NY). 2023 May–Jun;19(3):405–416. doi: 10.1016/j.explore.2022.08.004. Epub 2022 Aug 11. PMID: 35973933; PMCID: PMC9365743.
41. Pitkälä KH, Rautiainen L, Kautiainen H, Aalto UL, Kolster A, Laakkonen ML, Partonen T, Roitto HM, Puntscher S, Rochau U, Siebert U, Bartova A, Holmerová I, Coll-Planas L, Litt JS, Strandberg T, Jansson AH. Effectiveness of nature-based group intervention in loneliness and health-related quality-of-life in lonely older adults living in assisted living facilities-a randomised controlled trial. Age Ageing. 2026 Feb 1;55(2):afag009. doi: 10.1093/ageing/afag009. PMID: 41638234.
PTSD
42. Gelkopf M, Hasson-Ohayon I, Bikman M, Kravetz S. Nature adventure rehabilitation for combat-related posttraumatic chronic stress disorder: A randomized control trial. Psychiatry Res. 2013 Oct 30;209(3):485–493. doi: 10.1016/j.psychres.2013.01.026. Epub 2013 Mar 28. PMID: 23541513.
43. Littman AJ, Bratman GN, Lehavot K, Engel CC, Fortney JC, Peterson A, Jones A, Klassen C, Brandon J, Frumkin H. Nature versus urban hiking for Veterans with post-traumatic stress disorder: A pilot randomised trial conducted in the Pacific Northwest USA. BMJ Open. 2021 Sep 23;11(9):e051885. doi: 10.1136/bmjopen-2021-051885. PMID: 34556516; PMCID: PMC8461737.
44. Noushad S, Ansari B, Ahmed S. Effect of nature-based physical activity on post-traumatic growth among healthcare providers with post-traumatic stress. Stress Health. 2022 Oct;38(4):813–826. doi: 10.1002/smi.3135. Epub 2022 Feb 26. PMID: 35191173.
Psychotic disorders
45. Kim MH, Shim BS, Wi AJ, Yoon BS, Han YH, Oh EM, An KW. The influence of forest experience program on physiological and psychological states in psychiatric inpatients. J Korean For Soc. 2015;104:133–139.
Relevant meta-analyses
46. Kang MJ, Kim HS, Kim JY. Effects of forest-based interventions on mental health: A meta-analysis of randomized controlled trials. Int J Environ Res Public Health. 2022 Apr 17;19(8):4884. doi: 10.3390/ijerph19084884. PMID: 35457755; PMCID: PMC9031621.
47. Stevenson MP, Schilhab T, Bentsen P. Attention restoration theory II: A systematic review to clarify attention processes affected by exposure to natural environments. J Toxicol Environ Health B Crit Rev. 2018;21(4):227–268. doi: 10.1080/10937404.2018.1505571. Epub 2018 Aug 21. PMID: 30130463.
48. Jessen NH, Løvschall C, Skejø SD, Madsen LSS, Corazon SS, Maribo T, Poulsen DV. Effect of nature-based health interventions for individuals diagnosed with anxiety, depression and/or experiencing stress-a systematic review and meta-analysis. BMJ Open. 2025 Jul 24;15(7):e098598. doi: 10.1136/bmjopen-2024-098598. PMID: 40707146; PMCID: PMC12306343.
Dawn Simulator References
28 references
Seasonal (winter) depression
1. Avery D, Bolte MA, Millet M. Bright dawn simulation compared with bright morning light in the treatment of winter depression. Acta Psychiatr Scand. 1992 Jun;85(6):430–434. doi: 10.1111/j.1600-0447.1992.tb03206.x. PMID: 1642124.
2. Avery DH, Bolte MA, Cohen S, Millet MS. Gradual versus rapid dawn simulation treatment of winter depression. J Clin Psychiatry. 1992 Oct;53(10):359–363. PMID: 1429475.
3. Avery DH, Bolte MA, Dager SR, Wilson LG, Weyer M, Cox GB, Dunner DL. Dawn simulation treatment of winter depression: A controlled study. Am J Psychiatry. 1993 Jan;150(1):113–117. doi: 10.1176/ajp.150.1.113. PMID: 8417552.
4. Avery DH, Bolte MA, Ries R. Dawn simulation treatment of abstinent alcoholics with winter depression. J Clin Psychiatry. 1998 Jan;59(1):36–42; quiz 43–44. doi: 10.4088/jcp.v59n0109. PMID: 9491067.
5. Avery DH, Bolte MA, Wolfson JK, Kazaras AL. Dawn simulation compared with a dim red signal in the treatment of winter depression. Biol Psychiatry. 1994 Aug 1;36(3):180–188. doi: 10.1016/0006-3223(94)91223-8. PMID: 7948455.
6. Avery DH, Eder DN, Bolte MA, Hellekson CJ, Dunner DL, Vitiello MV, Prinz PN. Dawn simulation and bright light in the treatment of SAD: A controlled study. Biol Psychiatry. 2001 Aug 1;50(3):205–216. doi: 10.1016/s0006-3223(01)01200-8. PMID: 11513820.
7. Avery DH, Kouri ME, Monaghan K, Bolte MA, Hellekson C, Eder D. Is dawn simulation effective in ameliorating the difficulty awakening in seasonal affective disorder associated with hypersomnia? J Affect Disord. 2002 May;69(1–3):231–236. doi: 10.1016/s0165-0327(00)00360-8. PMID: 12103471.
8. Danilenko KV, Ivanova IA. Dawn simulation vs. bright light in seasonal affective disorder: Treatment effects and subjective preference. J Affect Disord. 2015 Jul 15;180:87–89. doi: 10.1016/j.jad.2015.03.055. Epub 2015 Apr 7. PMID: 25885065.
9. Lingjaerde O, Føreland AR, Dankertsen J. Dawn simulation vs. lightbox treatment in winter depression: A comparative study. Acta Psychiatr Scand. 1998 Jul;98(1):73–80. doi: 10.1111/j.1600-0447.1998.tb10045.x. PMID: 9696518.
10. Norden MJ, Avery DH. A controlled study of dawn simulation in subsyndromal winter depression. Acta Psychiatr Scand. 1993 Jul;88(1):67–71. doi: 10.1111/j.1600-0447.1993.tb03415.x. PMID: 8372698.
11. Terman M, Terman JS. Circadian rhythm phase advance with dawn simulation treatment for winter depression. J Biol Rhythms. 2010 Aug;25(4):297–301. doi: 10.1177/0748730410374000. PMID: 20679499.
Sleep inertia
12. Arakawa K, Shirakawa S, Kobayashi T, Oguri M, Kamei Y, Tumura T. Effects of the gradually increasing dawn light stimulation on sleep feeling. Psychiatry Clin Neurosci. 1998 Apr;52(2):247–248. doi: 10.1111/j.1440-1819.1998.tb01056.x. PMID: 9628177.
13. Campanella C, Byun K, Senerat A, Li L, Zhang R, Aristizabal S, Porter P, Bauer B. The efficacy of a multimodal bedroom-based ‘smart’ alarm system on mitigating the effects of sleep inertia. Clocks Sleep. 2024 Mar 18;6(1):183–199. doi: 10.3390/clockssleep6010013. PMID: 38534801; PMCID: PMC10969141.
14. Giménez MC, Hessels M, van de Werken M, de Vries B, Beersma DG, Gordijn MC. Effects of artificial dawn on subjective ratings of sleep inertia and dim light melatonin onset. Chronobiol Int. 2010 Jul;27(6):1219–1241. doi: 10.3109/07420528.2010.496912. PMID: 20653451.
15. Thompson A, Jones H, Gregson W, Atkinson G. Effects of dawn simulation on markers of sleep inertia and post-waking performance in humans. Eur J Appl Physiol. 2014 May;114(5):1049–1056. doi: 10.1007/s00421-014-2831-z. Epub 2014 Feb 11. PMID: 24509892.
16. Van De Werken M, Giménez MC, De Vries B, Beersma DG, Van Someren EJ, Gordijn MC. Effects of artificial dawn on sleep inertia, skin temperature, and the awakening cortisol response. J Sleep Res. 2010 Sep;19(3):425–435. doi: 10.1111/j.1365-2869.2010.00828.x. Epub 2010 Apr 7. PMID: 20408928.
Major depressive disorder
17. Canazei M, Weninger J, Pohl W, Marksteiner J, Weiss EM. Effects of dynamic bedroom lighting on measures of sleep and circadian rest-activity rhythm in inpatients with major depressive disorder. Sci Rep. 2022 Apr 12;12(1):6137. doi: 10.1038/s41598-022-10161-8. PMID: 35414714; PMCID: PMC9005730.
18. Volf C, Aggestrup AS, Petersen PM, Dam-Hansen C, Knorr U, Erkocevic Petersen E, Engstrøm J, Skov Hansen T, Østergaard Madsen H, Hageman I, Martiny K. Dynamic versus static LED-lighting for inpatients with major depression: Long-term antidepressant effects and short-term sleep improvement in a randomized controlled clinical trial. Chronobiol Int. 2025 Sep;42(9):1122–1136. doi: 10.1080/07420528.2025.2530129. Epub 2025 Aug 4. PMID: 40755281.
Sleep deprivation
19. Gabel V, Maire M, Reichert CF, Chellappa SL, Schmidt C, Hommes V, Cajochen C, Viola AU. Dawn simulation light impacts on different cognitive domains under sleep restriction. Behav Brain Res. 2015 Mar 15;281:258–266. doi: 10.1016/j.bbr.2014.12.043. Epub 2014 Dec 27. PMID: 25549858.
20. Gabel V, Maire M, Reichert CF, Chellappa SL, Schmidt C, Hommes V, Viola AU, Cajochen C. Effects of artificial dawn and morning blue light on daytime cognitive performance, well-being, cortisol and melatonin levels. Chronobiol Int. 2013 Oct;30(8):988–997. doi: 10.3109/07420528.2013.793196. Epub 2013 Jul 10. PMID: 23841684.
Sleep quality
21. Leppämäki S, Meesters Y, Haukka J, Lönnqvist J, Partonen T. Effect of simulated dawn on quality of sleep--a community-based trial. BMC Psychiatry. 2003 Oct 27;3:14. doi: 10.1186/1471-244X-3-14. PMID: 14577838; PMCID: PMC270037.
Dementia
22. Alrahyani M, Youngstedt S, Fani M, Yague N, Yu F, Guest MA, Yeom D, Sharp N. Effects of applying biodynamic lighting on improving sleep, depression, and agitation in older adults with dementia: A pilot clinical trial. Geriatr Nurs. 2025 Jul–Aug;64:103435. doi: 10.1016/j.gerinurse.2025.103435. Epub 2025 Jul 4. PMID: 40617163.
23. Bromundt V, Wirz-Justice A, Boutellier M, Winter S, Haberstroh M, Terman M, Münch M. Effects of a dawn-dusk simulation on circadian rest-activity cycles, sleep, mood and well-being in dementia patients. Exp Gerontol. 2019 Sep;124:110641. doi: 10.1016/j.exger.2019.110641. Epub 2019 Jun 25. PMID: 31252161.
24. Fontana Gasio P, Kräuchi K, Cajochen C, van Someren E, Amrhein I, Pache M, Savaskan E, Wirz-Justice A. Dawn-dusk simulation light therapy of disturbed circadian rest-activity cycles in demented elderly. Exp Gerontol. 2003 Jan–Feb;38(1–2):207–216. doi: 10.1016/s0531-5565(02)00164-x. PMID: 12543279.
25. Obeidat B, Abu Hamdan RM, Hayajneh AA. Pilot study of dynamic lighting and sleep consolidation among older adults in a Jordanian senior care facility. Sci Rep. 2025 Aug 29;15(1):31920. doi: 10.1038/s41598-025-17351-0. PMID: 40883467; PMCID: PMC12397485.
Traumatic brain injury
26. Angerer M, Pichler G, Angerer B, Scarpatetti M, Schabus M, Blume C. From dawn to dusk-mimicking natural daylight exposure improves circadian rhythm entrainment in patients with severe brain injury. Sleep. 2022 Jul 11;45(7):zsac065. doi: 10.1093/sleep/zsac065. PMID: 35290446; PMCID: PMC9272242.
Relevant meta-analyses
27. Hilditch CJ, Dorrian J, Banks S. Time to wake up: reactive countermeasures to sleep inertia. Ind Health. 2016 Dec 7;54(6):528–541. doi: 10.2486/indhealth.2015-0236. Epub 2016 May 18. PMID: 27193071; PMCID: PMC5136610.
28. Beute F, Aries MB. The importance of residential dusk and dawn light exposure for sleep quality, health, and well-being. Sleep Med Rev. 2023 Dec;72:101865. doi: 10.1016/j.smrv.2023.101865. Epub 2023 Oct 14. PMID: 37864914.
Light Therapy References
74 references
Major depressive disorder
1. Menegaz de Almeida A, Aquino de Moraes FC, Cavalcanti Souza ME, Cavalcanti Orestes Cardoso JH, Tamashiro F, Miranda C, Fernandes L, Kreuz M, Alves Kelly F. Bright light therapy for nonseasonal depressive disorders: A systematic review and meta-analysis. JAMA Psychiatry. 2025 Jan 1;82(1):38–46. doi: 10.1001/jamapsychiatry.2024.2871. PMID: 39356500; PMCID: PMC11447633.
2. Bais B, Kamperman AM, Bijma HH, Hoogendijk WJ, Souman JL, Knijff E, Lambregtse-van den Berg MP. Effects of bright light therapy for depression during pregnancy: A randomised, double-blind controlled trial. BMJ Open. 2020 Oct 28;10(10):e038030. doi: 10.1136/bmjopen-2020-038030. PMID: 33115894; PMCID: PMC7594358.
4. Chen IP, Huang CC, Huang HC, Yang FG, Ko KT, Lee YT, Sun FJ, Liu SI. Adjunctive bright light therapy for non-seasonal major depressive disorder: A randomized controlled trial. Int J Environ Res Public Health. 2022 Sep 29;19(19):12430. doi: 10.3390/ijerph191912430. PMID: 36231728; PMCID: PMC9566126.
5. Chojnacka M, Antosik-Wójcińska AZ, Dominiak M, Bzinkowska D, Borzym A, Sokół-Szawłowska M, Bodzak-Opolska G, Antoniak D, Święcicki Ł. A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression. J Affect Disord. 2016 Oct;203:1–8. doi: 10.1016/j.jad.2016.05.062. Epub 2016 May 26. PMID: 27267951.
6. Lam RW, Levitt AJ, Levitan RD, Michalak EE, Cheung AH, Morehouse R, Ramasubbu R, Yatham LN, Tam EM. Efficacy of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder: A randomized clinical trial. JAMA Psychiatry. 2016 Jan;73(1):56–63. doi: 10.1001/jamapsychiatry.2015.2235. PMID: 26580307.
7. Legenbauer T, Kirschbaum-Lesch I, Jörke C, Kölch M, Reis O, Berger C, Dück A, Schulte-Markwort M, Becker-Hebly I, Bienioschek S, Schroth J, Ruckes C, Deuster O, Holtmann M. Bright light therapy as add-on to inpatient treatment in youth with moderate to severe depression: A randomized clinical trial. JAMA Psychiatry. 2024 Jul 1;81(7):655–662. doi: 10.1001/jamapsychiatry.2024.0103. PMID: 38477894; PMCID: PMC10938243.
8. Liu L, Wu Z, Lu Y, Lu W, Su G, Zhou Z. Effects of phototherapy on biopterin, neopterin, tryptophan, and behavioral neuroinflammatory reaction in patients with post-stroke depression. Sci Rep. 2024 Aug 7;14(1):18368. doi: 10.1038/s41598-024-68799-5. PMID: 39112627; PMCID: PMC11306333.
9. Güzel Özdemir P, Boysan M, Smolensky MH, Selvi Y, Aydin A, Yilmaz E. Comparison of venlafaxine alone versus venlafaxine plus bright light therapy combination for severe major depressive disorder. J Clin Psychiatry. 2015 May;76(5):e645–e654. doi: 10.4088/JCP.14m09376. PMID: 26035199.
10. Barbini B, Attanasio F, Manfredi E, Cavallini MC, Zanardi R, Colombo C. Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: A pilot study. Int J Psychiatry Clin Pract. 2021 Nov;25(4):375–377. doi: 10.1080/13651501.2021.1894579. Epub 2021 Mar 18. PMID: 33734000.
11. Chan JW, Lam SP, Li SX, Chau SW, Chan SY, Chan NY, Zhang JH, Wing YK. Adjunctive bright light treatment with gradual advance in unipolar major depressive disorder with evening chronotype - A randomized controlled trial. Psychol Med. 2022 Jun;52(8):1448–1457. doi: 10.1017/S0033291720003232. Epub 2020 Sep 14. PMID: 32924897.
12. Deltito JA, Moline M, Pollak C, Martin LY, Maremmani I. Effects of phototherapy on non-seasonal unipolar and bipolar depressive spectrum disorders. J Affect Disord. 1991 Dec;23(4):231–237. doi: 10.1016/0165-0327(91)90105-2. PMID: 1791269.
13. Donmez M, Yorguner N, Kora K, Topcuoglu V. Efficacy of bright light therapy in perinatal depression: A randomized, double-blind, placebo-controlled study. J Psychiatr Res. 2022 May;149:315–322. doi: 10.1016/j.jpsychires.2022.02.027. Epub 2022 Mar 10. PMID: 35339911.
14. Garbazza C, Cirignotta F, D’Agostino A, Cicolin A, Hackethal S, Wirz-Justice A, Cajochen C, Manconi M; “Life-ON” study group. Sustained remission from perinatal depression after bright light therapy: A pilot randomised, placebo-controlled trial. Acta Psychiatr Scand. 2022 Oct;146(4):350–356. doi: 10.1111/acps.13482. Epub 2022 Aug 3. PMID: 35876837; PMCID: PMC9804451.
15. Niederhofer H, von Klitzing K. Bright light treatment as mono-therapy of non-seasonal depression for 28 adolescents. Int J Psychiatry Clin Pract. 2012 Sep;16(3):233–237. doi: 10.3109/13651501.2011.625123. Epub 2012 Jul 19. PMID: 22809107.
16. Wirz-Justice A, Bader A, Frisch U, Stieglitz RD, Alder J, Bitzer J, Hösli I, Jazbec S, Benedetti F, Terman M, Wisner KL, Riecher-Rössler A. A randomized, double-blind, placebo-controlled study of light therapy for antepartum depression. J Clin Psychiatry. 2011 Jul;72(7):986–993. doi: 10.4088/JCP.10m06188blu. Epub 2011 Apr 5. PMID: 21535997.
18. Xie B, Wu Z, Zhou Z, Lu W, Liu L, Zhang L. Effect of phototherapy on event-related potentials in patients with post-stroke depression through serum tetrahydrobiopterin level intervention: A clinical study. BMC Psychiatry. 2025 Jan 2;25(1):6. doi: 10.1186/s12888-024-06407-6. PMID: 39748298; PMCID: PMC11697855.
Major depressive disorder / Sleep phase delay
3. Chan JW, Feng H, Zhang J, Chan NY, Li TMH, Chau SW, Liu Y, Li SX, Wing YK. Objective and subjective sleep in patients with non-seasonal major depressive disorder and eveningness - Results from a randomized controlled trial of bright light therapy. Sleep Med. 2023 Dec;112:132–140. doi: 10.1016/j.sleep.2023.10.013. Epub 2023 Oct 13. PMID: 37857115.
Major depressive disorder / Insomnia
17. Xiao M, Feng L, Wang Q, Luan X, Chen S, He J. The therapeutic effects and safety of bright light therapy combined with escitalopram oxalate on insomnia in patients with poststroke depression. Int J Geriatr Psychiatry. 2021 Jan;36(1):182–189. doi: 10.1002/gps.5412. Epub 2020 Sep 4. PMID: 32830332.
Depressive symptoms
19. Baxendale S, O’Sullivan J, Heaney D. Bright light therapy for symptoms of anxiety and depression in focal epilepsy: Randomised controlled trial. Br J Psychiatry. 2013 May;202(5):352–356. doi: 10.1192/bjp.bp.112.122119. Epub 2013 Mar 21. PMID: 23520221.
20. Chen F, He G, Liu Y, Zhang X, Yang Y, Yan P, Tian P, Ye J, Feng H, Li H. Effect of light therapy and continuous health education on older adults with coronary heart disease and comorbid depressive symptoms: A randomized controlled trial. Geriatr Nurs. 2025 Jul–Aug;64:103402. doi: 10.1016/j.gerinurse.2025.103402. Epub 2025 Jun 28. PMID: 40582057.
21. Chen G, Chen P, Yang Z, Ma W, Yan H, Su T, Zhang Y, Qi Z, Fang W, Jiang L, Chen Z, Tao Q, Wang Y. Increased functional connectivity between the midbrain and frontal cortex following bright light therapy in subthreshold depression: A randomized clinical trial. Am Psychol. 2024 Apr;79(3):437–450. doi: 10.1037/amp0001218. Epub 2023 Nov 16. PMID: 37971845.
22. Chen P, Chen G, Tang G, Yang Z, Ma W, Chen C, Sun S, Zhang Y, Zhang S, Qi Z, Fang W, Jiang L, Huang L, Ma J, Tao Q, Wang Y. Effects of light therapy on amygdala connectivity and serotoninergic system in young adults with subthreshold depression. Dialogues Clin Neurosci. 2025 Dec;27(1):184–200. doi: 10.1080/19585969.2025.2503367. Epub 2025 Jun 1. PMID: 40451207; PMCID: PMC12128131.
23. Chen X, Liu L, Mei H, Jiang Z, Yan W, Shi L, Liu X, Yuan K, Zhang Y, Luo X, Zhang L, Zhao Y, Wu S, Chen B, Yuan J, Liu Z, Cai H, Meng S, Shi J, Li X, Hu B, Deng J, Lu L, Bao Y. Efficacy evaluation and facial expressions biomarker of light therapy in youths with subthreshold depression: A randomized control trial study. J Affect Disord. 2025 Jul 1;380:357–365. doi: 10.1016/j.jad.2025.03.123. Epub 2025 Mar 21. PMID: 40122251.
24. Desautels C, Savard J, Ivers H, Savard MH, Caplette-Gingras A. Treatment of depressive symptoms in patients with breast cancer: A randomized controlled trial comparing cognitive therapy and bright light therapy. Health Psychol. 2018 Jan;37(1):1–13. doi: 10.1037/hea0000539. Epub 2017 Nov 27. PMID: 29172605.
25. Hamers PCM, Festen DAM, Bindels PJE, Hermans H. The effect of bright light therapy on depressive symptoms in adults with intellectual disabilities: Results of a multicentre randomized controlled trial. J Appl Res Intellect Disabil. 2020 Nov;33(6):1428–1439. doi: 10.1111/jar.12770. Epub 2020 Jun 25. PMID: 32583931; PMCID: PMC7687277.
26. Huang SY, Koo M, Hsieh TC, Lee RP, Sung HC. Effect of bright light therapy on depressive symptoms in middle-aged and older patients receiving long-term hemodialysis. Int J Environ Res Public Health. 2020 Oct 23;17(21):7763. doi: 10.3390/ijerph17217763. PMID: 33114131; PMCID: PMC7660326.
27. Janas-Kozik M, Krzystanek M, Stachowicz M, Krupka-Matuszczyk I, Janas A, Rybakowski JK. Bright light treatment of depressive symptoms in patients with restrictive type of anorexia nervosa. J Affect Disord. 2011 May;130(3):462–465. doi: 10.1016/j.jad.2010.10.014. Epub 2010 Nov 13. PMID: 21075452.
28. Jiang L, Zhang S, Wang Y, So KF, Ren C, Tao Q. Efficacy of light therapy for a college student sample with non-seasonal subthreshold depression: An RCT study. J Affect Disord. 2020 Dec 1;277:443–449. doi: 10.1016/j.jad.2020.08.055. Epub 2020 Aug 26. PMID: 32871530.
29. Kim WH, Joa KL, Kim CB, Lee HS, Kang SG, Jung HY, Bae JN. The effect of bright light therapy on sleep and quality of life in patients with poststroke insomnia. Psychosom Med. 2022 Jan 1;84(1):123–130. doi: 10.1097/PSY.0000000000001014. PMID: 34581703.
30. Raymackers JM, Andrade M, Baey E, Vanneste M, Evrard F. Bright light therapy with a head-mounted device for anxiety, depression, sleepiness and fatigue in patients with Parkinson’s disease. Acta Neurol Belg. 2019 Dec;119(4):607–613. doi: 10.1007/s13760-019-01214-3. Epub 2019 Sep 30. PMID: 31571135.
31. Rutten S, Vriend C, Smit JH, Berendse HW, van Someren EJW, Hoogendoorn AW, Twisk JWR, van der Werf YD, van den Heuvel OA. Bright light therapy for depression in Parkinson disease: A randomized controlled trial. Neurology. 2019 Mar 12;92(11):e1145–e1156. doi: 10.1212/WNL.0000000000007090. Epub 2019 Feb 15. PMID: 30770426.
32. Tang G, Chen P, Chen G, Yang Z, Ma W, Yan H, Su T, Zhang Y, Zhang S, Qi Z, Fang W, Jiang L, Tao Q, Wang Y. Effects of bright light therapy on cingulate cortex dynamic functional connectivity and neurotransmitter activity in young adults with subthreshold depression. J Affect Disord. 2025 Apr 1;374:330–341. doi: 10.1016/j.jad.2025.01.035. Epub 2025 Jan 12. PMID: 39809355.
33. Wu MC, Sung HC, Lee WL, Smith GD. The effects of light therapy on depression and sleep disruption in older adults in a long-term care facility. Int J Nurs Pract. 2015 Oct;21(5):653–659. doi: 10.1111/ijn.12307. Epub 2014 Apr 22. PMID: 24750268.
34. LaRosa KN, MacArthur E, Wang F, Zhang H, Pan H, Brigden J, Pappo A, Wilson MW, Crabtree VM. Light therapy for QoL/depression in AYA with cancer: A randomized trial. J Pediatr Psychol. 2022 Mar 5;47(3):306–317. doi: 10.1093/jpepsy/jsab098. PMID: 34625800.
Seasonal (winter) depression
35. Chen ZW, Zhang XF, Tu ZM. Treatment measures for seasonal affective disorder: A network meta-analysis. J Affect Disord. 2024 Apr 1;350:531–536. doi: 10.1016/j.jad.2024.01.028. Epub 2024 Jan 12. PMID: 38220102.
Sleep phase delay
36. Gradisar M, Dohnt H, Gardner G, Paine S, Starkey K, Menne A, Slater A, Wright H, Hudson JL, Weaver E, Trenowden S. A randomized controlled trial of cognitive-behavior therapy plus bright light therapy for adolescent delayed sleep phase disorder. Sleep. 2011 Dec 1;34(12):1671–1680. doi: 10.5665/sleep.1432. PMID: 22131604; PMCID: PMC3208844.
37. Richardson C, Cain N, Bartel K, Micic G, Maddock B, Gradisar M. A randomised controlled trial of bright light therapy and morning activity for adolescents and young adults with delayed sleep-wake phase disorder. Sleep Med. 2018 May;45:114–123. doi: 10.1016/j.sleep.2018.02.001. Epub 2018 Feb 9. PMID: 29680419.
Bipolar depression
38. Dauphinais DR, Rosenthal JZ, Terman M, DiFebo HM, Tuggle C, Rosenthal NE. Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. Psychiatry Res. 2012 Mar 30;196(1):57–61. doi: 10.1016/j.psychres.2012.01.015. Epub 2012 Mar 15. PMID: 22424890.
39. Yorguner Kupeli N, Bulut NS, Carkaxhiu Bulut G, Kurt E, Kora K. Efficacy of bright light therapy in bipolar depression. Psychiatry Res. 2018 Feb;260:432–438. doi: 10.1016/j.psychres.2017.12.020. Epub 2017 Dec 12. PMID: 29268206.
40. Zhou TH, Dang WM, Ma YT, Hu CQ, Wang N, Zhang GY, Wang G, Shi C, Zhang H, Guo B, Zhou SZ, Feng L, Geng SX, Tong YZ, Tang GW, He ZK, Zhen L, Yu X. Clinical efficacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial. J Affect Disord. 2018 Feb;227:90–96. doi: 10.1016/j.jad.2017.09.038. Epub 2017 Sep 25. PMID: 29053981.
41. Sit DK, McGowan J, Wiltrout C, Diler RS, Dills JJ, Luther J, Yang A, Ciolino JD, Seltman H, Wisniewski SR, Terman M, Wisner KL. Adjunctive bright light therapy for bipolar depression: A randomized double-blind placebo-controlled trial. Am J Psychiatry. 2018 Feb 1;175(2):131–139. doi: 10.1176/appi.ajp.2017.16101200. Epub 2017 Oct 3. PMID: 28969438.
Insomnia
42. Yoon J, Heo S, Lee H, Sul E, Han T, Kwon YJ. Feasibility and efficacy of morning light therapy for adults with insomnia: A pilot, randomized, open-label, two-arm study. Medicina (Kaunas). 2023 Jun 1;59(6):1066. doi: 10.3390/medicina59061066. PMID: 37374270; PMCID: PMC10305051.
43. Videnovic A, Klerman EB, Wang W, Marconi A, Kuhta T, Zee PC. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017 Apr 1;74(4):411–418. doi: 10.1001/jamaneurol.2016.5192. PMID: 28241159; PMCID: PMC5470356.
44. Furihata R, Shimamoto T, Ikeda Y, Makino Y, Nakagami Y, Tateyama Y, Okabayashi S, Akahoshi T, Kiyohara K, Iwami T. Efficacy of digital brief behavioural treatment for insomnia using a smartphone application in conjunction with light therapy in university students with insomnia symptoms with late chronotypes: A pilot randomized-controlled trial. J Sleep Res. 2025 Apr;34(2):e14361. doi: 10.1111/jsr.14361. Epub 2024 Sep 23. PMID: 39313332.
45. Wang Q, Wu S, Luo Z, Pu L, Wang X, Guo M, Zhang M, Tang H, Chen M, Kong L, Huang P, Chen L, Li Z, Zhao D, Xiong Z. Effects of light therapy on sleep and circadian rhythm in older type 2 diabetics living in long-term care facilities: A randomized controlled trial. Front Endocrinol (Lausanne). 2024 Feb 5;15:1307537. doi: 10.3389/fendo.2024.1307537. PMID: 38375195; PMCID: PMC10876060.
46. Fregna L, Attanasio F, Colombo C. Evaluating the impact of adjunct bright light therapy on subjective sleep quality in major depressive disorder. J Affect Disord. 2024 Mar 1;348:175–178. doi: 10.1016/j.jad.2023.12.057. Epub 2023 Dec 28. PMID: 38158049.
PTSD
47. Millot F, Endomba FT, Forestier N. Light Therapy in Post-Traumatic Stress Disorder: A Systematic Review of Interventional Studies. J Clin Med. 2024;13(13):3926.
Back to categoriesTraumatic brain injury
48. Bell KR, Fogelberg D, Barber J, Nakase-Richardson R, Zumsteg JM, Dubiel R, Dams-O’Connor K, Hoffman JM. The effect of phototherapy on sleep during acute rehabilitation after traumatic brain injury: A randomized controlled trial. Brain Inj. 2021 Jan 18;35(2):180–188. doi: 10.1080/02699052.2021.1871952. Epub 2021 Jan 17. PMID: 33459040.
49. Connolly LJ, Rajaratnam SMW, Murray JM, Spitz G, Lockley SW, Ponsford JL. Home-based light therapy for fatigue following acquired brain injury: A pilot randomized controlled trial. BMC Neurol. 2021 Jul 5;21(1):262. doi: 10.1186/s12883-021-02292-8. PMID: 34225698; PMCID: PMC8256500.
50. Raikes AC, Dailey NS, Shane BR, Forbeck B, Alkozei A, Killgore WDS. Daily morning blue light therapy improves daytime sleepiness, sleep quality, and quality of life following a mild traumatic brain injury. J Head Trauma Rehabil. 2020 Sep/Oct;35(5):E405–E421. doi: 10.1097/HTR.0000000000000579. PMID: 32472836.
Bulimia
51. Blouin AG, Blouin JH, Iversen H, Carter J, Goldstein C, Goldfield G, Perez E. Light therapy in bulimia nervosa: A double-blind, placebo-controlled study. Psychiatry Res. 1996 Feb 28;60(1):1–9. doi: 10.1016/0165-1781(95)02532-4. PMID: 8852863.
52. Braun DL, Sunday SR, Fornari VM, Halmi KA. Bright light therapy decreases winter binge frequency in women with bulimia nervosa: A double-blind, placebo-controlled study. Compr Psychiatry. 1999 Nov–Dec;40(6):442–448. doi: 10.1016/s0010-440x(99)90088-3. PMID: 10579376.
53. Kambanis PE, Bottera AR, De Young KP. Responses to bright light exposure in individuals with binge-spectrum eating disorders characterized by high dietary restraint and negative affect. Int J Eat Disord. 2023 Dec;56(12):2250–2259. doi: 10.1002/eat.24054. Epub 2023 Aug 30. PMID: 37644851.
54. Lam RW, Goldner EM, Solyom L, Remick RA. A controlled study of light therapy for bulimia nervosa. Am J Psychiatry. 1994 May;151(5):744–750. doi: 10.1176/ajp.151.5.744. PMID: 8166318.
Dementia
55. Dowling GA, Hubbard EM, Mastick J, Luxenberg JS, Burr RL, Van Someren EJ. Effect of morning bright light treatment for rest-activity disruption in institutionalized patients with severe Alzheimer’s disease. Int Psychogeriatr. 2005 Jun;17(2):221–236. doi: 10.1017/s1041610205001584. PMID: 16050432; PMCID: PMC2387132.
56. Ancoli-Israel S, Martin JL, Kripke DF, Marler M, Klauber MR. Effect of light treatment on sleep and circadian rhythms in demented nursing home patients. J Am Geriatr Soc. 2002 Feb;50(2):282–289. doi: 10.1046/j.1532-5415.2002.50060.x. PMID: 12028210; PMCID: PMC2764401.
57. Zou C, Mei X, Li X, Hu J, Xu T, Zheng C. Effect of light therapy on delirium in older patients with Alzheimer’s disease-related dementia. J Psychiatr Res. 2022 May;149:124–127. doi: 10.1016/j.jpsychires.2022.03.003. Epub 2022 Mar 6. PMID: 35272209.
58. Kolberg E, Hjetland GJ, Thun E, Pallesen S, Nordhus IH, Husebo BS, Flo-Groeneboom E. The effects of bright light treatment on affective symptoms in people with dementia: A 24-week cluster randomized controlled trial. BMC Psychiatry. 2021 Jul 28;21(1):377. doi: 10.1186/s12888-021-03376-y. PMID: 34320937; PMCID: PMC8317398.
59. Graf A, Wallner C, Schubert V, Willeit M, Wlk W, Fischer P, Kasper S, Neumeister A. The effects of light therapy on Mini-Mental State Examination scores in demented patients. Biol Psychiatry. 2001 Nov 1;50(9):725–727. doi: 10.1016/s0006-3223(01)01178-7. PMID: 11704081.
60. Cheng W, Zhang D, Lei LL, Li K. Effects of bright light therapy on agitation among older adults living with dementia in Macao: A pilot study. J Gerontol Soc Work. 2024 Oct;67(7):1050–1068. doi: 10.1080/01634372.2024.2349603. Epub 2024 May 3. PMID: 38701196.
61. Dowling GA, Burr RL, Van Someren EJ, Hubbard EM, Luxenberg JS, Mastick J, Cooper BA. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer’s disease. J Am Geriatr Soc. 2008 Feb;56(2):239–246. doi: 10.1111/j.1532-5415.2007.01543.x. Epub 2007 Dec 7. PMID: 18070004; PMCID: PMC2642966.
62. Friedman L, Spira AP, Hernandez B, Mather C, Sheikh J, Ancoli-Israel S, Yesavage JA, Zeitzer JM. Brief morning light treatment for sleep/wake disturbances in older memory-impaired individuals and their caregivers. Sleep Med. 2012 May;13(5):546–549. doi: 10.1016/j.sleep.2011.11.013. Epub 2012 Mar 10. PMID: 22406033; PMCID: PMC3337852.
Hypoactive sexual desire disorder
63. Bossini L, Caterini C, Koukouna D, Casolaro I, Roggi M, Di Volo S, Fargnoli F, Ponchietti R, Benbow J, Fagiolini A. Rola fototerapii w leczeniu osób z zaburzeniami czynności seksualnych--weryfikacja wynik6w badania pilotaiowego [Light therapy as a treatment for sexual dysfunctions—beyond a pilot study]. Psychiatr Pol. 2013 Nov–Dec;47(6):1113–1122. Polish. PMID: 25007542.
64. Koukouna D, Bossini L, Casolaro I, Caterini C, Fagiolini A. Light therapy as a treatment for sexual dysfunction; focus on testosterone levels. European Neuropsychopharmacology. 2016;26(Suppl 2):S606. doi: 10.1016/S0924-977X(16)31685-6.
Schizophrenia
65. Guo CS, Phiri D, Lee HC, Lin YK, Metrado Kwa JA, Chung MH. Effect of bright light therapy on depression in patients with schizophrenia: A pilot study. J Psychiatr Res. 2025 Apr;184:325–332. doi: 10.1016/j.jpsychires.2025.02.050. Epub 2025 Mar 9. PMID: 40086221.
66. Roopram SM, Burger AM, van Dijk DA, Enterman J, Haffmans J. A pilot study of bright light therapy in schizophrenia. Psychiatry Res. 2016 Nov 30;245:317–320. doi: 10.1016/j.psychres.2016.07.034. Epub 2016 Jul 19. PMID: 27568303.
Shift work disorder
67. Huang LB, Tsai MC, Chen CY, Hsu SC. The effectiveness of light/dark exposure to treat insomnia in female nurses undertaking shift work during the evening/night shift. J Clin Sleep Med. 2013 Jul 15;9(7):641–646. doi: 10.5664/jcsm.2824. PMID: 23853555; PMCID: PMC3671326.
ADHD
68. Rybak YE, McNeely HE, Mackenzie BE, Jain UR, Levitan RD. An open trial of light therapy in adult attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006 Oct;67(10):1527–1535. doi: 10.4088/jcp.v67n1006. PMID: 17107243.
Panic disorder
69. Kanofsky JD, Sandyk R, Kaplan S, Yaryura-Tobias JA. Seasonal panic disorder responsive to light therapy. Lancet. 1991 May 4;337(8749):1103–1104. doi: 10.1016/0140-6736(91)91758-m. PMID: 1673531.
OCD
70. Brinkhuijsen M, Koenegracht F, Meesters Y. Symptoms of seasonal affective disorder and of obsessive-compulsive disorder reduced by light therapy. J Affect Disord. 2003 May;74(3):307–308. doi: 10.1016/s0165-0327(03)00003-x. PMID: 12738052.
71. Yoney TH, Pigott TA, L’Heureux F, Rosenthal NE. Seasonal variation in obsessive-compulsive disorder: Preliminary experience with light treatment. Am J Psychiatry. 1991 Dec;148(12):1727–1729. doi: 10.1176/ajp.148.12.1727. PMID: 1957938.
Relevant meta-analyses
72. Faulkner SM, Bee PE, Meyer N, Dijk DJ, Drake RJ. Light therapies to improve sleep in intrinsic circadian rhythm sleep disorders and neuro-psychiatric illness: A systematic review and meta-analysis. Sleep Med Rev. 2019 Aug;46:108–123. doi: 10.1016/j.smrv.2019.04.012. Epub 2019 Apr 30. PMID: 31108433.
73. Aini N, Chen R, Chu H, Chang CY, Lin HC, Jen HJ, Liu D, Lee TY, Chou KR. The effects of light therapy on sleep, depression, neuropsychiatric behaviors, and cognition among people living with dementia: A meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry. 2024 Jun;32(6):681–706. doi: 10.1016/j.jagp.2023.12.010. Epub 2023 Dec 23. PMID: 38216355.
74. Srisurapanont K, Samakarn Y, Kamklong B, Siratrairat P, Bumiputra A, Jaikwang M, Srisurapanont M. Blue-wavelength light therapy for post-traumatic brain injury sleepiness, sleep disturbance, depression, and fatigue: A systematic review and network meta-analysis. PLoS One. 2021 Feb 4;16(2):e0246172. doi: 10.1371/journal.pone.0246172. PMID: 33539446; PMCID: PMC7861530.
Dark Therapy and Blue Light Blockers References
20 references
Aggression
1. Kallestad H, Langsrud K, Simpson MR, Vestergaard CL, Vethe D, Kjørstad K, Faaland P, Lydersen S, Morken G, Ulsaker-Janke I, Saksvik SB, Scott J. Clinical benefits of modifying the evening light environment in an acute psychiatric unit: A single-centre, two-arm, parallel-group, pragmatic effectiveness randomised controlled trial. PLoS Med. 2024 Dec 6;21(12):e1004380. doi: 10.1371/journal.pmed.1004380. PMID: 39642162; PMCID: PMC11661622.
Insomnia
2. Zimmerman ME, Kim MB, Hale C, Westwood AJ, Brickman AM, Shechter A. Neuropsychological function response to nocturnal blue light blockage in individuals with symptoms of insomnia: A pilot randomized controlled study. J Int Neuropsychol Soc. 2019 Aug;25(7):668–677. doi: 10.1017/S1355617719000055. PMID: 30890197; PMCID: PMC7045510.
3. Makateb A, Rashidinia A, Khosravifard K, Dabaghi P. Investigating the effects of a blue-blocking software on the daily rhythm of sleep, melatonin, cortisol, positive and negative emotions. Chronobiol Int. 2023 Jul 3;40(7):896–902. doi: 10.1080/07420528.2023.2222816. Epub 2023 Jun 11. PMID: 37302816.
4. Burkhart K, Phelps JR. Amber lenses to block blue light and improve sleep: a randomized trial. Chronobiol Int. 2009 Dec;26(8):1602–1612. doi: 10.3109/07420520903523719. PMID: 20030543.
5. Bigalke JA, Greenlund IM, Nicevski JR, Carter JR. Effect of evening blue light blocking glasses on subjective and objective sleep in healthy adults: A randomized control trial. Sleep Health. 2021 Aug;7(4):485–490. doi: 10.1016/j.sleh.2021.02.004. Epub 2021 Mar 8. PMID: 33707105.
6. Shechter A, Kim EW, St-Onge MP, Westwood AJ. Blocking nocturnal blue light for insomnia: A randomized controlled trial. J Psychiatr Res. 2018 Jan;96:196–202. doi: 10.1016/j.jpsychires.2017.10.015. Epub 2017 Oct 21. PMID: 29101797; PMCID: PMC5703049.
7. Esaki Y, Kitajima T, Takeuchi I, Tsuboi S, Furukawa O, Moriwaki M, Fujita K, Iwata N. Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized, double-blind, placebo-controlled study. Chronobiol Int. 2017;34(6):753–761. doi: 10.1080/07420528.2017.1318893. Epub 2017 May 10. PMID: 28488943.
8. Verma S, Quin N, Astbury L, Wellecke C, Wiley JF, Davey M, Rajaratnam SMW, Bei B. Treating postpartum insomnia: A three arm randomised controlled trial of cognitive behavioural therapy and light dark therapy. Psychol Med. 2023 Sep;53(12):5459–5469. doi: 10.1017/S0033291722002616. Epub 2022 Sep 9. PMID: 36082412; PMCID: PMC10482724.
9. Janků K, Šmotek M, Fárková E, Kopřivová J. Block the light and sleep well: Evening blue light filtration as a part of cognitive behavioral therapy for insomnia. Chronobiol Int. 2020 Feb;37(2):248–259. doi: 10.1080/07420528.2019.1692859. Epub 2019 Nov 22. PMID: 31752544.
10. Liset R, Grønli J, Henriksen RE, Henriksen TEG, Nilsen RM, Pallesen S. A randomized controlled trial on the effects of blue-blocking glasses compared to partial blue-blockers on sleep outcomes in the third trimester of pregnancy. PLoS One. 2022 Jan 28;17(1):e0262799. doi: 10.1371/journal.pone.0262799. PMID: 35089982; PMCID: PMC8797219.
Sleep phase delay
11. Esaki Y, Takeuchi I, Tsuboi S, Fujita K, Iwata N, Kitajima T. A double-blind, randomized, placebo-controlled trial of adjunctive blue-blocking glasses for the treatment of sleep and circadian rhythm in patients with bipolar disorder. Bipolar Disord. 2020 Nov;22(7):739–748. doi: 10.1111/bdi.12912. Epub 2020 Apr 20. PMID: 32276301.
12. Perez Algorta G, Van Meter A, Dubicka B, Jones S, Youngstrom E, Lobban F. Blue blocking glasses worn at night in first year higher education students with sleep complaints: A feasibility study. Pilot Feasibility Stud. 2018 Nov 1;4:166. doi: 10.1186/s40814-018-0360-y. PMID: 30410784; PMCID: PMC6211454.
Sleep phase delay / Aggression
13. Maeda-Nishino NJ, Yoshimoto R, Ono T, Chiba S, Nishino S. Partial blue light blocking glasses at night advanced sleep phase and reduced daytime irritability, disruptive behavior and improved morning mood, but did not alter salivary melatonin secretion in Japanese male schoolchildren. PLoS One. 2025 Oct 30;20(10):e0332877. doi: 10.1371/journal.pone.0332877. PMID: 41166315; PMCID: PMC12574898.
Bipolar disorder
14. Henriksen TE, Skrede S, Fasmer OB, Schoeyen H, Leskauskaite I, Bjørke-Bertheussen J, Assmus J, Hamre B, Grønli J, Lund A. Blue-blocking glasses as additive treatment for mania: A randomized placebo-controlled trial. Bipolar Disord. 2016 May;18(3):221–232. doi: 10.1111/bdi.12390. PMID: 27226262; PMCID: PMC5089565.
15. Fiedorowicz JG, Mikhail E, Solmi M, Burns JK, Yu J, Siddiqi S, Nguyen T, Smith AL, Robillard R; Ottawa Sunglasses at Night Investigators and Coordinators. The Ottawa Sunglasses at Night study: A randomized controlled trial of blue-blocking glasses for mania. J Affect Disord. 2026 Apr 1;398:120910. doi: 10.1016/j.jad.2025.120910. Epub 2025 Dec 18. PMID: 41421618; PMCID: PMC12912815.
Cognition
16. Guarana CL, Barnes CM, Ong WJ. The effects of blue-light filtration on sleep and work outcomes [2 trials]. J Appl Psychol. 2021 May;106(5):784–796. doi: 10.1037/apl0000806. Epub 2020 Jul 13. PMID: 32658494.
Jet lag
17. Youngstrom E, Presentation, International Society of Bipolar Disorders, 2014; cited in Hester L, Dang D, Barker CJ, Heath M, Mesiya S, Tienabeso T, Watson K. Evening wear of blue-blocking glasses for sleep and mood disorders: A systematic review. Chronobiol Int. 2021 Oct;38(10):1375–1383. doi: 10.1080/07420528.2021.1930029. Epub 2021 May 24. PMID: 34030534.
Shift work sleep disorder
18. Martin JS, Laberge L, Sasseville A, Bérubé M, Alain S, Lavoie J, Houle J, Hébert M. Timely use of in-car dim blue light and blue blockers in the morning does not improve circadian adaptation of fast rotating shift workers. Chronobiol Int. 2021 May;38(5):705–719. doi: 10.1080/07420528.2021.1872592. Epub 2021 Feb 15. PMID: 33588653.
19. Sasseville A, Benhaberou-Brun D, Fontaine C, Charon MC, Hebert M. Wearing blue-blockers in the morning could improve sleep of workers on a permanent night schedule: A pilot study. Chronobiol Int. 2009 Jul;26(5):913–925. doi: 10.1080/07420520903044398. PMID: 19637050.
20. Huang LB, Tsai MC, Chen CY, Hsu SC. The effectiveness of light/dark exposure to treat insomnia in female nurses undertaking shift work during the evening/night shift. J Clin Sleep Med. 2013 Jul 15;9(7):641–646. doi: 10.5664/jcsm.2824. PMID: 23853555; PMCID: PMC3671326.
Acupuncture References
25 references
Depression
1. Smith CA, Armour M, Lee MS, Wang LQ, Hay PJ. Acupuncture for depression. Cochrane Database Syst Rev. 2018;3:CD004046. PMID: 29502347.
Insomnia
2. Cao HJ, Yu ML, Wang LQ, Fei YT, Xu H, Liu JP. Acupuncture for primary insomnia: An updated systematic review of randomized controlled trials. J Altern Complement Med. 2019 May;25(5):451–474. doi: 10.1089/acm.2018.0046. Epub 2019 Apr 23. PMID: 31013432.
Generalized anxiety disorder
3. Li M, Liu X, Ye X, Zhuang L. Efficacy of acupuncture for generalized anxiety disorder: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2022 Dec 9;101(49):e30076. doi: 10.1097/MD.0000000000030076. PMID: 36626458; PMCID: PMC9750622.
Schizophrenia
4. Huang C, Zhang P, Dong Y, Chang R, Lao J, Li Z, Lan D. A meta-analysis on the efficacy of acupuncture as an adjuvant therapy for schizophrenia. Neuropsychiatr Dis Treat. 2023 Nov 7;19:2381–2400. doi: 10.2147/NDT.S428518. PMID: 37954034; PMCID: PMC10638899.
Sexual function
5. Aydin S, Ercan M, Caşkurlu T, et al. Acupuncture and hypnotic suggestions in the treatment of non-organic male sexual dysfunction. Scand J Urol Nephrol. 1997;31(3):271-274. doi:10.3109/00365599709070347
6. Engelhardt PF, Daha LK, Zils T, Simak R, König K, Pflüger H. Acupuncture in the treatment of psychogenic erectile dysfunction: first results of a prospective randomized placebo-controlled study. Int J Impot Res. 2003;15(5):343-346. doi:10.1038/sj.ijir.3901021
7. Hullender Rubin LE, Mist SD, Schnyer RN, Chao MT, Leclair CM. Acupuncture Augmentation of Lidocaine for Provoked, Localized Vulvodynia: A Feasibility and Acceptability Study. J Low Genit Tract Dis. 2019;23(4):279-286. doi:10.1097/LGT.0000000000000489
8. Khamba B, Aucoin M, Lytle M, et al. Efficacy of acupuncture treatment of sexual dysfunction secondary to antidepressants. J Altern Complement Med. 2013;19(11):862-869. doi:10.1089/acm.2012.0751
9. Lee SW, Liong ML, Yuen KH, et al. Acupuncture versus sham acupuncture for chronic prostatitis/chronic pelvic pain. Am J Med. 2008;121(1):79.e1-79.e797. doi:10.1016/j.amjmed.2007.07.033
10. Ning S, Liu S, Chen X, Wang J. Acupuncture modification treatment for female sexual dysfunction: A meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2023;291:29-33. doi:10.1016/j.ejogrb.2023.09.026
11. Schlaeger JM, Steffen AD, Takakura N, et al. Long-lasting effect of penetrating acupuncture among responders: Double-blind RCT of acupuncture for vulvodynia. J Pain. 2026;38:105584. doi:10.1016/j.jpain.2025.105584
12. Schlaeger JM, Xu N, Mejta CL, Park CG, Wilkie DJ. Acupuncture for the treatment of vulvodynia: a randomized wait-list controlled pilot study. J Sex Med. 2015;12(4):1019-1027. doi:10.1111/jsm.12830
13. Sunay D, Sunay M, Aydoğmuş Y, et al. Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo-controlled clinical trial. Eur Urol. 2011;59(5):765-771. doi:10.1016/j.eururo.2011.01.019
14. Yan M, Zhu T, Xue K, et al. Efficacy and safety of acupuncture for erectile dysfunction: a systematic review and meta-analysis of randomized controlled trials. Sex Med Rev. 2026;14(2):qeag042. doi:10.1093/sxmrev/qeag042
15. Zhu M, Quan F, Xue K, Xiao C, Cui J. Acupuncture for erectile dysfunction: a randomized controlled trial. 针刺治疗勃起功能障碍：随机对照试验. Zhongguo Zhen Jiu. 2024;44(4):418-422. doi:10.13703/j.0255-2930.20231005-0001
Nicotine cessation
16. Fan S, Wang J, Wang X, Zhang H, Li H, Wang J, Zhang W, Wang J. Acupuncture for smoking cessation: An overview of systematic reviews. Front Public Health. 2026 Jan 15;13:1677231. doi: 10.3389/fpubh.2025.1677231. PMID: 41626375; PMCID: PMC12852475.
PTSD
17. Tang X, Lin S, Fang D, Lin B, Yao L, Wang L, Xu Q, Lu L, Xu N. Efficacy and underlying mechanisms of acupuncture therapy for PTSD: Evidence from animal and clinical studies. Front Behav Neurosci. 2023 May 2;17:1163718. doi: 10.3389/fnbeh.2023.1163718. PMID: 37200784; PMCID: PMC10187757.
Autism
18. Lun T, Lin S, Chen Y, Zhao Y, Wang D, Li L, Yu J. Acupuncture for children with autism spectrum disorder: A systematic review and meta-analysis. Medicine (Baltimore). 2023 Feb 22;102(8):e33079. doi: 10.1097/MD.0000000000033079. PMID: 36827010; PMCID: PMC11309618.
Alzheimer's dementia
19. Lin CJ, Yeh ML, Wu SF, Chung YC, Lee JC. Acupuncture-related treatments improve cognitive and physical functions in Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2022 May;36(5):609–635. doi: 10.1177/02692155221079117. Epub 2022 Mar 1. PMID: 35229686.
Vascular dementia
20. Wen J, Cao Y, Chang S, Huang Q, Zhang Z, Wei W, Yao J, Pei H, Li H. A network meta-analysis on the improvement of cognition in patients with vascular dementia by different acupuncture therapies. Front Neurosci. 2022 Dec 14;16:1053283. doi: 10.3389/fnins.2022.1053283. PMID: 36590305; PMCID: PMC9797048.
Traumatic brain injury
21. Wong V, Cheuk DK, Lee S, Chu V. Acupuncture for acute management and rehabilitation of traumatic brain injury. Cochrane Database Syst Rev. 2013 Mar 28;2013(3):CD007700. doi: 10.1002/14651858.CD007700.pub3. PMID: 23543554; PMCID: PMC11270637.
Delirium
22. Wu C, Wei X, Luo F, Li J, Kwan YYJ, Wang K, Zhou J. Electroacupuncture for the prevention of perioperative neurocognitive disorder in elderly patients undergoing general anesthesia: A systematic review and meta-analysis. Front Med (Lausanne). 2026 Jan 23;13:1729153. doi: 10.3389/fmed.2026.1729153. PMID: 41658594; PMCID: PMC12876244.
Substance use disorders
23. Grant S, Kandrack R, Motala A, Shanman R, Booth M, Miles J, Sorbero M, Hempel S. Acupuncture for substance use disorders: A systematic review and meta-analysis. Drug Alcohol Depend. 2016 Jun 1;163:1–15. doi: 10.1016/j.drugalcdep.2016.02.034. Epub 2016 Mar 3. PMID: 26968093.
Benzodiazepine withdrawal
24. Fan ZQ, Gao YS, Chen YH, Zhang J, Lu W, Yang D, Xiang XH, Liu J, Yu K, Chen Y. Acupuncture combined with gradual benzodiazepine reduction for benzodiazepine-dependent insomnia: A multicenter randomized controlled trial. Explore (NY). 2026 Apr 15;22(4):103421. doi: 10.1016/j.explore.2026.103421. Epub ahead of print. PMID: 42066590.
25. Yeung WF, Chung KF, Zhang ZJ, Zhang SP, Chan WC, Ng RM, Chan CL, Ho LM, Yu BY, Chau JC, Lau NC, Lao LX. Electroacupuncture for tapering off long-term benzodiazepine use: A randomized controlled trial. J Psychiatr Res. 2019 Feb;109:59–67. doi: 10.1016/j.jpsychires.2018.11.015. Epub 2018 Nov 22. PMID: 30504097.
Air Ionization References
8 references
Seasonal affective disorder
1. Flory R, Ametepe J, Bowers B. A randomized, placebo-controlled trial of bright light and high-density negative air ions for treatment of seasonal affective disorder. Psychiatry Res. 2010;177:101–108. doi: 10.1016/j.psychres.2008.08.011. Epub 2010 Apr 9. PMID: 20381162.
2. Terman M, Terman JS, Ross DC. A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Arch Gen Psychiatry. 1998;55:875–882. doi: 10.1001/archpsyc.55.10.875. PMID: 9783557.
3. Terman M, Terman JS. Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder. Am J Psychiatry. 2006;163:2126–2133. doi: 10.1176/ajp.2006.163.12.2126. Erratum in: Am J Psychiatry. 2007 Mar;164(3):529. PMID: 17151164.
4. Terman M, Terman JS. Treatment of seasonal affective disorder with a high-output negative ionizer. J Altern Complement Med. 1995;1:87–92. doi: 10.1089/acm.1995.1.87. PMID: 9395604.
Chronic major depressive disorder
5. Goel N, Terman M, Terman JS, Macchi MM, Stewart JW. Controlled trial of bright light and negative air ions for chronic depression. Psychol Med. 2005;35:945–955. doi: 10.1017/s0033291705005027. PMID: 16045061.
Bipolar depression
6. Dauphinais DR, Rosenthal JZ, Terman M, DiFebo HM, Tuggle C, Rosenthal NE. Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. Psychiatry Res. 2012 Mar 30;196(1):57–61. doi: 10.1016/j.psychres.2012.01.015. Epub 2012 Mar 15. PMID: 22424890.
Autism
7. Yates A, Gray F, Beutler LE, Sherman DE, Segerstrom EM. Effect of negative air ionization on hyperactive and autistic children. Am J Phys Med. 1987 Oct;66(5):264–268. PMID: 3434628.
Relevant meta-analysis
8. Perez V, Alexander DD, Bailey WH. Air ions and mood outcomes: A review and meta-analysis. BMC Psychiatry. 2013;13:29. doi: 10.1186/1471-244X-13-29. PMID: 23320516; PMCID: PMC3598548.
Aromatherapy References
75 references
Depressive / anxious symptoms
1. Abdelhakim AM, Hussein AS, Doheim MF, Sayed AK. The effect of inhalation aromatherapy in patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2020 Jan;48:102256. doi: 10.1016/j.ctim.2019.102256. Epub 2019 Nov 23. PMID: 31987220.
2. Babatabar Darzi H, Vahedian-Azimi A, Ghasemi S, Ebadi A, Sathyapalan T, Sahebkar A. The effect of aromatherapy with rose and lavender on anxiety, surgical site pain, and extubation time after open-heart surgery: A double-center randomized controlled trial. Phytother Res. 2020 Oct;34(10):2675–2684. doi: 10.1002/ptr.6698. Epub 2020 Apr 8. PMID: 32267031.
3. Carlson LE, Ismaila N, Addington EL, Asher GN, Atreya C, Balneaves LG, Bradt J, Fuller-Shavel N, Goodman J, Hoffman CJ, Huston A, Mehta A, Paller CJ, Richardson K, Seely D, Siwik CJ, Temel JS, Rowland JH. Integrative oncology care of symptoms of anxiety and depression in adults with cancer: Society for Integrative Oncology-ASCO guideline. J Clin Oncol. 2023 Oct 1;41(28):4562–4591. doi: 10.1200/JCO.23.00857. Epub 2023 Aug 15. PMID: 37582238.
4. Cho K, Kim M. Effects of aromatherapy on depression: A meta-analysis of randomized controlled trials. Gen Hosp Psychiatry. 2023 Sep–Oct;84:215–225. doi: 10.1016/j.genhosppsych.2023.08.003. Epub 2023 Aug 15. PMID: 37619300.
5. Firoozeei TS, Feizi A, Rezaeizadeh H, Zargaran A, Roohafza HR, Karimi M. The antidepressant effects of lavender (Lavandula angustifolia Mill.): A systematic review and meta-analysis of randomized controlled clinical trials. Complement Ther Med. 2021 Jun;59:102679. doi: 10.1016/j.ctim.2021.102679. Epub 2021 Feb 4. PMID: 33549687.
6. Guo P, Li P, Zhang X, Liu N, Wang J, Yang S, Yu L, Zhang W. The effectiveness of aromatherapy on preoperative anxiety in adults: A systematic review and meta-analysis of randomized controlled trials. Int J Nurs Stud. 2020 Nov;111:103747. doi: 10.1016/j.ijnurstu.2020.103747. Epub 2020 Aug 12. PMID: 32861206.
7. Han X, Gibson J, Eggett DL, Parker TL. Bergamot (Citrus bergamia) essential oil inhalation improves positive feelings in the waiting room of a mental health treatment center: A pilot study. Phytother Res. 2017 May;31(5):812–816. doi: 10.1002/ptr.5806. Epub 2017 Mar 24. PMID: 28337799; PMCID: PMC5434918.
8. Itai T, Amayasu H, Kuribayashi M, Kawamura N, Okada M, Momose A, Tateyama T, Narumi K, Uematsu W, Kaneko S. Psychological effects of aromatherapy on chronic hemodialysis patients. Psychiatry Clin Neurosci. 2000 Aug;54(4):393–397. doi: 10.1046/j.1440-1819.2000.00727.x. PMID: 10997854.
9. Kim RW, Kim M. Effects of aromatherapy on anxiety and blood pressure in patients with acute coronary syndrome: A meta-analysis of randomized controlled trials. J Integr Complement Med. 2024 Oct;30(10):940–952. doi: 10.1089/jicm.2023.0577. Epub 2024 May 17. PMID: 38757732.
11. Ozen N, Sayilan AA, Ok E, Sayilan S, Ozen V, Sousa CN, Ovayolu O, Eyileten T. Effects of long-term administration of inhaled lavender during hemodialysis on patients' invasive pain, anxiety, and comfort during cannulation: A single-blind randomized controlled trial. Altern Ther Health Med. 2023 Mar;29(2):6–12. PMID: 35212648.
13. Rambod M, Pasyar N, Karimian Z, Farbood A. The effect of lemon inhalation aromatherapy on pain, nausea, as well as vomiting and neurovascular assessment in patients for lower extremity fracture surgery: A randomized trial. BMC Complement Med Ther. 2023 Jun 24;23(1):208. doi: 10.1186/s12906-023-04047-z. PMID: 37355604; PMCID: PMC10290404.
14. Sánchez-Vidaña DI, Ngai SP, He W, Chow JK, Lau BW, Tsang HW. The effectiveness of aromatherapy for depressive symptoms: A systematic review. Evid Based Complement Alternat Med. 2017;2017:5869315. doi: 10.1155/2017/5869315. Epub 2017 Jan 4. PMID: 28133489; PMCID: PMC5241490.
15. Son HK, So WY, Kim M. Effects of aromatherapy combined with music therapy on anxiety, stress, and fundamental nursing skills in nursing students: A randomized controlled trial. Int J Environ Res Public Health. 2019 Oct 29;16(21):4185. doi: 10.3390/ijerph16214185. PMID: 31671873; PMCID: PMC6861884.
17. Wakui N, Ichikawa K, Okami A, Kagi H, Kawakubo S, Togawa C, Matsuoka R, Watanabe M, Yamamura M, Shirozu S, Tsubota Y, Yoshizawa Y, Machida Y. Evaluating the effectiveness of applying aroma seals to masks in reducing stress caused by wearing masks: A randomized controlled trial. PLoS One. 2023 Nov 16;18(11):e0294357. doi: 10.1371/journal.pone.0294357. PMID: 37971989; PMCID: PMC7653515.
19. Wang YR, Ho YC, Yeh YC. Short- and long-term effects of inhaled lavender essential oil on anxiety, fatigue, blood pressure, and sleep quality in middle-aged adults with hypertension: A randomized placebo-controlled pilot study. Complement Ther Med. 2025 Dec;95:103296. doi: 10.1016/j.ctim.2025.103296. Epub 2025 Oct 31. PMID: 41177368.
21. Xiong M, Li Y, Tang P, Zhang Y, Cao M, Ni J, Xing M. Effectiveness of aromatherapy massage and inhalation on symptoms of depression in chinese community-dwelling older adults. J Altern Complement Med. 2018 Jul;24(7):717–724. doi: 10.1089/acm.2017.0320. Epub 2018 Mar 22. PMID: 29565630.
22. Zhang F, Cheng L, Qin S, Wang L, Liu Y, Liu Y, Yang J, Fang S, An N, Zhang Y, Liu J. Effect of aromatherapy massage with lavender essential oil on sleep quality, pain, and mental and psychiatric disorders among breast cancer patients undergoing chemotherapy: A randomized controlled trial. Support Care Cancer. 2025 Jul 14;33(8):689. doi: 10.1007/s00520-025-09741-x. PMID: 40653563.
Depressive / anxious symptoms / Insomnia
10. Mascarenhas VHA, Caroci-Becker A, Nick JM, Sahin S, Drigo RTDC, Riesco ML, Lima MOP. Effectiveness of aromatherapy on physiological and psychological symptoms during pregnancy: A systematic review and meta-analysis. Complement Ther Med. 2025 Dec;95:103279. doi: 10.1016/j.ctim.2025.103279. Epub 2025 Nov 3. PMID: 41192533.
12. Pasyar N, Aghababaei M, Rambod M, Zarshenas MM. The effectiveness of Melissa officinalis L. essential oil inhalation on anxiety and symptom burden of hemodialysis patients: A randomized trial study. BMC Complement Med Ther. 2025 Mar 13;25(1):103. doi: 10.1186/s12906-025-04840-y. PMID: 40082838; PMCID: PMC11907815.
16. Takeda A, Watanuki E, Koyama S. Effects of inhalation aromatherapy on symptoms of sleep disturbance in the elderly with dementia. Evid Based Complement Alternat Med. 2017;2017:1902807. doi: 10.1155/2017/1902807. Epub 2017 Mar 19. PMID: 28400839; PMCID: PMC5376423.
18. Wakui N, Togawa C, Ichikawa K, Matsuoka R, Watanabe M, Okami A, Shirozu S, Yamamura M, Machida Y. Relieving psychological stress and improving sleep quality by bergamot essential oil use before bedtime and upon awakening: A randomized crossover trial. Complement Ther Med. 2023 Oct;77:102976. doi: 10.1016/j.ctim.2023.102976. Epub 2023 Aug 23. PMID: 37625623.
20. Wang Z, Mao C, Zeng S, Chen L, Feng Z, Liu W. The effects of aromatherapy on anxiety and sleep quality in maternal women: A systematic review and meta-analysis. Front Public Health. 2025 Nov 28;13:1701126. doi: 10.3389/fpubh.2025.1701126. PMID: 41393037; PMCID: PMC12698402.
Insomnia
23. Ahn JH, Kim M. Effects of aromatherapy on cancer patients' sleep and fatigue: A systematic review and meta-analysis. J Integr Complement Med. 2023 Apr;29(4):212–223. doi: 10.1089/jicm.2022.0601. Epub 2022 Nov 7. PMID: 36342966.
24. Cheng H, Lin L, Wang S, Zhang Y, Liu T, Yuan Y, Chen Q, Tian L. Aromatherapy with single essential oils can significantly improve the sleep quality of cancer patients: A meta-analysis. BMC Complement Med Ther. 2022 Jul 14;22(1):187. doi: 10.1186/s12906-022-03668-0. PMID: 35836211; PMCID: PMC9284915.
25. Cheong MJ, Kim S, Kim JS, Lee H, Lyu YS, Lee YR, Jeon B, Kang HW. A systematic literature review and meta-analysis of the clinical effects of aroma inhalation therapy on sleep problems. Medicine (Baltimore). 2021 Mar 5;100(9):e24652. doi: 10.1097/MD.0000000000024652. PMID: 33655928; PMCID: PMC7939222.
26. Cho MY, Min ES, Hur MH, Lee MS. Effects of aromatherapy on the anxiety, vital signs, and sleep quality of percutaneous coronary intervention patients in intensive care units. Evid Based Complement Alternat Med. 2013;2013:381381. doi: 10.1155/2013/381381. Epub 2013 Feb 17. PMID: 23476690; PMCID: PMC3588400.
27. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825–e873. doi: 10.1097/CCM.0000000000003299. PMID: 30113379.
28. Fang CS, Tu YK, Chou FH, Fang CJ, Chang SL. Effect of inhaled aromatherapy on sleep quality in critically ill patients: A systematic review and network meta-analysis. J Clin Nurs. 2025 Mar;34(3):1000–1012. doi: 10.1111/jocn.17368. Epub 2024 Jul 23. PMID: 39041491.
29. Hamzeh S, Safari-Faramani R, Khatony A. Effects of aromatherapy with lavender and peppermint essential oils on the sleep quality of cancer patients: A randomized controlled trial. Evid Based Complement Alternat Med. 2020 Mar 25;2020:7480204. doi: 10.1155/2020/7480204. PMID: 32308715; PMCID: PMC7132346.
30. Her J, Cho MK. Effect of aromatherapy on sleep quality of adults and elderly people: A systematic literature review and meta-analysis. Complement Ther Med. 2021 Aug;60:102739. doi: 10.1016/j.ctim.2021.102739. Epub 2021 Jun 21. PMID: 34166869.
31. Ko LW, Su CH, Yang MH, Liu SY, Su TP. A pilot study on essential oil aroma stimulation for enhancing slow-wave EEG in sleeping brain. Sci Rep. 2021 Jan 13;11(1):1078. doi: 10.1038/s41598-020-80171-x. PMID: 33441798; PMCID: PMC7806966.
32. McDonnell B, Newcomb P. Trial of essential oils to improve sleep for patients in cardiac rehabilitation. J Altern Complement Med. 2019 Dec;25(12):1193–1199. doi: 10.1089/acm.2019.0222. Epub 2019 Sep 26. PMID: 31556690.
33. Motlagh MA, Tirgari B, Rashtabadi OR, Ahmadinejad M, Jahani Y. The effects of aromatherapy massage with mint and sweet almond oils on the sleep quality of patients with traumatic brain injury admitted to intensive care unit: A randomized clinical trial. Sleep Breath. 2025 Mar 8;29(1):126. doi: 10.1007/s11325-025-03295-2. PMID: 40056322.
34. Nasiri Lari Z, Hajimonfarednejad M, Riasatian M, Abolhassanzadeh Z, Iraji A, Vojoud M, Heydari M, Shams M. Efficacy of inhaled Lavandula angustifolia Mill. Essential oil on sleep quality, quality of life and metabolic control in patients with diabetes mellitus type II and insomnia. J Ethnopharmacol. 2020 Apr 6;251:112560. doi: 10.1016/j.jep.2020.112560. Epub 2020 Jan 10. PMID: 31931160.
35. Ostovar M, Khademizadeh MH, Namjoyan F, Kazemi A, Vakili S, Mosavat SH, Mohit M, Hashempur MH. A systematic review and meta-analysis of clinical trials on lavender for sleep disorders in older adults. Exp Gerontol. 2025 Nov;211:112919. doi: 10.1016/j.exger.2025.112919. Epub 2025 Oct 5. PMID: 41057090.
36. Salehi-Pourmehr H, Mojtahedi M, Asnaashari S, Farshbaf-Khalili A, Ostadrahimi A. The impact of aromatherapy with Citrus bergamia- Lavandula angustifolia essential oil and/or mindfulness-based therapy on postmenopausal health: A factorial randomized controlled trial. Complement Ther Med. 2025 Aug;91:103190. doi: 10.1016/j.ctim.2025.103190. Epub 2025 May 14. PMID: 40378898.
37. Tang Y, Gong M, Qin X, Su H, Wang Z, Dong H. The therapeutic effect of aromatherapy on insomnia: A meta-analysis. J Affect Disord. 2021 Jun 1;288:1–9. doi: 10.1016/j.jad.2021.03.066. Epub 2021 Mar 26. PMID: 33839552.
38. Xu S, Shen X, Xu L, Xue L, Wu P, Wang S, Hu X. The effects of Rosa damascene aromatherapy on mood and sleep: A systematic review and meta-analysis. Front Public Health. 2025 Nov 4;13:1646592. doi: 10.3389/fpubh.2025.1646592. PMID: 41262694; PMCID: PMC12623198.
39. Ye C, Huang X, Wang Z, Zuo S, Lin L. Effects of aromatherapy on sleep quality in hospitalized cardiac patients: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2025 Nov;94:103247. doi: 10.1016/j.ctim.2025.103247. Epub 2025 Sep 21. PMID: 40987424.
40. Yildirim D, Harman Ozdogan M, Erdal S, Selcuk S, Guneri A, Simsek EB, Can TB, Gunduz H, Kuni A. The efficacy of lavender oil on fatigue and sleep quality in patients with hematological malignancy receiving chemotherapy: A single-blind randomized controlled trial. Support Care Cancer. 2025 Jan 8;33(2):79. doi: 10.1007/s00520-024-09143-5. PMID: 39775962; PMCID: PMC11711766.
41. Zhen H, Wang Y, Zheng F, Yang B, Sun X, Yang X. The effectiveness of aromatic extract on insomnia: A meta-analysis. Sleep Breath. 2024 Nov 30;29(1):33. doi: 10.1007/s11325-024-03215-w. PMID: 39615005.
Agitation in dementia
42. Ball EL, Owen-Booth B, Gray A, Shenkin SD, Hewitt J, McCleery J. Aromatherapy for dementia. Cochrane Database Syst Rev. 2020 Aug 19;8(8):CD003150. doi: 10.1002/14651858.CD003150.pub3. PMID: 32813272; PMCID: PMC7437395.
43. Ballard CG, O'Brien JT, Reichelt K, Perry EK. Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: The results of a double-blind, placebo-controlled trial with Melissa. J Clin Psychiatry. 2002 Jul;63(7):553–558. doi: 10.4088/jcp.v63n0703. PMID: 12143909.
44. Mascherona I, Ferretti M, Soldini E, Biggiogero M, Maggioli C, Fontana PE. Essential oil therapy for the short-term treatment of behavioral and psychological symptoms of dementia: A monocentric randomized pilot study. Aging Clin Exp Res. 2021 Aug;33(8):2251–2259. doi: 10.1007/s40520-020-01754-2. Epub 2020 Nov 12. PMID: 33184771.
45. Noguchi-Shinohara M, Ono K, Hamaguchi T, Nagai T, Kobayashi S, Komatsu J, Samuraki-Yokohama M, Iwasa K, Yokoyama K, Nakamura H, Yamada M. Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer's disease progression. Sci Rep. 2020 Oct 29;10(1):18627. doi: 10.1038/s41598-020-73729-2. PMID: 33122694; PMCID: PMC7596544.
46. Wang PH, Lin HW, Nguyen TTT, Hu CJ, Huang LK, Tam KW, Kuan YC. Efficacy of aromatherapy against behavioral and psychological disturbances in people with dementia: A meta-analysis of randomized controlled trials. J Am Med Dir Assoc. 2024 Nov;25(11):105199. doi: 10.1016/j.jamda.2024.105199. Epub 2024 Aug 9. PMID: 39128826.
47. Watson K, Hatcher D, Good A. A randomised controlled trial of lavender (Lavandula angustifolia) and lemon balm (Melissa officinalis) essential oils for the treatment of agitated behaviour in older people with and without dementia. Complement Ther Med. 2019 Feb;42:366–373. doi: 10.1016/j.ctim.2018.12.016. Epub 2018 Dec 21. PMID: 30670268.
48. Xiao S, Wang Y, Duan S, Li B. Effects of aromatherapy on agitation and aggression in cognitive impairment: A meta-analysis. J Clin Nurs. 2025 Dec;34(12):4974–4988. doi: 10.1111/jocn.15984. Epub 2021 Aug 5. PMID: 34355444.
Delirium (prevention)
49. Kang J, Cho YS, Lee M, Yun S, Jeong YJ, Won YH, Hong J, Kim S. Effects of nonpharmacological interventions on sleep improvement and delirium prevention in critically ill patients: A systematic review and meta-analysis. Aust Crit Care. 2023 Jul;36(4):640–649. doi: 10.1016/j.aucc.2022.04.006. Epub 2022 Jun 17. PMID: 35718628.
50. Liu M, Tang H, Zhou Z, Yang M, Shen J, Ji Z, Zhang M. Effect of inhalation of peppermint essential oil aromatherapy on postoperative delirium in old patients following major lower limb joint arthroplasty surgery: A randomized controlled trial. Explore (NY). 2025 Nov–Dec;21(6):103272. doi: 10.1016/j.explore.2025.103272. Epub 2025 Oct 21. PMID: 41390992.
Mild cognitive impairment / Smoking cessation
51. Su G, Liu F, Yang X, Chen Z, Kang Y, Gao S. The effect of inhaled aromatherapy on cognitive function in patients with cognitive impairment: A systematic review and meta-analysis. Gen Hosp Psychiatry. 2025 Mar–Apr;93:20–31. doi: 10.1016/j.genhosppsych.2025.01.002. Epub 2025 Jan 9. PMID: 39799712.
Mild cognitive impairment
52. Can S, Yildirim Usta Y, Yildiz S, Tayfun K. The effect of lavender and rosemary aromatherapy application on cognitive functions, anxiety, and sleep quality in the elderly with diabetes. Explore (NY). 2024 Nov–Dec;20(6):103033. doi: 10.1016/j.explore.2024.103033. Epub 2024 Jul 11. PMID: 39047346.
53. Mohammad Rezaie S, Shahabinejad M, Loripoor M, Sayadi AR. The effect of aromatherapy with lavender essential oil on the working memory of women with multiple sclerosis. J Med Life. 2021 Nov–Dec;14(6):776–781. doi: 10.25122/jml-2020-0115. PMID: 35126747; PMCID: PMC8811666.
54. Chao Y, Tong X, Zhang B, Yang H, Zhang L, Wu K, Zhang Y, Li Q, Zhang Z, Bi Y. Olfactory training improves cognition and modifies brain networks in type 2 diabetes patients with mild cognitive impairment: A 16-week randomised controlled trial. Diabetes Obes Metab. 2025 Dec;27(12):7040–7051. doi: 10.1111/dom.70103. Epub 2025 Sep 5. PMID: 40908892.
55. Haehner A, Chen B, Espin M, Haussmann R, Matthes C, Desser D, Loessner L, Brandt MD, Donix M, Hummel T. Training with odors impacts hippocampal thickness in patients with mild cognitive impairment. J Alzheimers Dis. 2022;88(2):743–755. doi: 10.3233/JAD-220248. PMID: 35694924.
56. Chen B, Espin M, Haussmann R, Matthes C, Donix M, Hummel T, Haehner A. The effect of olfactory training on olfaction, cognition, and brain function in patients with mild cognitive impairment. J Alzheimers Dis. 2022;85(2):745–754. doi: 10.3233/JAD-215257. PMID: 34864678.
57. Oleszkiewicz A, Abriat A, Doelz G, Azema E, Hummel T. Beyond olfaction: Beneficial effects of olfactory training extend to aging-related cognitive decline. Behav Neurosci. 2021 Dec;135(6):732–740. doi: 10.1037/bne0000478. Epub 2021 Jun 10. PMID: 34110862.
58. Oleszkiewicz A, Bottesi L, Pieniak M, Fujita S, Krasteva N, Nelles G, Hummel T. Olfactory training with aromastics: Olfactory and cognitive effects. Eur Arch Otorhinolaryngol. 2022 Jan;279(1):225–232. doi: 10.1007/s00405-021-06810-9. Epub 2021 Apr 16. PMID: 33864109; PMCID: PMC8051546.
Sexual dysfunction
59. Abazari L, Tirgari B. The effect of aromatherapy with lavender essential oil on odor intensity, sexual quality of life, and ostomy adjustment: A clinical trial. Eur J Oncol Nurs. 2025 Oct;78:102975. doi: 10.1016/j.ejon.2025.102975. Epub 2025 Sep 4. PMID: 40939480.
60. Akbarzadeh G, Abedi P, Jahanfar S, Mansurkhani HS, Fakhri A, Maraghi E. The effect of rose damascene extract on anxiety and sexual function of breastfeeding women: A randomized controlled trial. Front Med (Lausanne). 2024 Dec 5;11:1466341. doi: 10.3389/fmed.2024.1466341. PMID: 39703518; PMCID: PMC11655233.
61. Choi SY, Kang P, Lee HS, Seol GH. Effects of Inhalation of Essential oil of Citrus aurantium L. var. amara on menopausal symptoms, stress, and estrogen in postmenopausal women: A randomized controlled trial. Evid Based Complement Alternat Med. 2014;2014:796518. doi: 10.1155/2014/796518. Epub 2014 Jun 12. PMID: 25024731; PMCID: PMC4082953.
62. Farnia V, Hojatitabar S, Shakeri J, Rezaei M, Yazdchi K, Bajoghli H, Holsboer-Trachsler E, Brand S. Adjuvant Rosa damascena has a small effect on SSRI-induced sexual dysfunction in female patients suffering from MDD. Pharmacopsychiatry. 2015 Jul;48(4–5):156–163. doi: 10.1055/s-0035-1554712. Epub 2015 Jun 22. PMID: 26098128.
63. Farnia V, Shirzadifar M, Shakeri J, Rezaei M, Bajoghli H, Holsboer-Trachsler E, Brand S. Rosa damascena oil improves SSRI-induced sexual dysfunction in male patients suffering from major depressive disorders: Results from a double-blind, randomized, and placebo-controlled clinical trial. Neuropsychiatr Dis Treat. 2015 Mar 9;11:625–635. doi: 10.2147/NDT.S78696. PMID: 25834441; PMCID: PMC4358691.
64. Farnia V, Tatari F, Alikhani M, Shakeri J, Taghizadeh M, Karbasizadeh H, Sadeghi Bahmani D, Holsboer-Trachsler E, Brand S. Rosa damascena oil improved sexual function and testosterone in male patients with opium use disorder under methadone maintenance therapy-results from a double-blind, randomized, placebo-controlled clinical trial. Drug Alcohol Depend. 2017 Jul 1;176:117–125. doi: 10.1016/j.drugalcdep.2017.02.008. Epub 2017 Apr 6. PMID: 28531768.
65. Farnia V, Tatari F, Alikhani M, Yazdchi K, Taghizadeh M, Sadeghi Bahmani D, Karbasizadeh H, Holsboer-Trachsler E, Brand S. Rosa damascena oil improved methadone-related sexual dysfunction in females with opioid use disorder under methadone maintenance therapy - results from a double-blind, randomized, and placebo-controlled trial. J Psychiatr Res. 2017 Dec;95:260–268. doi: 10.1016/j.jpsychires.2017.08.011. Epub 2017 Aug 16. PMID: 28923720.
66. Heydarpour S, Sharifipour F, Heydarpour F. Effect of Salvia officinalis scent on postmenopausal women's sexual function and satisfaction: A randomized controlled trial. BMC Womens Health. 2023 Aug 23;23(1):442. doi: 10.1186/s12905-023-02605-8. PMID: 37612717; PMCID: PMC10463902.
67. Khadivzadeh T, Najafi MN, Ghazanfarpour M, Irani M, Dizavandi FR, Shariati K. Aromatherapy for sexual problems in menopausal women: A systematic review and meta-analysis. J Menopausal Med. 2018 Apr;24(1):56–61. doi: 10.6118/jmm.2018.24.1.56. Epub 2018 Apr 30. PMID: 29765928; PMCID: PMC5949309.
68. Lee HW, Ang L, Choi J, Lee MS. Aromatherapy for managing menopausal symptoms: A systematic review and meta-analysis of randomized placebo-controlled trials. J Altern Complement Med. 2021 Oct;27(10):813–823. doi: 10.1089/acm.2020.0315. Epub 2021 Jul 8. PMID: 34242093.
69. Sharifipour F, Heydarpour S, Salari N. Comparison of aromatherapy with Citrus aurantium and lavender on sexual satisfaction in breastfeeding women: A randomized controlled trial. Breastfeed Med. 2023 Jan;18(1):23–29. doi: 10.1089/bfm.2022.0179. Epub 2023 Jan 5. PMID: 36603110.
70. Teimori Z, Mirzaee F, Ghazanfarpour M, Azimi M, Ahmadi A, Javadi A. Comparing the effects of lavender aromatherapy and mindfulness-based cognitive therapy on sexual function in women in Iran. Nurs Womens Health. 2024 Oct;28(5):e1–e10. doi: 10.1016/j.nwh.2024.03.006. Epub 2024 Aug 28. PMID: 39214150.
Smoking cessation
71. Cordell B, Buckle J. The effects of aromatherapy on nicotine craving on a U.S. campus: A small comparison study. J Altern Complement Med. 2013 Aug;19(8):709–713. doi: 10.1089/acm.2012.0537. Epub 2013 Mar 28. PMID: 23536963.
72. Ebihara T, Yamasaki M, Kozaki K, Ebihara S. Medical aromatherapy in geriatric syndrome. Geriatr Gerontol Int. 2021 May;21(5):377–385. doi: 10.1111/ggi.14157. Epub 2021 Mar 31. PMID: 33789361.
73. Rose JE, Behm FM. Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms. Drug Alcohol Depend. 1994 Feb;34(3):225–229. doi: 10.1016/0376-8716(94)90160-0. PMID: 8033760.
74. Sayette MA, Marchetti MA, Herz RS, Martin LM, Bowdring MA. Pleasant olfactory cues can reduce cigarette craving. J Abnorm Psychol. 2019 May;128(4):327–340. doi: 10.1037/abn0000431. Epub 2019 Apr 15. PMID: 30985171; PMCID: PMC6529945.
75. Westman EC, Behm FM, Rose JE. Airway sensory replacement combined with nicotine replacement for smoking cessation: A randomized, placebo-controlled trial using a citric acid inhaler. Chest. 1995 May;107(5):1358–1364. doi: 10.1378/chest.107.5.1358. PMID: 7750331.
Breathwork References
61 references
Anxiety / mood in healthy adults
1. Balban MY, Neri E, Kogon MM, Weed L, Nouriani B, Jo B, Holl G, Zeitzer JM, Spiegel D, Huberman AD. Brief structured respiration practices enhance mood and reduce physiological arousal. Cell Rep Med. 2023 Jan 17;4(1):100895. doi: 10.1016/j.xcrm.2022.100895. Epub 2023 Jan 10. PMID: 36630953; PMCID: PMC9873947.
2. Bentley TGK, D'Andrea-Penna G, Rakic M, Arce N, LaFaille M, Berman R, Cooley K, Sprimont P. Breathing practices for stress and anxiety reduction: Conceptual framework of implementation guidelines based on a systematic review of the published literature. Brain Sci. 2023 Nov 21;13(12):1612. doi: 10.3390/brainsci13121612. PMID: 38137060; PMCID: PMC10741869.
3. Blake RL. Efficacy of online conscious connected breathwork in reducing symptoms of anxiety: A randomized waitlist control trial. J Affect Disord. 2026 Feb 1;394(Pt A):120565. doi: 10.1016/j.jad.2025.120565. Epub 2025 Oct 29. PMID: 41167435.
4. Chandla SS, Sood S, Dogra R, Das S, Shukla SK, Gupta S. Effect of short-term practice of pranayamic breathing exercises on cognition, anxiety, general well being and heart rate variability. J Indian Med Assoc. 2013 Oct;111(10):662–665. PMID: 24968492.
5. Chen YF, Huang XY, Chien CH, Cheng JF. The effectiveness of diaphragmatic breathing relaxation training for reducing anxiety. Perspect Psychiatr Care. 2017 Oct;53(4):329–336. doi: 10.1111/ppc.12184. Epub 2016 Aug 23. PMID: 27553981.
6. Conlon A, Arnold R, Preatoni E, Moore LJ. Pulling the trigger: The effect of a 5-minute slow diaphragmatic breathing intervention on psychophysiological stress responses and pressurized pistol shooting performance. J Sport Exerc Psychol. 2022 Apr 25;44(3):206–219. doi: 10.1123/jsep.2021-0213. PMID: 35468589.
7. Kamath A, Urval RP, Shenoy AK. Effect of alternate nostril breathing exercise on experimentally induced anxiety in healthy volunteers using the simulated public speaking model: A randomized controlled pilot study. Biomed Res Int. 2017;2017:2450670. doi: 10.1155/2017/2450670. Epub 2017 Oct 11. PMID: 29159176; PMCID: PMC5660749.
8. Khng KH. A better state-of-mind: Deep breathing reduces state anxiety and enhances test performance through regulating test cognitions in children. Cogn Emot. 2017 Nov;31(7):1502–1510. doi: 10.1080/02699931.2016.1233095. Epub 2016 Sep 26. PMID: 27666392.
9. Little A, Stainer M, MacQuarrie AS, Wiseman N, Haskins B. Examining the effectiveness of breathwork to improve resilience and psychological wellbeing while reducing anxiety, depression, stress, and insomnia in paramedicine students: A single-blind randomised controlled trial. Stress Health. 2026 Apr;42(2):e70161. doi: 10.1002/smi.70161. PMID: 41787752; PMCID: PMC12963692.
11. Novaes MM, Palhano-Fontes F, Onias H, Andrade KC, Lobão-Soares B, Arruda-Sanchez T, Kozasa EH, Santaella DF, de Araujo DB. Effects of yoga respiratory practice (bhastrika pranayama) on anxiety, affect, and brain functional connectivity and activity: A randomized controlled trial. Front Psychiatry. 2020 May 21;11:467. doi: 10.3389/fpsyt.2020.00467. PMID: 32528330; PMCID: PMC7253694.
12. Okado Y, De Pace D, Ewing E, Rowley C. Brief relaxation training for the prevention of stress-related difficulties: A pilot study. Int Q Community Health Educ. 2020 Apr;40(3):193–200. doi: 10.1177/0272684X19873787. Epub 2019 Sep 4. PMID: 31483743.
13. Schmalzl L, Powers C, Zanesco AP, Yetz N, Groessl EJ, Saron CD. The effect of movement-focused and breath-focused yoga practice on stress parameters and sustained attention: A randomized controlled pilot study. Conscious Cogn. 2018;65:109–125. doi: 10.1016/j.concog.2018.07.012. Epub 2018 Aug 9. PMID: 30099318.
14. Sellakumar G. Effect of slow-deep breathing exercise to reduce anxiety among adolescent school students in a selected higher secondary school in Coimbatore, India. J Psychol Educ Res (JPER). 2015;23:54–72.
15. Fincham GW, Strauss C, Montero-Marin J, Cavanagh K. Effect of breathwork on stress and mental health: A meta-analysis of randomised-controlled trials. Sci Rep. 2023 Jan 9;13(1):432. doi: 10.1038/s41598-022-27247-y. PMID: 36624160; PMCID: PMC9828383.
16. Sharma SK, Kala N, Telles S. Volitional yoga breathing influences attention and anxiety: An Exploratory Randomized Crossover Study. Complement Med Res. 2022;29(2):120–126. doi: 10.1159/000519715. Epub 2021 Nov 16. PMID: 34784592.
17. Sharma VK, Trakroo M, Subramaniam V, Rajajeyakumar M, Bhavanani AB, Sahai A. Effect of fast and slow pranayama on perceived stress and cardiovascular parameters in young health-care students. Int J Yoga. 2013;6:104–110. doi: 10.4103/0973-6131.113400. PMID: 23930028; PMCID: PMC3734635.
18. Yilmaz M, Bulut Y. The effect of progressive breathing relaxation training on preoperative anxiety and surgical stress response. International Journal of Caring Sciences. 2020;13(2):1287–1296.
Anxiety / mood in healthy adults / Cognition
10. Ma X, Yue ZQ, Gong ZQ, Zhang H, Duan NY, Shi YT, Wei GX, Li YF. The effect of diaphragmatic breathing on attention, negative affect and stress in healthy adults. Front Psychol. 2017 Jun 6;8:874. doi: 10.3389/fpsyg.2017.00874. PMID: 28626434; PMCID: PMC5455070.
Cognition
19. Bahameish M, Stockman T. Short-term effects of heart rate variability biofeedback on working memory. Appl Psychophysiol Biofeedback. 2024 Jun;49(2):219–231. doi: 10.1007/s10484-024-09624-7. Epub 2024 Feb 16. PMID: 38366274; PMCID: PMC11101506.
20. Bögge L, Colás-Blanco I, Piolino P. Respiratory sinus arrhythmia during biofeedback is linked to persistent improvements in attention, short-term memory, and positive self-referential episodic memory. Front Neurosci. 2022 Sep 13;16:791498. doi: 10.3389/fnins.2022.791498. PMID: 36177356; PMCID: PMC9514056.
21. Ferreira L, Tanaka K, Santos-Galduróz RF, Galduróz JC. Respiratory training as strategy to prevent cognitive decline in aging: A randomized controlled trial. Clin Interv Aging. 2015 Mar 20;10:593–603. doi: 10.2147/CIA.S79560. PMID: 25848235; PMCID: PMC4374650.
22. Fox N, Biddell H, King J. A semi-randomised control trial assessing psychophysiological effects of breathwork and cold immersion. Sci Rep. 2025 Dec 12;15(1):43879. doi: 10.1038/s41598-025-29187-9. PMID: 41388053; PMCID: PMC12708851.
23. Kramer AC, Neubauer AB, Schmiedek F. The effectiveness of a slow-paced diaphragmatic breathing exercise in children's daily life: A micro-randomized trial. J Clin Child Adolesc Psychol. 2023 Nov–Dec;52(6):797–810. doi: 10.1080/15374416.2022.2084743. Epub 2022 Jun 15. PMID: 35704507.
24. Liang WM, Xiao J, Ren FF, Chen ZS, Li CR, Bai ZM, Rukšėnas O. Acute effect of breathing exercises on muscle tension and executive function under psychological stress. Front Psychol. 2023 May 25;14:1155134. doi: 10.3389/fpsyg.2023.1155134. PMID: 37303921; PMCID: PMC10249663.
25. Manser P, de Bruin ED. "Brain-IT": Exergame training with biofeedback breathing in neurocognitive disorders. Alzheimers Dement. 2024 Jul;20(7):4747–4764. doi: 10.1002/alz.13913. Epub 2024 May 29. PMID: 38809948; PMCID: PMC11247687.
26. Masmoudi K, Chaari F, Ben Waer F, Rebai H, Sahli S. A single session of slow-paced breathing improved cognitive functions and postural control among middle-aged women: A randomized single blinded controlled trial. Menopause. 2025 Feb 1;32(2):158–165. doi: 10.1097/GME.0000000000002470. Epub 2024 Dec 17. PMID: 39689252.
27. Phansikar M, Gothe N, Hernandez R, Lara-Cinisomo S, Mullen SP. Feasibility and impact of a remote moderate-intensity yoga intervention on stress and executive functioning in working adults: A randomized controlled trial. J Behav Med. 2023 Oct;46(5):720–731. doi: 10.1007/s10865-022-00385-4. Epub 2023 Feb 8. PMID: 36754937; PMCID: PMC9908305.
28. Pilcher JJ, Byrne KA, Weiskittel SE, Clark EC, Brancato MG, Rosinski ML, Spinelli MR. Brief slow-paced breathing improves working memory, mood, and stress in college students. Anxiety Stress Coping. 2025 Sep;38(5):528–543. doi: 10.1080/10615806.2025.2505897. Epub 2025 May 20. PMID: 40392328.
29. Voltmer K, Hondrich F, von Salisch M. Daily breath-based mindfulness exercises in a randomized controlled trial improve primary school children's performance in arithmetic. Sci Rep. 2023 Dec 13;13(1):22169. doi: 10.1038/s41598-023-49354-0. PMID: 38092836; PMCID: PMC10719295.
30. Yunus N, Yunus AE, Yunus PS, Taşkın BR, Binboğa E. Cognitive and autonomic effects of a single HRV biofeedback session during a time-pressured chess task: A randomized controlled pilot study. Percept Mot Skills. 2026 Mar 19:315125261435294. doi: 10.1177/00315125261435294. PMID: 41854263.
Generalized anxiety disorder
31. Chai J, Li S, He L, Yang J, Wu T, Ou K, Chen X, Ma K, Zhao S. Clinical application of abdominal breathing training and evaluation of physical and mental benefits in anxiety patients. Front Psychol. 2025 Dec 9;16:1695622. doi: 10.3389/fpsyg.2025.1695622. PMID: 41446603; PMCID: PMC12722957.
32. Clark ME, Hirschman R. Effects of paced respiration on anxiety reduction in a clinical population. Biofeedback Self Regul. 1990 Sep;15(3):273–284. doi: 10.1007/BF01011109. PMID: 2223892.
33. Maleki A, Ravanbakhsh M, Saadat M, Bargard MS, Latifi SM. Effect of breathing exercises on respiratory indices and anxiety level in individuals with generalized anxiety disorder: A randomized double-blind clinical trial. J Phys Ther Sci. 2022 Apr;34(4):247–251. doi: 10.1589/jpts.34.247. Epub 2022 Apr 8. PMID: 35400836; PMCID: PMC8989478.
34. Simon NM, Hofmann SG, Rosenfield D, Hoeppner SS, Hoge EA, Bui E, Khalsa SBS. Efficacy of yoga vs cognitive behavioral therapy vs stress education for the treatment of generalized anxiety disorder: A randomized clinical trial. JAMA Psychiatry. 2021 Jan 1;78(1):13–20. doi: 10.1001/jamapsychiatry.2020.2496. PMID: 32805013; PMCID: PMC7788465.
Insomnia
35. Eide EM, Hernes HM, Grønli J. Slow breathing techniques before bedtime and the effects on sleep: A systematic review. Sleep Med Rev. 2026 Mar 20;87:102284. doi: 10.1016/j.smrv.2026.102284. PMID: 41886931.
Nicotine
36. Janes AC, Datko M, Roy A, Barton B, Druker S, Neal C, Ohashi K, Benoit H, van Lutterveld R, Brewer JA. Quitting starts in the brain: A randomized controlled trial of app-based mindfulness shows decreases in neural responses to smoking cues that predict reductions in smoking. Neuropsychopharmacology. 2019 Aug;44(9):1631–1638. doi: 10.1038/s41386-019-0403-y. Epub 2019 Apr 30. PMID: 31039580; PMCID: PMC6785102.
37. Lotfalian S, Spears CA, Juliano LM. The effects of mindfulness-based yogic breathing on craving, affect, and smoking behavior. Psychol Addict Behav. 2020 Mar;34(2):351–359. doi: 10.1037/adb0000536. Epub 2019 Nov 21. PMID: 31750699; PMCID: PMC7064378.
38. Price JL, Bates ME, Morgano J, Todaro S, Uhouse SG, Vaschillo E, Vaschillo B, Pawlak A, Buckman JF. Effects of arousal modulation via resonance breathing on craving and affect in women with substance use disorder. Addict Behav. 2022 Apr;127:107207. doi: 10.1016/j.addbeh.2021.107207. Epub 2021 Dec 17. PMID: 34953433; PMCID: PMC9069782.
39. Sarkar BK, West R, Arora M, Ahluwalia JS, Reddy KS, Shahab L. Effectiveness of a brief community outreach tobacco cessation intervention in India: A cluster-randomised controlled trial (the BABEX trial). Thorax. 2017 Feb;72(2):167–173. doi: 10.1136/thoraxjnl-2016-208732. Epub 2016 Oct 5. PMID: 27708113; PMCID: PMC5284331.
40. Shahab L, Sarkar BK, West R. The acute effects of yogic breathing exercises on craving and withdrawal symptoms in abstaining smokers. Psychopharmacology (Berl). 2013 Feb;225(4):875–882. doi: 10.1007/s00213-012-2876-9. Epub 2012 Sep 20. PMID: 22993051.
Long COVID
41. Abo Elyazed TI, Abd El-Hakim AAE, Saleh OI, Sonbol MMF, Eid HA, Moazen E, Alhassoon MH, Elfeky SEF. Diaphragmatic strengthening exercises for patients with post COVID-19 condition after mild-to-moderate acute COVID-19 infection: A randomized controlled study. J Rehabil Med. 2024 Jun 11;56:jrm25491. doi: 10.2340/jrm.v56.25491. PMID: 38860716; PMCID: PMC11182030.
42. Cossu G, Kalcev G, Primavera D, Lorrai S, Perra A, Galetti A, Demontis R, Tramontano E, Bert F, Montisci R, Maleci A, Castilla PJF, Jaramillo SG, Kurotschka PK, Rocha NB, Carta MG. The use of heart rate variability-biofeedback (HRV-BF) as an adjunctive intervention in chronic fatigue syndrome (CSF/ME) in long COVID: Results of a phase II controlled feasibility trial. J Clin Med. 2025 Jul 29;14(15):5363. doi: 10.3390/jcm14155363. PMID: 40806985; PMCID: PMC12347631.
43. Greenhalgh T, Sivan M, Perlowski A, Nikolich JŽ. Long COVID: A clinical update. Lancet. 2024 Aug 17;404(10453):707–724. doi: 10.1016/S0140-6736(24)01136-X. Epub 2024 Jul 31. PMID: 39096925.
44. Jung JH, Lee JW, Ko JY. Effectiveness of breathing exercises and stabilization techniques on patients with COVID-19: Quasi-experimental study. J Clin Med. 2025;14(21):7730. doi: 10.3390/jcm14217730. PMID: 41227126; PMCID: PMC12610470.
45. Maley JH, Alba GA, Barry JT, Bartels MN, Fleming TK, Oleson CV, Rydberg L, Sampsel S, Silver JK, Sipes S, Verduzco-Gutierrez M, Wood J, Zibrak JD, Whiteson J. Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of breathing discomfort and respiratory sequelae in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PM R. 2022 Jan;14(1):77–95. doi: 10.1002/pmrj.12744. PMID: 34902224.
46. McNarry MA, Berg RMG, Shelley J, Hudson J, Saynor ZL, Duckers J, Lewis K, Davies GA, Mackintosh KA. Inspiratory muscle training enhances recovery post-COVID-19: A randomised controlled trial. Eur Respir J. 2022 Oct 6;60(4):2103101. doi: 10.1183/13993003.03101-2021. PMID: 35236727; PMCID: PMC8900538.
47. Philip KEJ, Owles H, McVey S, Pagnuco T, Bruce K, Brunjes H, Banya W, Mollica J, Lound A, Zumpe S, Abrahams AM, Padmanaban V, Hardy TH, Lewis A, Lalvani A, Elkin S, Hopkinson NS. An online breathing and wellbeing programme (ENO Breathe) for people with persistent symptoms following COVID-19: A parallel-group, single-blind, randomised controlled trial. Lancet Respir Med. 2022 Sep;10(9):851–862. doi: 10.1016/S2213-2600(22)00125-4. Epub 2022 Apr 27. PMID: 35489367; PMCID: PMC9045747.
48. Pouliopoulou DV, Macdermid JC, Saunders E, Peters S, Brunton L, Miller E, Quinn KL, Pereira TV, Bobos P. Rehabilitation interventions for physical capacity and quality of life in adults with post-COVID-19 condition: A systematic review and meta-analysis. JAMA Netw Open. 2023 Sep 5;6(9):e2333838. doi: 10.1001/jamanetworkopen.2023.33838. PMID: 37725376; PMCID: PMC10509723.
Major depressive disorder
49. Chien HC, Chung YC, Yeh ML, Lee JF. Breathing exercise combined with cognitive behavioural intervention improves sleep quality and heart rate variability in major depression. J Clin Nurs. 2015 Nov;24(21–22):3206–3214. doi: 10.1111/jocn.12972. Epub 2015 Sep 25. PMID: 26404039.
50. Erkkilä J, Brabant O, Hartmann M, Mavrolampados A, Ala-Ruona E, Snape N, Saarikallio S, Gold C. Music therapy for depression enhanced with listening homework and slow paced breathing: A randomised controlled trial. Front Psychol. 2021 Feb 16;12:613821. doi: 10.3389/fpsyg.2021.613821. PMID: 33664693; PMCID: PMC7920974.
51. Sharma A, Barrett MS, Cucchiara AJ, Gooneratne NS, Thase ME. A breathing-based meditation intervention for patients with major depressive disorder following inadequate response to antidepressants: A randomized pilot study. J Clin Psychiatry. 2017 Jan;78(1):e59–e63. doi: 10.4088/JCP.16m10819. PMID: 27898207; PMCID: PMC5272872.
52. Streeter CC, Gerbarg PL, Whitfield TH, Owen L, Johnston J, Silveri MM, Gensler M, Faulkner CL, Mann C, Wixted M, Hernon AM, Nyer MB, Brown ER, Jensen JE. Treatment of major depressive disorder with iyengar yoga and coherent breathing: A randomized controlled dosing study. J Altern Complement Med. 2017 Mar;23(3):201–207. doi: 10.1089/acm.2016.0140. Epub 2017 Feb 16. PMID: 28296480; PMCID: PMC5359682.
PTSD
53. Bayley PJ, Schulz-Heik RJ, Tang JS, Mathersul DC, Avery T, Wong M, Zeitzer JM, Rosen CS, Burn AS, Hernandez B, Lazzeroni LC, Seppälä EM. Randomised clinical non-inferiority trial of breathing-based meditation and cognitive processing therapy for symptoms of post-traumatic stress disorder in military veterans. BMJ Open. 2022 Aug 25;12(8):e056609. doi: 10.1136/bmjopen-2021-056609. PMID: 36008059; PMCID: PMC9422818.
54. Chadwick TM, Tatschl JM, Fujiyama H, Drummond PD, Mathersul DC. Heart rate variability biofeedback improves co-occurring posttraumatic stress disorder and chronic pain symptoms: A randomised waitlist controlled trial. J Affect Disord. 2026 Feb 1;394(Pt A):120558. doi: 10.1016/j.jad.2025.120558. Epub 2025 Oct 25. PMID: 41284543.
55. Fonkoue IT, Hu Y, Jones T, Vemulapalli M, Sprick JD, Rothbaum B, Park J. Eight weeks of device-guided slow breathing decreases sympathetic nervous reactivity to stress in posttraumatic stress disorder. Am J Physiol Regul Integr Comp Physiol. 2020 Oct 1;319(4):R466–R475. doi: 10.1152/ajpregu.00079.2020. Epub 2020 Aug 26. PMID: 32847397; PMCID: PMC7642907.
56. Fonkoue IT, Marvar PJ, Norrholm SD, Kankam ML, Li Y, DaCosta D, Rothbaum BO, Park J. Acute effects of device-guided slow breathing on sympathetic nerve activity and baroreflex sensitivity in posttraumatic stress disorder. Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H141–H149. doi: 10.1152/ajpheart.00098.2018. Epub 2018 Apr 13. PMID: 29652544; PMCID: PMC6087774.
57. Ostacher MJ, Fischer E, Bowen ER, Lyu J, Robbins DJ, Suppes T. Investigation of a capnometry guided respiratory intervention in the treatment of posttraumatic stress disorder. Appl Psychophysiol Biofeedback. 2021 Dec;46(4):367–376. doi: 10.1007/s10484-021-09521-3. PMID: 34468913; PMCID: PMC8553693.
58. Seppälä EM, Nitschke JB, Tudorascu DL, Hayes A, Goldstein MR, Nguyen DT, Perlman D, Davidson RJ. Breathing-based meditation decreases posttraumatic stress disorder symptoms in U.S. military veterans: A randomized controlled longitudinal study. J Trauma Stress. 2014 Aug;27(4):397–405. doi: 10.1002/jts.21936. PMID: 25158633; PMCID: PMC4309518.
59. Wahbeh H, Goodrich E, Goy E, Oken BS. Mechanistic pathways of mindfulness meditation in combat veterans with posttraumatic stress disorder. J Clin Psychol. 2016 Apr;72(4):365–383. doi: 10.1002/jclp.22255. Epub 2016 Jan 21. PMID: 26797725; PMCID: PMC4803530.
60. Wallace T, Morris JT, Glickstein R, Anderson RK, Gore RK. Implementation of a mobile technology-supported diaphragmatic breathing intervention in military mTBI with PTSD. J Head Trauma Rehabil. 2022 May–Jun 01;37(3):152–161. doi: 10.1097/HTR.0000000000000774. PMID: 35703895; PMCID: PMC9204778.
Bipolar disorder
61. Serafim SD, da Ponte FDR, Lima FM, Martins DS, Rosa AR, Kunz M. Effects of deep breathing in patients with bipolar disorder. Perspect Psychiatr Care. 2019 Jan;55(1):119–125. doi: 10.1111/ppc.12325. Epub 2018 Sep 6. PMID: 30189115.
Massage References
77 references
Agitation in dementia
1. Liu X, Zang L, Lu Q, Zhang Y, Meng Q. Effect of massage and touch on agitation in dementia: A meta-analysis. J Clin Nurs. 2025 May;34(5):1948–1964. doi: 10.1111/jocn.17674. Epub 2025 Feb 4. PMID: 39902611.
2. Fung JKK, Tsang HW. Management of behavioural and psychological symptoms of dementia by an aroma-massage with acupressure treatment protocol: A randomised clinical trial. J Clin Nurs. 2018 May;27(9–10):1812–1825. doi: 10.1111/jocn.14101. Epub 2017 Dec 4. PMID: 28986942.
3. Leng M, Zhao Y, Wang Z. Comparative efficacy of non-pharmacological interventions on agitation in people with dementia: A systematic review and Bayesian network meta-analysis. Int J Nurs Stud. 2020 Feb;102:103489. doi: 10.1016/j.ijnurstu.2019.103489. Epub 2019 Nov 25. PMID: 31862527.
4. Margenfeld F, Klocke C, Joos S. Manual massage for persons living with dementia: A systematic review and meta-analysis. Int J Nurs Stud. 2019 Aug;96:132–142. doi: 10.1016/j.ijnurstu.2018.12.012. Epub 2019 Jan 4. PMID: 30679034.
5. Schaub C, Von Gunten A, Morin D, Wild P, Gomez P, Popp J. The effects of hand massage on stress and agitation among people with dementia in a hospital setting: A pilot study. Appl Psychophysiol Biofeedback. 2018 Dec;43(4):319–332. doi: 10.1007/s10484-018-9416-2. PMID: 30209712; PMCID: PMC6223738.
6. Watt JA, Goodarzi Z, Veroniki AA, Nincic V, Khan PA, Ghassemi M, Thompson Y, Tricco AC, Straus SE. Comparative efficacy of interventions for aggressive and agitated behaviors in dementia: A systematic review and network meta-analysis. Ann Intern Med. 2019 Nov 5;171(9):633–642. doi: 10.7326/M19-0993. Epub 2019 Oct 15. PMID: 31610547.
7. Wu J, Wang Y, Wang Z. The effectiveness of massage and touch on behavioural and psychological symptoms of dementia: A quantitative systematic review and meta-analysis. J Adv Nurs. 2017 Oct;73(10):2283–2295. doi: 10.1111/jan.13311. Epub 2017 May 19. PMID: 28378347.
8. Yang YP, Wang CJ, Wang JJ. Effect of aromatherapy massage on agitation and depressive mood in individuals with dementia. J Gerontol Nurs. 2016 Sep 1;42(9):38–46. doi: 10.3928/00989134-20160615-03. Epub 2016 Jun 20. PMID: 27319407.
Depressive / anxious symptoms
9. Atchison K, Watt JA, Ewert D, Toohey AM, Ismail Z, Goodarzi Z. Non-pharmacologic and pharmacologic treatments for anxiety in long-term care: A systematic review and meta-analysis. Age Ageing. 2022 Sep 2;51(9):afac195. doi: 10.1093/ageing/afac195. PMID: 36057989.
10. Bahrami T, Rejeh N, Heravi-Karimooi M, Vaismoradi M, Tadrisi SD, Sieloff C. Effect of aromatherapy massage on anxiety, depression, and physiologic parameters in older patients with the acute coronary syndrome: A randomized clinical trial. Int J Nurs Pract. 2017 Dec;23(6):e12601. doi: 10.1111/ijn.12601. Epub 2017 Oct 25. PMID: 29071755.
11. Beider S, Moyer CA. Randomized controlled trials of pediatric massage: A review. Evid Based Complement Alternat Med. 2007 Mar;4(1):23–34. doi: 10.1093/ecam/nel068. Epub 2006 Nov 3. PMID: 17342238; PMCID: PMC1810360.
12. Cho YC, Tsay SL. The effect of acupressure with massage on fatigue and depression in patients with end-stage renal disease. J Nurs Res. 2004 Mar;12(1):51–59. doi: 10.1097/01.jnr.0000387488.63438.9a. PMID: 15136963.
14. Field T, Figueiredo B, Hernandez-Reif M, Diego M, Deeds O, Ascencio A. Massage therapy reduces pain in pregnant women, alleviates prenatal depression in both parents and improves their relationships. J Bodyw Mov Ther. 2008 Apr;12(2):146–150. doi: 10.1016/j.jbmt.2007.06.003. Epub 2007 Oct 2. PMID: 19083666.
15. Hall HG, Cant R, Munk N, Carr B, Tremayne A, Weller C, Fogarty S, Lauche R. The effectiveness of massage for reducing pregnant women's anxiety and depression; systematic review and meta-analysis. Midwifery. 2020 Nov;90:102818. doi: 10.1016/j.midw.2020.102818. Epub 2020 Aug 14. PMID: 32827841.
17. Reychler G, Caty G, Arcq A, Lebrun L, Belkhir L, Yombi JC, Marot JC. Effects of massage therapy on anxiety, depression, hyperventilation and quality of life in HIV infected patients: A randomized controlled trial. Complement Ther Med. 2017 Jun;32:109–114. doi: 10.1016/j.ctim.2017.05.002. Epub 2017 May 11. PMID: 28619295.
18. Shin ES, Seo KH, Lee SH, Jang JE, Jung YM, Kim MJ, Yeon JY. Massage with or without aromatherapy for symptom relief in people with cancer. Cochrane Database of Systematic Reviews. 2016;6:CD009873. doi: 10.1002/14651858.CD009873.pub3. PMID: 27258432; PMCID: PMC10406396.
20. Wilkinson SM, Love SB, Westcombe AM, Gambles MA, Burgess CC, Cargill A, Young T, Maher EJ, Ramirez AJ. Effectiveness of aromatherapy massage in the management of anxiety and depression in patients with cancer: A multicenter randomized controlled trial. J Clin Oncol. 2007 Feb 10;25(5):532–539. doi: 10.1200/JCO.2006.08.9987. PMID: 17290062.
21. Xiong M, Li Y, Tang P, Zhang Y, Cao M, Ni J, Xing M. Effectiveness of aromatherapy massage and inhalation on symptoms of depression in chinese community-dwelling older adults. J Altern Complement Med. 2018 Jul;24(7):717–724. doi: 10.1089/acm.2017.0320. Epub 2018 Mar 22. PMID: 29565630.
Depressive / anxious symptoms / Stress
13. Eguchi E, Funakubo N, Tomooka K, Ohira T, Ogino K, Tanigawa T. The effects of aroma foot massage on blood pressure and anxiety in japanese community-dwelling men and women: A crossover randomized controlled trial. PLoS One. 2016 Mar 24;11(3):e0151712. doi: 10.1371/journal.pone.0151712. PMID: 27010201; PMCID: PMC4807074.
Depressive / anxious symptoms / Major depressive disorder
16. Hou WH, Chiang PT, Hsu TY, Chiu SY, Yen YC. Treatment effects of massage therapy in depressed people: A meta-analysis. J Clin Psychiatry. 2010 Jul;71(7):894–901. doi: 10.4088/JCP.09r05009blu. Epub 2010 Mar 23. PMID: 20361919.
Depressive / anxious symptoms / Sleep
19. Wang WL, Hung HY, Chen YR, Chen KH, Yang SN, Chu CM, Chan YY. Effect of foot reflexology intervention on depression, anxiety, and sleep quality in adults: A meta-analysis and metaregression of randomized controlled trials. Evid Based Complement Alternat Med. 2020 Sep 15;2020:2654353. doi: 10.1155/2020/2654353. PMID: 33014101; PMCID: PMC7512096.
Sleep
22. Albayrak G, Çağlıyan Türk A, Özgül S. Effects of connective tissue massage on physical and emotional symptoms, insomnia, and quality of life in postmenopausal women: A randomized, sham-controlled trial. Maturitas. 2025 Jan;191:108149. doi: 10.1016/j.maturitas.2024.108149. Epub 2024 Nov 7. PMID: 39522476.
23. Arslan G, Ceyhan Ö, Mollaoğlu M. The influence of foot and back massage on blood pressure and sleep quality in females with essential hypertension: A randomized controlled study. J Hum Hypertens. 2021 Jul;35(7):627–637. doi: 10.1038/s41371-020-0371-z. Epub 2020 Jul 16. PMID: 32678299.
24. Ayik C, Özden D. The effects of preoperative aromatherapy massage on anxiety and sleep quality of colorectal surgery patients: A randomized controlled study. Complement Ther Med. 2018 Feb;36:93–99. doi: 10.1016/j.ctim.2017.12.002. Epub 2017 Dec 6. PMID: 29458940.
25. Feng G, Han M, Li X, Geng L, Miao Y. Clinical effectiveness of tui na for insomnia compared with estazolam: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2019 Dec;47:102186. doi: 10.1016/j.ctim.2019.08.020. Epub 2019 Oct 22. PMID: 31779989.
26. Gökbulut N, Ibici Akça E, Karakayali Ay Ç. The impact of foot massage given to postmenopausal women on anxiety, fatigue, and sleep: A randomized-controlled trial. Menopause. 2022 Nov 1;29(11):1254–1262. doi: 10.1097/GME.0000000000002062. Epub 2022 Sep 20. PMID: 36126237.
27. Gu HJ, Lee OS. Effects of non-pharmacological sleep interventions in older adults: A systematic review and meta-analysis. Int J Environ Res Public Health. 2023 Feb 10;20(4):3101. doi: 10.3390/ijerph20043101. PMID: 36833796; PMCID: PMC9966498.
28. Kim YJ, Kim HR, Jung YH, Park YH, Seo SW. Effects of electrical automatic massage on cognition and sleep quality in Alzheimer's disease spectrum patients: A randomized controlled trial. Yonsei Med J. 2021 Aug;62(8):717–725. doi: 10.3349/ymj.2021.62.8.717. PMID: 34296549; PMCID: PMC8298867.
29. Kırca AŞ, Çetin NŞ. The effect of classical foot massage on insomnia and anxiety in preeclamptic pregnant women: A randomized controlled study. Rev Assoc Med Bras (1992). 2024 Feb 26;70(2):e20230744. doi: 10.1590/1806-9282.20230744. PMID: 38422316; PMCID: PMC10903275.
30. Ko YL, Lee HJ. Randomised controlled trial of the effectiveness of using back massage to improve sleep quality among Taiwanese insomnia postpartum women. Midwifery. 2014 Jan;30(1):60–64. doi: 10.1016/j.midw.2012.11.005. Epub 2013 Feb 11. PMID: 23410501.
31. Koc M, Atar NY. The effect of hand massage on pain, comfort, and sleep quality in palliative care oncology patients. Support Care Cancer. 2026 Mar 12;34(4):308. doi: 10.1007/s00520-026-10558-5. PMID: 41813939; PMCID: PMC12979306.
32. Kudchadkar SR, Berger J, Patel R, Barnes S, Twose C, Walker T, Mitchell R, Song J, Anton B, Punjabi NM. Non-pharmacological interventions for sleep promotion in hospitalized children. Cochrane Database of Systematic Reviews. 2022;6:CD012908. doi: 10.1002/14651858.CD012908.pub2. PMID: 35703367; PMCID: PMC9199068.
33. Luo Y, He H, Cao C, Xu R, Tian X, Jiang G. Efficacy of non-pharmacological interventions on sleep quality in patients with cancer-related insomnia: A network meta-analysis. Front Neurol. 2024 Sep 20;15:1421469. doi: 10.3389/fneur.2024.1421469. PMID: 39372699; PMCID: PMC11449704.
34. Nerbass FB, Feltrim MI, Souza SA, Ykeda DS, Lorenzi-Filho G. Effects of massage therapy on sleep quality after coronary artery bypass graft surgery. Clinics (Sao Paulo). 2010;65(11):1105–1110. doi: 10.1590/s1807-59322010001100008. PMID: 21243280; PMCID: PMC2999703.
35. Oliveira DS, Hachul H, Goto V, Tufik S, Bittencourt LR. Effect of therapeutic massage on insomnia and climacteric symptoms in postmenopausal women. Climacteric. 2012 Feb;15(1):21–29. doi: 10.3109/13697137.2011.587557. Epub 2011 Oct 23. PMID: 22017318.
36. Pinar R, Afsar F. Back massage to decrease state anxiety, cortisol level, blood pressure, heart rate and increase sleep quality in family caregivers of patients with cancer: A randomised controlled trial. Asian Pac J Cancer Prev. 2015;16(18):8127–8133. doi: 10.7314/apjcp.2015.16.18.8127. PMID: 26745049.
37. Sarris J, Byrne GJ. A systematic review of insomnia and complementary medicine. Sleep Med Rev. 2011 Apr;15(2):99–106. doi: 10.1016/j.smrv.2010.04.001. Epub 2010 Jun 8. PMID: 20965131.
38. Tang H, Chen Z, Pang J, Mo Q. [Treatment of insomnia with shujing massage therapy: A randomized controlled trial]. Zhongguo Zhen Jiu. 2015 Aug;35(8):816–818. Chinese. PMID: 26571900.
39. Tien YT, Wang CJ, Chang CH, Chang YJ, Hung HY. Effects of effleurage massage on sleep quality in women hospitalized for high-risk pregnancies: A randomized crossover design. Appl Nurs Res. 2025 Jun;83:151955. doi: 10.1016/j.apnr.2025.151955. Epub 2025 Apr 11. PMID: 40473357.
40. Wang Z, Xu H, Wang Z, Zhou H, Zhang L, Wang Y, Li M, Zhou Y. Effect of tuina on sleep quality, psychological state and neurotransmitter level in patients with insomnia: A systematic review and meta-analysis. Front Neurol. 2024 Feb 21;15:1273194. doi: 10.3389/fneur.2024.1273194. PMID: 38450067; PMCID: PMC10914942.
41. Wang Z, Yang H, Li S, Cheng L, Yuan Y, Bai Y, Su J, Li Y, Wang T, Xu Z. Effectiveness of nonpharmacological interventions for menopause-related insomnia: A systematic review and Bayesian network meta-analysis. Maturitas. 2025 Nov;202:108713. doi: 10.1016/j.maturitas.2025.108713. Epub 2025 Aug 30. PMID: 40907338.
42. Yu Y, Wang H, Li W, Guo H, Chen Y. Non-pharmacological interventions for sleep in older adults: An umbrella review and evidence map of randomized controlled trials. Front Neurol. 2025 Sep 2;16:1655192. doi: 10.3389/fneur.2025.1655192. PMID: 40963939; PMCID: PMC12439529.
Stress
43. Baek JY, Lee E, Gil B, Jung HW, Jang IY. Clinical effects of using a massage chair on stress measures in adults: A pilot randomized controlled trial. Complement Ther Med. 2022 Jun;66:102825. doi: 10.1016/j.ctim.2022.102825. Epub 2022 Mar 24. PMID: 35339652.
44. Buttagat V, Eungpinichpong W, Chatchawan U, Kharmwan S. The immediate effects of traditional Thai massage on heart rate variability and stress-related parameters in patients with back pain associated with myofascial trigger points. J Bodyw Mov Ther. 2011 Jan;15(1):15–23. doi: 10.1016/j.jbmt.2009.06.005. Epub 2009 Jul 22. PMID: 21147414.
45. Chen PJ, Chou CC, Yang L, Tsai YL, Chang YC, Liaw JJ. Effects of aromatherapy massage on pregnant women's stress and immune function: A longitudinal, prospective, randomized controlled trial. J Altern Complement Med. 2017 Oct;23(10):778–786. doi: 10.1089/acm.2016.0426. Epub 2017 Aug 7. PMID: 28783372.
46. Krohn M, Listing M, Tjahjono G, Reisshauer A, Peters E, Klapp BF, Rauchfuss M. Depression, mood, stress, and Th1/Th2 immune balance in primary breast cancer patients undergoing classical massage therapy. Support Care Cancer. 2011 Sep;19(9):1303–1311. doi: 10.1007/s00520-010-0946-2. Epub 2010 Jul 20. PMID: 20644965.
47. Kurebayashi LFS, Gnatta JR, Kuba G, Giaponesi ALL, Souza TPB, Turrini RNT. Massage and reiki to reduce stress and improve quality of life: A randomized clinical trial. Rev Esc Enferm USP. 2020 Oct 12;54:e03612. doi: 10.1590/S1980-220X2018059103612. PMID: 33053005.
48. Liu MW, Shi YK, Zhang BC, Ma ZQ, He QK, Duan XY. Effect of acupoint application and massage on the comfort degree and stress state of patients undergoing noninvasive mechanical ventilation due to acute chronic obstructive pulmonary exacerbation in Dali, China. Niger J Clin Pract. 2025 Jul 1;28(7):838–847. doi: 10.4103/njcp.njcp_167_24. Epub 2025 Jul 28. PMID: 40717055.
49. Meier M, Unternaehrer E, Dimitroff SJ, Benz ABE, Bentele UU, Schorpp SM, Wenzel M, Pruessner JC. Standardized massage interventions as protocols for the induction of psychophysiological relaxation in the laboratory: A block randomized, controlled trial. Sci Rep. 2020 Sep 8;10(1):14774. doi: 10.1038/s41598-020-71173-w. PMID: 32901072; PMCID: PMC7479151.
50. Montibeler J, Domingos TDS, Braga EM, Gnatta JR, Kurebayashi LFS, Kurebayashi AK. Effectiveness of aromatherapy massage on the stress of the surgical center nursing team: A pilot study. Rev Esc Enferm USP. 2018 Aug 23;52:03348. doi: 10.1590/S1980-220X2017038303348. PMID: 30156654.
51. Sripongngam T, Eungpinichpong W, Sirivongs D, Kanpittaya J, Tangvoraphonkchai K, Chanaboon S. Psychological stress can be decreased by traditional Thai massage. J Med Assoc Thai. 2015 Jun;98 Suppl 5:S29–S35. PMID: 26387408.
52. Thadanatthaphak Y, Kanpittaya J, Takong W, Chanaboon S, Tudpor K. Immediate effects of Thai foot massage on renal blood flow, psychological stress, and heart rate variability in community-dwelling older adults: A randomized controlled trial. F1000Res. 2024 Jul 26;13:838. doi: 10.12688/f1000research.148453.1. PMID: 39569008; PMCID: PMC11576562.
53. Van Dijk W, Huizink AC, Müller J, Uvnäs-Moberg K, Ekström-Bergström A, Handlin L. The effect of mechanical massage and mental training on heart rate variability and cortisol in Swedish employees-a randomized explorative pilot study. Front Public Health. 2020 Mar 19;8:82. doi: 10.3389/fpubh.2020.00082. PMID: 32266197; PMCID: PMC7098265.
54. Wu CY, Lee HF, Chang CW, Chiang HC, Tsai YH, Liu HE. The immediate effects of lavender aromatherapy massage versus massage in work stress, burnout, and HRV parameters: A randomized controlled trial. Evid Based Complement Alternat Med. 2020 Nov 23;2020:8830083. doi: 10.1155/2020/8830083. PMID: 33488750; PMCID: PMC7803172.
Major depressive disorder
55. Field T, Deeds O, Diego M, Hernandez-Reif M, Gauler A, Sullivan S, Wilson D, Nearing G. Benefits of combining massage therapy with group interpersonal psychotherapy in prenatally depressed women. J Bodyw Mov Ther. 2009 Oct;13(4):297–303. doi: 10.1016/j.jbmt.2008.10.002. Epub 2009 Jan 31. PMID: 19761951; PMCID: PMC2785018.
56. Field T, Diego M, Hernandez-Reif M, Medina L, Delgado J, Hernandez A. Yoga and massage therapy reduce prenatal depression and prematurity. J Bodyw Mov Ther. 2012 Apr;16(2):204–209. doi: 10.1016/j.jbmt.2011.08.002. Epub 2011 Sep 23. PMID: 22464118; PMCID: PMC3319349.
57. Müller-Oerlinghausen B, Berg C, Droll W. Die Slow Stroke Massage als ein körpertherapeutischer Ansatz bei Depression [The efficacy of slow stroke massage in depression]. Psychiatr Prax. 2007 Sep;34 Suppl 3:S305–S308. German. doi: 10.1055/s-2007-970988. PMID: 17786889.
58. Poland RE, Gertsik L, Favreau JT, Smith SI, Mirocha JM, Rao U, Daar ES. Open-label, randomized, parallel-group controlled clinical trial of massage for treatment of depression in HIV-infected subjects. J Altern Complement Med. 2013 Apr;19(4):334–340. doi: 10.1089/acm.2012.0058. Epub 2012 Oct 25. PMID: 23098696; PMCID: PMC3627430.
ADHD
59. Chen SC, Yu BY, Suen LK, Yu J, Ho FY, Yang JJ, Yeung WF. Massage therapy for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents: A systematic review and meta-analysis. Complement Ther Med. 2019 Feb;42:389–399. doi: 10.1016/j.ctim.2018.12.011. Epub 2018 Dec 21. PMID: 30670272.
60. Chen SC, Yu J, Wang HS, Wang DD, Sun Y, Cheng HL, Suen LK, Yeung WF. Parent-administered pediatric tuina for attention deficit/hyperactivity disorder symptoms in preschool children: A pilot randomized controlled trial embedded with a process evaluation. Phytomedicine. 2022 Jul 20;102:154191. doi: 10.1016/j.phymed.2022.154191. Epub 2022 May 22. PMID: 35636174.
61. Field TM, Quintino O, Hernandez-Reif M, Koslovsky G. Adolescents with attention deficit hyperactivity disorder benefit from massage therapy. Adolescence. 1998 Spring;33(129):103–108. PMID: 9583664.
62. Khilnani S, Field T, Hernandez-Reif M, Schanberg S. Massage therapy improves mood and behavior of students with attention-deficit/hyperactivity disorder. Adolescence. 2003 Winter;38(152):623–638. PMID: 15053490.
63. Sibley MH, Bruton AM, Zhao X, Johnstone JM, Mitchell J, Hatsu I, Arnold LE, Basu HH, Levy L, Vyas P, Macphee F, Gonzalez ES, Kelley M, Jusko ML, Bolden CR, Zulauf-McCurdy C, Manzano M, Torres G. Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents. Lancet Child Adolesc Health. 2023 Jun;7(6):415–428. doi: 10.1016/S2352-4642(22)00381-9. Epub 2023 Mar 9. PMID: 36907194; PMCID: PMC10370370.
Autism
64. Escalona A, Field T, Singer-Strunck R, Cullen C, Hartshorn K. Brief report: Improvements in the behavior of children with autism following massage therapy. J Autism Dev Disord. 2001 Oct;31(5):513–516. doi: 10.1023/a:1012273110194. PMID: 11794416.
65. Fadlalmola HA, Abedelwahed HH, Hamid HI, Ali AB, Algadi HAA, Farg SJ, Ali NMA, Elbashir AA, Mohammed MH, Mohmmed SS, Mousa SA, Gaafar DA, Eltyeb AA. Effects of massage on self-regulatory difficulties, tactile and oral abnormalities, and parenting stress in children with autism spectrum disorder (ASD): A systematic review and meta-analysis. Int J Ther Massage Bodywork. 2024 Dec 12;17(4):4–19. doi: 10.3822/ijtmb.v17i4.1079. PMID: 39669546; PMCID: PMC11623315.
66. Lee MS, Kim JI, Ernst E. Massage therapy for children with autism spectrum disorders: A systematic review. J Clin Psychiatry. 2011 Mar;72(3):406–411. doi: 10.4088/JCP.09r05848whi. Epub 2010 Dec 28. PMID: 21208598.
67. Piravej K, Tangtrongchitr P, Chandarasiri P, Paothong L, Sukprasong S. Effects of Thai traditional massage on autistic children's behavior. J Altern Complement Med. 2009 Dec;15(12):1355–1361. doi: 10.1089/acm.2009.0258. PMID: 20001837.
68. Ruan H, Eungpinichpong W, Wu H, Aonsri C. Effects of parent-delivered traditional Thai massage on gait and heart rate variability in children with autism: A randomized controlled trial. J Integr Complement Med. 2024 Mar;30(3):269–278. doi: 10.1089/jicm.2023.0338. Epub 2023 Sep 15. PMID: 37713302; PMCID: PMC10954606.
69. Ruan H, Eungpinichpong W, Wu H, Shen M, Zhang A. Insufficient evidence for the efficacy of massage as intervention for autism spectrum disorder: A systematic review. Evid Based Complement Alternat Med. 2022 Sep 24;2022:5328320. doi: 10.1155/2022/5328320. PMID: 36193150; PMCID: PMC9526643.
70. Silva LM, Ayres R, Schalock M. Outcomes of a pilot training program in a qigong massage intervention for young children with autism. Am J Occup Ther. 2008 Sep–Oct;62(5):538–546. doi: 10.5014/ajot.62.5.538. PMID: 18826014.
71. Silva LM, Schalock M, Ayres R, Bunse C, Budden S. Qigong massage treatment for sensory and self-regulation problems in young children with autism: A randomized controlled trial. Am J Occup Ther. 2009 Jul–Aug;63(4):423–432. doi: 10.5014/ajot.63.4.423. PMID: 19708471.
72. Silva LM, Schalock M, Gabrielsen K. Early intervention for autism with a parent-delivered Qigong massage program: A randomized controlled trial. Am J Occup Ther. 2011 Sep–Oct;65(5):550–559. doi: 10.5014/ajot.2011.000661. PMID: 22026323.
Generalized anxiety disorder
73. Field T, Morrow C, Valdeon C, Larson S, Kuhn C, Schanberg S. Massage reduces anxiety in child and adolescent psychiatric patients. J Am Acad Child Adolesc Psychiatry. 1992 Jan;31(1):125–131. doi: 10.1097/00004583-199201000-00019. PMID: 1537763.
74. Rapaport MH, Schettler PJ, Larson ER, Edwards SA, Dunlop BW, Rakofsky JJ, Kinkead B. A preliminary descriptive report of the longevity of the effects of Swedish massage therapy for subjects with generalized anxiety disorder. J Bodyw Mov Ther. 2023 Jan;33:176–181. doi: 10.1016/j.jbmt.2022.11.001. Epub 2022 Nov 24. PMID: 36775516; PMCID: PMC12757998.
75. Rapaport MH, Schettler P, Larson ER, Edwards SA, Dunlop BW, Rakofsky JJ, Kinkead B. Acute Swedish massage monotherapy successfully remediates symptoms of generalized anxiety disorder: A proof-of-concept, randomized controlled study. J Clin Psychiatry. 2016 Jul;77(7):e883–e891. doi: 10.4088/JCP.15m10151. PMID: 27464321; PMCID: PMC11708495.
76. Rapaport MH, Schettler PJ, Larson ER, Dunlop BW, Rakofsky JJ, Kinkead B. Six versus twelve weeks of Swedish massage therapy for generalized anxiety disorder: Preliminary findings. Complement Ther Med. 2021 Jan;56:102593. doi: 10.1016/j.ctim.2020.102593. Epub 2020 Oct 14. PMID: 33197668; PMCID: PMC7770051.
77. Sherman KJ, Ludman EJ, Cook AJ, Hawkes RJ, Roy-Byrne PP, Bentley S, Brooks MZ, Cherkin DC. Effectiveness of therapeutic massage for generalized anxiety disorder: A randomized controlled trial. Depress Anxiety. 2010 May;27(5):441–450. doi: 10.1002/da.20671. PMID: 20186971; PMCID: PMC2922919.
Vitamin B6 References
35 references
Prolactinemia on antipsychotics
1. Zhuo C, Xu Y, Wang H, Fang T, Chen J, Zhou C, Li Q, Liu J, Xu S, Yao C, Yang W, Yang A, Li B, Chen Y, Tian H, Lin C. Safety and efficacy of high-dose vitamin B6 as an adjunctive treatment for antipsychotic-induced hyperprolactinemia in male patients with treatment-resistant schizophrenia. Front Psychiatry. 2021 Aug 26;12:681418. doi: 10.3389/fpsyt.2021.681418. PMID: 34512411; PMCID: PMC8426548.
Akathisia
2. Furukawa Y, Imai K, Takahashi Y, Efthimiou O, Leucht S. Comparative efficacy and acceptability of treatment strategies for antipsychotic-induced akathisia: A systematic review and network meta-analysis. Schizophr Bull. 2026 Mar 7;52(2):sbae098. doi: 10.1093/schbul/sbae098. PMID: 38869177; PMCID: PMC12996876.
3. Lerner V, Bergman J, Statsenko N, Miodownik C. Vitamin B6 treatment in acute neuroleptic-induced akathisia: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2004 Nov;65(11):1550–1554. doi: 10.4088/jcp.v65n1118. PMID: 15554771.
4. Miodownik C, Lerner V, Statsenko N, Dwolatzky T, Nemets B, Berzak E, Bergman J. Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: A randomized, double-blind, controlled study. Clin Neuropharmacol. 2006 Mar–Apr;29(2):68–72. doi: 10.1097/00002826-200603000-00002. PMID: 16614537.
5. Shams-Alizadeh N, Bakhshayesh H, Rezaei F, Ghaderi E, Shams-Alizadeh N, Hassanzadeh K. Effect of vitamin B6 versus propranolol on antipsychotic-induced akathisia: A pilot comparative double-blind study. Iran J Pharm Res. 2018 Winter;17(Suppl):130–135. PMID: 29796037; PMCID: PMC5958332.
Premenstrual syndrome
6. Barr W. Pyridoxine supplements in the premenstrual syndrome. Practitioner. 1984 Apr;228(1390):425–427. PMID: 6539473.
7. De Souza MC, Walker AF, Robinson PA, Bolland K. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: A randomized, double-blind, crossover study. J Womens Health Gend Based Med. 2000 Mar;9(2):131–139. doi: 10.1089/152460900318623. PMID: 10746516.
8. Diegoli MS, da Fonseca AM, Diegoli CA, Pinotti JA. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet. 1998 Jul;62(1):63–67. doi: 10.1016/s0020-7292(98)00035-6. PMID: 9722128.
9. Doll H, Brown S, Thurston A, Vessey M. Pyridoxine (vitamin B6) and the premenstrual syndrome: A randomized crossover trial. J R Coll Gen Pract. 1989 Sep;39(326):364–368. PMID: 2558186; PMCID: PMC1711872.
10. Hagen I, Nesheim BI, Tuntland T. No effect of vitamin B-6 against premenstrual tension. A controlled clinical study. Acta Obstet Gynecol Scand. 1985;64(8):667–670. doi: 10.3109/00016348509158211. PMID: 3914180.
11. Kashanian M, Mazinani R, Jalalmanesh S, Babayanzad Ahari S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet. 2007 Jan;96(1):43–44. doi: 10.1016/j.ijgo.2006.09.014. Epub 2006 Dec 21. PMID: 17187801.
12. Kendall KE, Schnurr PP. The effects of vitamin B6 supplementation on premenstrual symptoms. Obstet Gynecol. 1987 Aug;70(2):145–149. PMID: 3299182.
13. Malmgren R, Collins A, Nilsson CG. Platelet serotonin uptake and effects of vitamin B6-treatment in premenstrual tension. Neuropsychobiology. 1987;18(2):83–86. doi: 10.1159/000118398. PMID: 3330183.
14. Retallick-Brown H, Blampied N, Rucklidge JJ. A pilot randomized treatment-controlled trial comparing vitamin B6 with broad-spectrum micronutrients for premenstrual syndrome. J Altern Complement Med. 2020 Feb;26(2):88–97. doi: 10.1089/acm.2019.0305. Epub 2020 Jan 10. PMID: 31928364.
15. Sharma P, Kulshreshtha S, Singh GM, Bhagoliwal A. Role of bromocriptine and pyridoxine in premenstrual tension syndrome. Indian J Physiol Pharmacol. 2007 Oct–Dec;51(4):368–374. PMID: 18476391.
16. Stokes J, Mendels J. Pyridoxine and premenstrual tension. Lancet. 1972 May 27;1(7761):1177–1178. doi: 10.1016/s0140-6736(72)91399-2. PMID: 4113076.
17. Williams MJ, Harris RI, Dean BC. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res. 1985;13(3):174–179. doi: 10.1177/030006058501300305. PMID: 3891456.
18. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: Systematic review. BMJ. 1999 May 22;318(7195):1375–1381. doi: 10.1136/bmj.318.7195.1375.
Tardive dyskinesia
19. Artukoglu BB, Li F, Szejko N, Bloch MH. Pharmacologic treatment of tardive dyskinesia: A meta-analysis and systematic review. J Clin Psychiatry. 2020 May 26;81(4):19r12798. doi: 10.4088/JCP.19r12798.
20. Lerner V, Miodownik C, Kaptsan A, Bersudsky Y, Libov I, Sela BA, Witztum E. Vitamin B6 treatment for tardive dyskinesia: A randomized, double-blind, placebo-controlled, crossover study. J Clin Psychiatry. 2007 Nov;68(11):1648–1654. doi: 10.4088/jcp.v68n1103.
Tremor on lithium
21. Miodownik C, Witztum E, Lerner V. Lithium-induced tremor treated with vitamin B6: A preliminary case series. Int J Psychiatry Med. 2002;32(1):103–108. doi: 10.2190/DB1V-85M4-E65T-R3QA.
Extrapyramidal symptoms
22. Gimena J, Tello Margeli F. Syndrome extrapiramidal tratado con la vitamina B6 [Extrapyramidal syndrome treated with vitamin B6]. Bol Patol Med. 1948 Aug;3(8):151–153. Spanish.
23. Klapetek J. Extrapyramidaler Tremor und Vitamin B6 in hohen Dosen. Eine therapeutische Anmerkung [Extrapyramidal tremor and vitamin B6 in high doses. A therapeutic note]. Nervenarzt. 1970 May;41(5):251–255. German.
24. Lerner V, Miodownik C, Kaptsan A, Bersudsky Y, Libov I, Sela BA, Witztum E. Vitamin B6 treatment for tardive dyskinesia: A randomized, double-blind, placebo-controlled, crossover study. J Clin Psychiatry. 2007 Nov;68(11):1648–1654. doi: 10.4088/jcp.v68n1103.
Autism
25. Findling RL, Maxwell K, Scotese-Wojtila L, Huang J, Yamashita T, Wiznitzer M. High-dose pyridoxine and magnesium administration in children with autistic disorder: An absence of salutary effects in a double-blind, placebo-controlled study. J Autism Dev Disord. 1997 Aug;27(4):467–478. doi: 10.1023/a:1025861522935.
Bipolar mania
26. Akbarzadeh F, Talaei A, Nematy M, Ganji D, Ebrahimi A, Talaei A. Short-term effects of folate supplementation in combination with vitamin B6 for treating acute manic episodes in bipolar I disorder: A randomized controlled trial. Brain Behav. 2025 Apr;15(4):e70432. doi: 10.1002/brb3.70432.
27. Badrfam R, Mostafavi SA, Khaleghi A, Akhondzadeh S, Zandifar A, Farid M, Mohammadian Khonsari N, Mohammadi MR. The efficacy of vitamin B6 as an adjunctive therapy to lithium in improving the symptoms of acute mania in patients with bipolar disorder, type 1; a double-blind, randomized, placebo-controlled, clinical trial. Brain Behav. 2021 Nov;11(11):e2394. doi: 10.1002/brb3.2394. Epub 2021 Oct 17.
28. Zandifar A, Mousavi S, Schmidt NB, Badrfam R, Seif E, Qorbani M, Mehrabani Natanzi M. Efficacy of vitamins B1 and B6 as an adjunctive therapy to lithium in bipolar-I disorder: A double-blind, randomized, placebo-controlled, clinical trial. J Affect Disord. 2024 Jan 15;345:103–111. doi: 10.1016/j.jad.2023.10.121. Epub 2023 Oct 20.
Depressive / anxious symptoms in healthy adults
29. Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002 Jun;132(6):1345–1356. doi: 10.1093/jn/132.6.1345.
30. Curtin A, Johnston CS. Vitamin B6 supplementation reduces symptoms of depression in college women taking oral contraceptives: A randomized, double-blind crossover trial. J Diet Suppl. 2023;20(4):550–562. doi: 10.1080/19390211.2022.2030843. Epub 2022 Feb 2.
31. Deijen JB, van der Beek EJ, Orlebeke JF, van den Berg H. Vitamin B-6 supplementation in elderly men: Effects on mood, memory, performance and mental effort. Psychopharmacology (Berl). 1992;109(4):489–496. doi: 10.1007/BF02247729.
32. Field DT, Cracknell RO, Eastwood JR, Scarfe P, Williams CM, Zheng Y, Tavassoli T. High-dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression. Hum Psychopharmacol. 2022;37(6):e2852. doi: 10.1002/hup.2852. Epub 2022 Jul 19.
33. Noah L, Dye L, Bois De Fer B, Mazur A, Pickering G, Pouteau E. Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post-hoc analysis of a randomised controlled trial. Stress Health. 2021 Dec;37(5):1000–1009. doi: 10.1002/smi.3051. Epub 2021 May 6.
34. Pouteau E, Kabir-Ahmadi M, Noah L, Mazur A, Dye L, Hellhammer J, Pickering G, Dubray C. Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial. PLoS One. 2018 Dec 18;13(12):e0208454. doi: 10.1371/journal.pone.0208454.
Fibromyalgia
35. Ghavidel-Parsa B, Naeimi A, Gharibpoor F, Sattari N, Jafari A, Masooleh IS, Montazeri A. Effect of vitamin B6 on pain, disease severity, and psychological profile of fibromyalgia patients; A randomized, double-blinded clinical trial. BMC Musculoskelet Disord. 2022 Jul 13;23(1):664. doi: 10.1186/s12891-022-05637-7.
Vitamin B9 References
34 references
Mild cognitive impairment
1. Bai D, Fan J, Li M, Dong C, Gao Y, Fu M, Huang G, Liu H. Effects of folic acid combined with DHA supplementation on cognitive function and amyloid-beta-related biomarkers in older adults with mild cognitive impairment by a randomized, double blind, placebo-controlled trial. J Alzheimers Dis. 2021;81(1):155–167. doi: 10.3233/JAD-200997.
2. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208–216. doi: 10.1016/S0140-6736(07)60109-3.
3. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, Schneede J, Blom HJ, Hoefnagels WH, van Staveren WA. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: A randomized, placebo-controlled trial. Am J Clin Nutr. 2006 Aug;84(2):361–370. doi: 10.1093/ajcn/84.1.361.
4. Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: A randomized double-blind, placebo-controlled trial. Eur J Nutr. 2021 Jun;60(4):1795–1808. doi: 10.1007/s00394-020-02373-3. Epub 2020 Aug 28.
7. Ma F, Zhou X, Li Q, Zhao J, Song A, An P, Du Y, Xu W, Huang G. Effects of folic acid and vitamin B12, alone and in combination on cognitive function and inflammatory factors in the elderly with mild cognitive impairment: A single-blind experimental design. Curr Alzheimer Res. 2019;16(7):622–632. doi: 10.2174/1567205016666190725144629.
Mild cognitive impairment / Cognition
5. Liu Y, Yu Z, Cai Z, Zhao L, Wang Y, Guo Y, Su X, Miao Y, Yi B, Wang Y, Zhang X. Folic acid supplementation improves cognitive function in participants with cerebral small vascular disease-related cognitive impairment: A randomized controlled trial. J Prev Alzheimers Dis. 2026 Jan;13(1):100369. doi: 10.1016/j.tjpad.2025.100369. Epub 2025 Sep 12.
6. Ma F, Li Q, Zhou X, Zhao J, Song A, Li W, Liu H, Xu W, Huang G. Effects of folic acid supplementation on cognitive function and A-beta-related biomarkers in mild cognitive impairment: A randomized controlled trial. Eur J Nutr. 2019 Feb;58(1):345–356. doi: 10.1007/s00394-017-1598-5. Epub 2017 Dec 18.
Autism
8. Batebi N, Moghaddam HS, Hasanzadeh A, Fakour Y, Mohammadi MR, Akhondzadeh S. Folinic acid as adjunctive therapy in treatment of inappropriate speech in children with autism: A double-blind and placebo-controlled randomized trial. Child Psychiatry Hum Dev. 2021 Oct;52(5):928–938. doi: 10.1007/s10578-020-01072-8. Epub 2020 Oct 7.
9. Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: A randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247–256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18.
10. Panda PK, Sharawat IK, Saha S, Gupta D, Palayullakandi A, Meena K. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: A randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024 Nov;183(11):4827–4835. doi: 10.1007/s00431-024-05762-6. Epub 2024 Sep 7.
11. Renard E, Leheup B, Guéant-Rodriguez RM, Oussalah A, Quadros EV, Guéant JL. Folinic acid improves the score of autism in the EFFET placebo-controlled randomized trial. Biochimie. 2020 Jun;173:57–61. doi: 10.1016/j.biochi.2020.04.019. Epub 2020 May 7.
12. Zhang C, Chen Y, Hou F, Li Y, Wang W, Guo L, Zhang C, Li L, Lu C. Safety and efficacy of high-dose folinic acid in children with autism: The impact of folate metabolism gene polymorphisms. Nutrients. 2025 May 7;17(9):1602. doi: 10.3390/nu17091602.
13. Goldman ID, Chabner BA. Cerebral folate deficiency, autism, and the role of leucovorin. N Engl J Med. 2026 Feb 26;394(9):833–835. doi: 10.1056/NEJMp2516268. Epub 2026 Jan 21.
Dementia
14. Chen H, Liu S, Ji L, Wu T, Ji Y, Zhou Y, Zheng M, Zhang M, Xu W, Huang G. Folic acid supplementation mitigates Alzheimer’s disease by reducing inflammation: A randomized controlled trial. Mediators Inflamm. 2016;2016:5912146. doi: 10.1155/2016/5912146. Epub 2016 Jun 2.
15. Connelly PJ, Prentice NP, Cousland G, Bonham J. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry. 2008 Feb;23(2):155–160. doi: 10.1002/gps.1856.
Major depressive disorder / Schizophrenia
16. Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392–395. doi: 10.1016/0140-6736(90)91942-4.
Major depressive disorder
17. Kakar SM, Jehangir S, Mustafa M, Khattak H. Therapeutic efficacy of combination therapy of L-methylfolate and escitalopram in depression. PAFMJ. 2017;67(6):976–981.
18. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012 Dec;169(12):1267–1274. doi: 10.1176/appi.ajp.2012.11071114.
19. Bedson E, Bell D, Carr D, Carter B, Hughes D, Jorgensen A, Lewis H, Lloyd K, McCaddon A, Moat S, Pink J, Pirmohamed M, Roberts S, Russell I, Sylvestre Y, Tranter R, Whitaker R, Wilkinson C, Williams N. Folate augmentation of treatment--evaluation for depression (FolATED): Randomised trial and economic evaluation. Health Technol Assess. 2014 Jul;18(48):vii–viii, 1–159. doi: 10.3310/hta18480.
20. de Koning EJ, van der Zwaluw NL, van Wijngaarden JP, Sohl E, Brouwer-Brolsma EM, van Marwijk HW, Enneman AW, Swart KM, van Dijk SC, Ham AC, van der Velde N, Uitterlinden AG, Penninx BW, Elders PJ, Lips P, Dhonukshe-Rutten RA, van Schoor NM, de Groot LC. Effects of two-year vitamin B12 and folic acid supplementation on depressive symptoms and quality of life in older adults with elevated homocysteine concentrations: Additional results from the B-PROOF study, an RCT. Nutrients. 2016 Nov 23;8(11):748. doi: 10.3390/nu8110748.
21. Maruf AA, Poweleit EA, Brown LC, Strawn JR, Bousman CA. Systematic review and meta-analysis of L-methylfolate augmentation in depressive disorders. Pharmacopsychiatry. 2022 May;55(3):139–147. doi: 10.1055/a-1681-2047. Epub 2021 Nov 18.
22. Venkatasubramanian R, Kumar CN, Pandey RS. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J Affect Disord. 2013 Sep 5;150(2):644–648. doi: 10.1016/j.jad.2013.02.029. Epub 2013 Mar 15.
Anorexia
23. Loria-Kohen V, Gómez-Candela C, Palma-Milla S, Amador-Sastre B, Hernanz A, Bermejo LM. A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders. Nutr Hosp. 2013 May–Jun;28(3):807–815. doi: 10.3305/nh.2013.28.3.6335.
Bipolar depression
24. Nierenberg AA, Montana R, Kinrys G, Deckersbach T, Dufour S, Baek JH. L-Methylfolate for bipolar I depressive episodes: An open trial proof-of-concept registry. J Affect Disord. 2017 Jan 1;207:429–433. doi: 10.1016/j.jad.2016.09.053. Epub 2016 Oct 1.
25. Simon J, Geddes JR, Gardiner A, Rendell J, Goodwin GM, Mayer S. Comparative economic evaluation of quetiapine plus lamotrigine combination vs quetiapine monotherapy (and folic acid vs placebo) in patients with bipolar depression (CEQUEL). Bipolar Disord. 2018 Dec;20(8):733–745. doi: 10.1111/bdi.12713. Epub 2018 Dec 17.
Bipolar mania
26. Akbarzadeh F, Talaei A, Nematy M, Ganji D, Ebrahimi A, Talaei A. Short-term effects of folate supplementation in combination with vitamin B6 for treating acute manic episodes in bipolar I disorder: A randomized controlled trial. Brain Behav. 2025 Apr;15(4):e70432. doi: 10.1002/brb3.70432.
27. Behzadi AH, Omrani Z, Chalian M, Asadi S, Ghadiri M. Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: A double-blind randomized controlled trial. Acta Psychiatr Scand. 2009 Dec;120(6):441–445. doi: 10.1111/j.1600-0447.2009.01368.x. Epub 2009 Mar 10.
Schizophrenia
28. Hill M, Shannahan K, Jasinski S, Macklin EA, Raeke L, Roffman JL, Goff DC. Folate supplementation in schizophrenia: A possible role for MTHFR genotype. Schizophr Res. 2011 Apr;127(1–3):41–45. doi: 10.1016/j.schres.2010.12.006. Epub 2011 Feb 21.
29. Roffman JL, Petruzzi LJ, Tanner AS, Brown HE, Eryilmaz H, Ho NF, Giegold M, Silverstein NJ, Bottiglieri T, Manoach DS, Smoller JW, Henderson DC, Goff DC. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: A randomized controlled trial. Mol Psychiatry. 2018 Feb;23(2):316–322. doi: 10.1038/mp.2017.41. Epub 2017 Mar 14.
Sexual function in postmenopausal women
30. Asadi M, Riazi H, Abbasinazari M, Majd HA, Montazeri A. Effect of folic acid on the sexual function of postmenopausal women: A triple-blind randomized controlled trial. J Sex Med. 2023 Aug 25;20(9):1180–1187. doi: 10.1093/jsxmed/qdad086.
ADHD
31. Surman C, Ceranoglu A, Vaudreuil C, Albright B, Uchida M, Yule A, Spencer A, Boland H, Grossman R, Rhodewalt L, Fitzgerald M, Biederman J. Does L-methylfolate supplement methylphenidate pharmacotherapy in attention-deficit/hyperactivity disorder?: Evidence of lack of benefit from a double-blind, placebo-controlled, randomized clinical trial. J Clin Psychopharmacol. 2019 Jan/Feb;39(1):28–38. doi: 10.1097/JCP.0000000000000990.
Depression in healthy adults
32. Sharpley AL, Hockney R, McPeake L, Geddes JR, Cowen PJ. Folic acid supplementation for prevention of mood disorders in young people at familial risk: A randomised, double blind, placebo controlled trial. J Affect Disord. 2014;167:306–311. doi: 10.1016/j.jad.2014.06.011. Epub 2014 Jun 20.
33. Williams E, Stewart-Knox B, Bradbury I, Rowland I, Pentieva K, Helander A, McNulty H. Effect of folic acid supplementation on mood and serotonin response in healthy males. Br J Nutr. 2005 Oct;94(4):602–608. doi: 10.1079/bjn20051501.
OCD
34. Tural Ü, Çorapçıoğlu A, Boşgelmez Ş, Köroğlu G, Ünver H, Duman C, Önder E. Double blind controlled study of adding folic acid to fluoxetine in the treatment of OCD. Psychiatr Danub. 2019 Mar;31(1):69–77. doi: 10.24869/psyd.2019.69.
Vitamin B12 References
13 references
Autism
1. Bertoglio K, Jill James S, Deprey L, Brule N, Hendren RL. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010 May;16(5):555–560. doi: 10.1089/acm.2009.0177.
2. Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, Bent S. Randomized, placebo-controlled trial of methyl B12 for children with autism. J Child Adolesc Psychopharmacol. 2016;26(9):774–783. doi: 10.1089/cap.2015.0159. Epub 2016 Feb 18.
Prevention of cognitive decline
3. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: A randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774–1783. doi: 10.1001/jama.300.15.1774.
4. Dangour AD, Allen E, Clarke R, Elbourne D, Fletcher AE, Letley L, Richards M, Whyte K, Uauy R, Mills K. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: A randomized controlled trial. Am J Clin Nutr. 2015 Sep;102(3):639–647. doi: 10.3945/ajcn.115.110775. Epub 2015 Jul 1.
5. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, Schneede J, Blom HJ, Hoefnagels WH, van Staveren WA. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: A randomized, placebo-controlled trial. Am J Clin Nutr. 2006 Aug;84(2):361–370. doi: 10.1093/ajcn/84.1.361.
6. Kvestad I, Taneja S, Upadhyay RP, Hysing M, Bhandari N, Strand TA. Vitamin B12, folate, and cognition in 6- to 9-year-olds: A randomized controlled trial. Pediatrics. 2020 Mar;145(3):e20192316. doi: 10.1542/peds.2019-2316. Epub 2020 Feb 4.
7. Kwok T, Lee J, Ma RC, Wong SY, Kung K, Lam A, Ho CS, Lee V, Harrison J, Lam L. A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12. Clin Nutr. 2017 Dec;36(6):1509–1515. doi: 10.1016/j.clnu.2016.10.018. Epub 2016 Oct 27.
8. Ma F, Zhou X, Li Q, Zhao J, Song A, An P, Du Y, Xu W, Huang G. Effects of folic acid and vitamin B12, alone and in combination on cognitive function and inflammatory factors in the elderly with mild cognitive impairment: A single-blind experimental design. Curr Alzheimer Res. 2019;16(7):622–632. doi: 10.2174/1567205016666190725144629.
9. Zhou L, Bai X, Huang J, Tan Y, Yang Q. Vitamin B12 supplementation improves cognitive function in middle aged and elderly patients with cognitive impairment. Nutr Hosp. 2023 Aug 28;40(4):724–731. doi: 10.20960/nh.04394.
Prevention of depression
10. Walker JG, Mackinnon AJ, Batterham P, Jorm AF, Hickie I, McCarthy A, Fenech M, Christensen H. Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: Randomised controlled trial. Br J Psychiatry. 2010 Jul;197(1):45–54. doi: 10.1192/bjp.bp.109.075291.
Seasonal affective disorder
11. Oren DA, Teicher MH, Schwartz PJ, Glod C, Turner EH, Ito YN, Sedway J, Rosenthal NE, Wehr TA. A controlled trial of cyanocobalamin (vitamin B12) in the treatment of winter seasonal affective disorder. J Affect Disord. 1994 Nov;32(3):197–200. doi: 10.1016/0165-0327(94)90018-3.
Schizophrenia
12. Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013 May;70(5):481–489. doi: 10.1001/jamapsychiatry.2013.900.
Delayed sleep phase (insomnia in night owls)
13. Okawa M, Takahashi K, Egashira K, Furuta H, Higashitani Y, Higuchi T, Ichikawa H, Ichimaru Y, Inoue Y, Ishizuka Y, Ito N, Kamei K, Kaneko M, Kim Y, Kohsaka M, Komori T, Kotorii T, Matsumoto M, Mishima K, Mizuki Y, Morimoto K, Nagayama H, Ohta T, Okamoto N, Sakamoto K, Shirakawa S, Sugita Y, Tamiya S, Yamada N, Yamadera H, Yamazaki J, Takahashi S. Vitamin B12 treatment for delayed sleep phase syndrome: A multi-center double-blind study. Psychiatry Clin Neurosci. 1997 Oct;51(5):275–279. doi: 10.1111/j.1440-1819.1997.tb03198.x.
Vitamin D References
36 references
Major depressive disorder
1. Alavi NM, Khademalhoseini S, Vakili Z, Assarian F. Effect of vitamin D supplementation on depression in elderly patients: A randomized clinical trial. Clin Nutr. 2019;38(5):2065–2070. doi: 10.1016/j.clnu.2018.09.011. Epub 2018 Sep 19.
2. Alghamdi S, Alsulami N, Khoja S, Alsufiani H, Tayeb HO, Tarazi FI. Vitamin D supplementation ameliorates severity of major depressive disorder. J Mol Neurosci. 2020 Feb;70(2):230–235. doi: 10.1007/s12031-019-01461-2. Epub 2019 Dec 13.
3. Amini S, Amani R, Jafarirad S, Cheraghian B, Sayyah M, Hemmati AA. The effect of vitamin D and calcium supplementation on inflammatory biomarkers, estradiol levels and severity of symptoms in women with postpartum depression: A randomized double-blind clinical trial. Nutr Neurosci. 2022 Jan;25(1):22–32. doi: 10.1080/1028415X.2019.1707396. Epub 2020 Jan 3.
4. Frandsen TB, Pareek M, Hansen JP, Nielsen CT. Vitamin D supplementation for treatment of seasonal affective symptoms in healthcare professionals: A double-blind randomised placebo-controlled trial. BMC Res Notes. 2014 Aug 14;7:528. doi: 10.1186/1756-0500-7-528.
5. Hansen JP, Pareek M, Hvolby A, Schmedes A, Toft T, Dahl E, Nielsen CT. Vitamin D3 supplementation and treatment outcomes in patients with depression (D3-vit-dep). BMC Res Notes. 2019 Apr 3;12(1):203. doi: 10.1186/s13104-019-4218-z.
6. Kaviani M, Nikooyeh B, Etesam F, Behnagh SJ, Kangarani HM, Arefi M, Yaghmaei P, Neyestani TR. Effects of vitamin D supplementation on depression and some selected pro-inflammatory biomarkers: A double-blind randomized clinical trial. BMC Psychiatry. 2022 Nov 11;22(1):694. doi: 10.1186/s12888-022-04305-3.
7. Kaviani M, Nikooyeh B, Zand H, Yaghmaei P, Neyestani TR. Effects of vitamin D supplementation on depression and some involved neurotransmitters. J Affect Disord. 2020 May 15;269:28–35. doi: 10.1016/j.jad.2020.03.029. Epub 2020 Mar 13.
8. Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A, Djazayery A. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013 Mar;47(3):271–275. doi: 10.1177/0004867412465022. Epub 2012 Oct 23.
9. Kumar PNS, Menon V, Andrade C. A randomized, double-blind, placebo-controlled, 12-week trial of vitamin D augmentation in major depressive disorder associated with vitamin D deficiency. J Affect Disord. 2022 Oct 1;314:143–149. doi: 10.1016/j.jad.2022.07.014. Epub 2022 Jul 16.
10. Libuda L, Timmesfeld N, Antel J, Hirtz R, Bauer J, Führer D, Zwanziger D, Öztürk D, Langenbach G, Hahn D, Ring S, Peters T, Hinney A, Bühlmeier J, Hebebrand J, Grasemann C, Föcker M. Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: Results of a randomized controlled trial. Eur J Nutr. 2020 Dec;59(8):3415–3424. doi: 10.1007/s00394-020-02176-6. Epub 2020 Feb 27.
11. Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM, Hadinedoushan H, Barzegar K. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: A randomized clinical trial. J Clin Psychopharmacol. 2013 Jun;33(3):378–385. doi: 10.1097/JCP.0b013e31828f619a.
12. Mustonen A, Taipale H, Denissoff A, Ellilä V, Di Forti M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J, Niemelä S. Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis. Br J Psychiatry. 2025 May 6;228(4):1–7. doi: 10.1192/bjp.2025.72. Epub ahead of print.
13. Rahman ST, Waterhouse M, Romero BD, Baxter C, English DR, Almeida OP, Berk M, Ebeling PR, Armstrong BK, McLeod DSA, Hartel G, O'Connell RL, Pham H, Scott JG, van der Pols JC, Venn AJ, Webb PM, Whiteman DC, Neale RE. Effect of vitamin D supplementation on depression in older Australian adults. Int J Geriatr Psychiatry. 2023 Jan;38(1):e5847. doi: 10.1002/gps.5847.
14. Vellekkatt F, Menon V, Rajappa M, Sahoo J. Effect of adjunctive single dose parenteral vitamin D supplementation in major depressive disorder with concurrent vitamin D deficiency: A double-blind randomized placebo-controlled trial. J Psychiatr Res. 2020 Oct;129:250–256. doi: 10.1016/j.jpsychires.2020.07.037. Epub 2020 Aug 4.
15. Zhao W, Zhu DM, Shen Y, Zhang Y, Chen T, Cai H, Zhu J, Yu Y. The protective effect of vitamin D supplementation as adjunctive therapy to antidepressants on brain structural and functional connectivity of patients with major depressive disorder: A randomized controlled trial. Psychol Med. 2024 Jul;54(10):2403–2413. doi: 10.1017/S0033291724000539. Epub 2024 Mar 14.
Depressive symptoms in type 2 diabetes / Cognition
16. Jones KE, Riek AE, Castelblanco E, Oh J, Porta D, Villatoro C, Carney RM, Dusso AS, Bernal-Mizrachi C. The effect of vitamin D supplementation on mental and functional health outcomes in African Americans with type 2 diabetes. J Steroid Biochem Mol Biol. 2025 Apr;248:106698. doi: 10.1016/j.jsbmb.2025.106698. Epub 2025 Feb 12.
Depressive symptoms in type 2 diabetes
17. Fazelian S, Amani R, Paknahad Z, Kheiri S, Khajehali L. Effect of vitamin D supplement on mood status and inflammation in vitamin D deficient type 2 diabetic women with anxiety: A randomized clinical trial. Int J Prev Med. 2019 Feb 12;10:17. doi: 10.4103/ijpvm.IJPVM_174_18.
18. Omidian M, Mahmoudi M, Abshirini M, Eshraghian MR, Javanbakht MH, Zarei M, Hasani H, Djalali M. Effects of vitamin D supplementation on depressive symptoms in type 2 diabetes mellitus patients: Randomized placebo-controlled double-blind clinical trial. Diabetes Metab Syndr. 2019 Jul–Aug;13(4):2375–2380. doi: 10.1016/j.dsx.2019.06.011. Epub 2019 Jun 11.
19. Penckofer S, Ridosh M, Adams W, Grzesiak M, Woo J, Byrn M, Kouba J, Sheean P, Kordish C, Durazo-Arvizu R, Wallis D, Emanuele MA, Halaris A. Vitamin D supplementation for the treatment of depressive symptoms in women with type 2 diabetes: A randomized clinical trial. J Diabetes Res. 2022 Mar 3;2022:4090807. doi: 10.1155/2022/4090807.
20. Putranto R, Setiati S, Nasrun MW, Witjaksono F, Immanuel S, Subekti I, Harimurti K, Siswanto A, Shatri H, Suwarto S, Megantara MA. Effects of cholecalciferol supplementation on depressive symptoms, C-peptide, serotonin, and neurotrophin-3 in type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial. Narra J. 2024 Dec;4(3):e1342. doi: 10.52225/narra.v4i3.1342. Epub 2024 Oct 30.
Long COVID
21. Atieh O, Daher J, Durieux JC, Abboud M, Labbato D, Baissary J, Koberssy Z, Ailstock K, Cummings M, Funderburg NT, McComsey GA. Vitamins K2 and D3 improve long COVID, fungal translocation, and inflammation: Randomized controlled trial. Nutrients. 2025;17(2):304. Published 2025 Jan 16. doi: 10.3390/nu17020304.
22. Charoenporn V, Tungsukruthai P, Teacharushatakit P, Hanvivattanakul S, Sriyakul K, Sukprasert S, Kamalashiran C, Tungsukruthai S, Charernboon T. Effects of an 8-week high-dose vitamin D supplementation on fatigue and neuropsychiatric manifestations in post-COVID syndrome: A randomized controlled trial. Psychiatry Clin Neurosci. 2024 Oct;78(10):595–604. doi: 10.1111/pcn.13716. Epub 2024 Jul 28.
23. Rodríguez-Morán M, Guerrero-Romero F, Barragán-Zuñiga J, Gamboa-Gómez CI, Weyman-Vela Y, Arce-Quiñones M, Simental-Mendía LE, Martínez-Aguilar G. Combined oral supplementation with magnesium plus vitamin D alleviates mild to moderate depressive symptoms related to long-COVID: An open-label randomized, controlled clinical trial. Magnes Res. 2024;37(3):143–151. doi: 10.1684/mrh.2024.0535.
Sleep quality
24. Majid MS, Ahmad HS, Bizhan H, Hosein HZM, Mohammad A. The effect of vitamin D supplement on the score and quality of sleep in 20-50 year-old people with sleep disorders compared with control group. Nutr Neurosci. 2018 Sep;21(7):511–519. doi: 10.1080/1028415X.2017.1317395. Epub 2017 May 5.
25. Miao Y, Zhang L, Zhang D, Feng M, Zhang C, Zhao T, Song H, Zhong X, Jiang Z, Li L, Wei X, Li W, Li X. Effects of vitamin D and/or calcium intervention on sleep quality in individuals with prediabetes: A post hoc analysis of a randomized controlled trial. Eur J Nutr. 2024 Jun;63(4):1187–1201. doi: 10.1007/s00394-024-03345-7. Epub 2024 Feb 16.
ADHD in children
26. Hemamy M, Pahlavani N, Amanollahi A, Islam SMS, McVicar J, Askari G, Malekahmadi M. The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: A randomized controlled trial. BMC Pediatr. 2021 Apr 17;21(1):178. doi: 10.1186/s12887-021-02631-1.
27. Mirhosseini H, Maayeshi N, Hooshmandi H, Moradkhani S, Hosseinzadeh M. The effect of vitamin D supplementation on the brain mapping and behavioral performance of children with ADHD: A double-blinded randomized controlled trials. Nutr Neurosci. 2024 Jun;27(6):566–576. doi: 10.1080/1028415X.2023.2233752. Epub 2023 Jul 25.
28. Mohammadpour N, Jazayeri S, Tehrani-Doost M, Djalali M, Hosseini M, Effatpanah M, Davari-Ashtiani R, Karami E. Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double blind, placebo-controlled trial. Nutr Neurosci. 2018 Apr;21(3):202–209. doi: 10.1080/1028415X.2016.1262097. Epub 2016 Dec 7.
29. Rahmani M, Mahvelati A, Farajinia AH, Shahyad S, Khaksarian M, Nooripour R, Hassanvandi S. Comparison of vitamin D, neurofeedback, and neurofeedback combined with vitamin D supplementation in children with attention-deficit/hyperactivity disorder. Arch Iran Med. 2022 May 1;25(5):285–393. doi: 10.34172/aim.2022.47.
Autism in children
30. Dehbokri N, Noorazar G, Ghaffari A, Mehdizadeh G, Sarbakhsh P, Ghaffary S. Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder. World J Pediatr. 2019 Feb;15(1):78–84. doi: 10.1007/s12519-018-0209-8. Epub 2018 Nov 19.
31. Javadfar Z, Abdollahzad H, Moludi J, Rezaeian S, Amirian H, Foroughi AA, Nachvak SM, Goharmehr N, Mostafai R. Effects of vitamin D supplementation on core symptoms, serum serotonin, and interleukin-6 in children with autism spectrum disorders: A randomized clinical trial. Nutrition. 2020 Nov–Dec;79–80:110986. doi: 10.1016/j.nut.2020.110986. Epub 2020 Aug 28.
32. Kerley CP, Power C, Gallagher L, Coghlan D. Lack of effect of vitamin D3 supplementation in autism: A 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030–1036. doi: 10.1136/archdischild-2017-312783. Epub 2017 Jun 16.
33. Mazahery H, Conlon CA, Beck KL, Mugridge O, Kruger MC, Stonehouse W, Camargo CA Jr, Meyer BJ, Jones B, von Hurst PR. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with autism spectrum disorder. J Steroid Biochem Mol Biol. 2019 Mar;187:9–16. doi: 10.1016/j.jsbmb.2018.10.017. Epub 2018 Oct 26.
Dementia / Cognition
34. Jia J, Hu J, Huo X, Miao R, Zhang Y, Ma F. Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer's disease: A randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1347–1352. doi: 10.1136/jnnp-2018-320199. Epub 2019 Jul 11.
Generalized anxiety disorder
35. Eid A, Khoja S, AlGhamdi S, Alsufiani H, Alzeben F, Alhejaili N, Tayeb HO, Tarazi FI. Vitamin D supplementation ameliorates severity of generalized anxiety disorder (GAD). Metab Brain Dis. 2019 Dec;34(6):1781–1786. doi: 10.1007/s11011-019-00486-1. Epub 2019 Sep 2.
Opioid use disorder on maintenance addiction therapy / Cognition
36. Ghaderi A, Rasouli-Azad M, Farhadi MH, Mirhosseini N, Motmaen M, Pishyareh E, Omidi A, Asemi Z. Exploring the effects of vitamin D supplementation on cognitive functions and mental health status in subjects under methadone maintenance treatment. J Addict Med. 2020 Jan/Feb;14(1):18–25. doi: 10.1097/ADM.0000000000000550.
Vitamin E References
16 references
Premenstrual syndrome
1. Ataei-Almanghadim K, Farshbaf-Khalili A, Ostadrahimi AR, Shaseb E, Mirghafourvand M. The effect of oral capsule of curcumin and vitamin E on the hot flashes and anxiety in postmenopausal women: A triple blind randomised controlled trial. Complement Ther Med. 2020 Jan;48:102267. doi: 10.1016/j.ctim.2019.102267. Epub 2019 Nov 26.
Sleep
2. Thongchumnum W, Vallibhakara SA, Sophonsritsuk A, Vallibhakara O. Effect of vitamin E supplementation on chronic insomnia disorder in postmenopausal women: A prospective, double-blinded randomized controlled trial. Nutrients. 2023 Feb 27;15(5):1187. doi: 10.3390/nu15051187.
Tardive dyskinesia
3. Adler LA, Edson R, Lavori P, Peselow E, Duncan E, Rosenthal M, Rotrosen J. Long-term treatment effects of vitamin E for tardive dyskinesia. Biol Psychiatry. 1998 Jun 15;43(12):868–872. doi: 10.1016/s0006-3223(97)00027-9.
4. Adler LA, Peselow E, Rotrosen J, Duncan E, Lee M, Rosenthal M, Angrist B. Vitamin E treatment of tardive dyskinesia. Am J Psychiatry. 1993 Sep;150(9):1405–1407. doi: 10.1176/ajp.150.9.1405.
5. Adler LA, Rotrosen J, Edson R, Lavori P, Lohr J, Hitzemann R, Raisch D, Caligiuri M, Tracy K; Veterans Affairs Cooperative Study #394 Study Group. Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry. 1999 Sep;56(9):836–841. doi: 10.1001/archpsyc.56.9.836.
6. Akhtar S, Jajor TR, Kumar S. Vitamin E in the treatment of tardive dyskinesia. J Postgrad Med. 1993 Jul–Sep;39(3):124–126. PMID: 7914238.
7. Dabiri LM, Pasta D, Darby JK, Mosbacher D. Effectiveness of vitamin E for treatment of long-term tardive dyskinesia. Am J Psychiatry. 1994 Jun;151(6):925–926. doi: 10.1176/ajp.151.6.925.
8. Dorevitch A, Kalian M, Shlafman M, Lerner V. Treatment of long-term tardive dyskinesia with vitamin E. Biol Psychiatry. 1997 Jan 1;41(1):114–116. doi: 10.1016/s0006-3223(96)00367-8.
9. Egan MF, Hyde TM, Albers GW, Elkashef A, Alexander RC, Reeve A, Blum A, Saenz RE, Wyatt RJ. Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry. 1992 Jun;149(6):773–777. doi: 10.1176/ajp.149.6.773.
10. Elkashef AM, Ruskin PE, Bacher N, Barrett D. Vitamin E in the treatment of tardive dyskinesia. Am J Psychiatry. 1990 Apr;147(4):505–506. doi: 10.1176/ajp.147.4.505.
11. Lam LC, Chiu HF, Hung SF. Vitamin E in the treatment of tardive dyskinesia: A replication study. J Nerv Ment Dis. 1994 Feb;182(2):113–114. doi: 10.1097/00005053-199402000-00009.
12. Lohr JB, Cadet JL, Lohr MA, Jeste DV, Wyatt RJ. Alpha-tocopherol in tardive dyskinesia. Lancet. 1987 Apr 18;1(8538):913–914. doi: 10.1016/s0140-6736(87)92878-9.
13. Lohr JB, Cadet JL, Lohr MA, Larson L, Wasli E, Wade L, Hylton R, Vidoni C, Jeste DV, Wyatt RJ. Vitamin E in the treatment of tardive dyskinesia: The possible involvement of free radical mechanisms. Schizophr Bull. 1988;14(2):291–296. doi: 10.1093/schbul/14.2.291.
14. Lohr JB, Caligiuri MP. A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. J Clin Psychiatry. 1996 Apr;57(4):167–173.
15. Sajjad SH. Vitamin E in the treatment of tardive dyskinesia: A preliminary study over 7 months at different doses. Int Clin Psychopharmacol. 1998 Jul;13(4):147–155. doi: 10.1097/00004850-199807000-00001.
16. Shriqui CL, Bradwejn J, Annable L, Jones BD. Vitamin E in the treatment of tardive dyskinesia: A double-blind placebo-controlled study. Am J Psychiatry. 1992 Mar;149(3):391–393. doi: 10.1176/ajp.149.3.391.
Iron References
20 references
Depressive symptoms
1. McClung JP, Karl JP, Cable SJ, Williams KW, Nindl BC, Young AJ, Lieberman HR. Randomized, double-blind, placebo-controlled trial of iron supplementation in female soldiers during military training: Effects on iron status, physical performance, and mood. Am J Clin Nutr. 2009 Jul;90(1):124–131. doi: 10.3945/ajcn.2009.27774. Epub 2009 May 27.
2. Dugan C, Peeling P, Buissink P, MacLean B, Lim J, Jayasuriya P, Richards T. Effect of intravenous iron therapy on exercise performance, fatigue scores and mood states in iron-deficient recreationally active females of reproductive age: A double-blind, randomised control trial (IRONWOMAN trial). Br J Sports Med. 2025 Jun 18;59(13):921–930. doi: 10.1136/bjsports-2024-108240.
3. Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Lüscher TF, Mori C, Willenheimer R, Ponikowski P, Anker SD. The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: A subanalysis of the FAIR-HF study. Eur Heart J. 2013 Jan;34(1):30–38. doi: 10.1093/eurheartj/ehr504. Epub 2012 Jan 31.
Fatigue
4. Booth CK, Carins JE, Robertson IK. Randomised double-blind, placebo-controlled trial of iron supplementation attenuates fatigue and declining iron stores for female officers-in-training. J Mil Veterans’ Health. 2014;22(3):13–24.
5. Vaucher P, Druais PL, Waldvogel S, Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: A randomized controlled trial. CMAJ. 2012 Aug 7;184(11):1247–1254. doi: 10.1503/cmaj.110950. Epub 2012 Jul 9.
6. Krayenbuehl PA, Battegay E, Breymann C, Furrer J, Schulthess G. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood. 2011 Sep 22;118(12):3222–3227. doi: 10.1182/blood-2011-04-346304. Epub 2011 Jun 24.
7. D’Adamo CR, Novick JS, Feinberg TM, Dawson VJ, Miller LE. A food-derived dietary supplement containing a low dose of iron improved markers of iron status among nonanemic iron-deficient women. J Am Coll Nutr. 2018 May–Jun;37(4):342–349. doi: 10.1080/07315724.2018.1427158. Epub 2018 Mar 13.
8. Favrat B, Balck K, Breymann C, Hedenus M, Keller T, Mezzacasa A, Gasche C. Evaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women--PREFER a randomized, placebo-controlled study. PLoS One. 2014 Apr 21;9(4):e94217. doi: 10.1371/journal.pone.0094217.
9. Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, Bischoff T, de Vevey M, Studer JP, Herzig L, Chapuis C, Tissot J, Pécoud A, Favrat B. Iron supplementation for unexplained fatigue in non-anaemic women: Double blind randomised placebo controlled trial. BMJ. 2003 May 24;326(7399):1124. doi: 10.1136/bmj.326.7399.1124.
10. Sultana N, Bajwa FA, Sikandar MZ, Haider MM, Majeed T. Effect of iron therapy on fatigue symptoms in non-anaemic iron deficient women of reproductive age- a randomized controlled trial. J Pak Med Assoc. 2026 Jan;76(1):4–7. doi: 10.47391/JPMA.22068.
Cognition
11. Gopaldas T, Kale M, Bhardwaj P. Prophylactic iron supplementation for underprivileged school boys. II. Impact on selected tests of cognitive function. Indian Pediatr. 1985 Oct;22(10):737–743.
12. Hod EA, Habeck C, Zhuang H, Dimov A, Spincemaille P, Kessler D, Bitan ZC, Feit Y, Fliginger D, Stone EF, Roh D, Eisler L, Dashnaw S, Caccappolo E, McMahon DJ, Stern Y, Wang Y, Spitalnik SL, Brittenham GM. Effects of iron repletion on brain iron content, myelination, neural network activation, and cognition. JCI Insight. 2025 Oct 21;10(23):e194442. doi: 10.1172/jci.insight.194442.
13. Bürker BS, Brautaset Englund KV, Myrdal Østby C, Andersson S, Gullestad L, Broch K. Cognitive function among heart transplant recipients before and after intravenous iron supplement for iron deficiency: Results from a randomized, placebo-controlled, double-blind treatment trial. Clin Transplant. 2025 Nov;39(11):e70370. doi: 10.1111/ctr.70370.
14. Groner JA, Holtzman NA, Charney E, Mellits ED. A randomized trial of oral iron on tests of short-term memory and attention span in young pregnant women. J Adolesc Health Care. 1986 Jan;7(1):44–48. doi: 10.1016/s0197-0070(86)80094-8.
15. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996 Oct 12;348(9033):992–996. doi: 10.1016/S0140-6736(96)02341-0.
16. Rezaeian A, Ghayour-Mobarhan M, Mazloum SR, Yavari M, Jafari SA. Effects of iron supplementation twice a week on attention score and haematologic measures in female high school students. Singapore Med J. 2014 Nov;55(11):587–592. doi: 10.11622/smedj.2014156.
17. Devaki PB, Chandra RK, Geisser P. Effects of oral iron(III) hydroxide polymaltose complex supplementation on hemoglobin increase, cognitive function, affective behavior and scholastic performance of adolescents with varying iron status: A single centre prospective placebo controlled study. Arzneimittelforschung. 2009;59(6):303–310. doi: 10.1055/s-0031-1296401.
ADHD
18. Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaïm M, Mouren MC, Arnulf I. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008 Jan;38(1):20–26. doi: 10.1016/j.pediatrneurol.2007.08.014.
19. Pongpitakdamrong A, Chirdkiatgumchai V, Ruangdaraganon N, Roongpraiwan R, Sirachainan N, Soongprasit M, Udomsubpayakul U. Effect of iron supplementation in children with attention-deficit/hyperactivity disorder and iron deficiency: A randomized controlled trial. J Dev Behav Pediatr. 2022 Feb–Mar 01;43(2):80–86. doi: 10.1097/DBP.0000000000000993.
20. Saha D, Sarkar UK, Parvin J, Mistry B, Khan HA, Begum SA, Saha NC, Saha CK. The effect of combined iron and methylphenidate use in iron deficient attention deficit hyperactivity disorder (ADHD) children of Bangladesh. Mymensingh Med J. 2026 Apr;35(2):569–577.
Lithium References
7 references
Mild cognitive impairment
1. Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: Randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668–674. doi: 10.1192/bjp.2019.76.
2. Damiano RF, Loureiro JC, Pais MV, Pereira RF, Corradi MM, Di Santi T, Bezerra GAM, Radanovic M, Talib LL, Forlenza OV. Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment. Braz J Psychiatry. 2023 Mar 11;45(1):46–49. doi: 10.47626/1516-4446-2022-2767.
3. Gildengers AG, Ibrahim TS, Anderson SJ, Emanuel JE, Santini T, Diaz JL, Lopresti BJ, Royse SK, Lopez OL, Zeng X, de Almeida B, Alkhateeb SK, Chu C, Karikari TK, Lee L, Weinstein AM, Butters MA. Low-dose lithium for mild cognitive impairment: A pilot randomized clinical trial. JAMA Neurol. 2026 Apr 1;83(4):310–319. doi: 10.1001/jamaneurol.2026.0072.
Opioid use disorder
4. Schrauzer GN, de Vroey E. Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users. Biol Trace Elem Res. 1994 Jan;40(1):89–101. doi: 10.1007/BF02916824.
Preservation of cognition / Schizophrenia
5. Zhuo C, Hu S, Chen G, Yang L, Cai Z, Tian H, Jiang D, Chen C, Wang L, Ma X, Li R. Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: A follow-up pilot study. Schizophrenia (Heidelb). 2023 Oct 14;9(1):71. doi: 10.1038/s41537-023-00400-w.
Alcohol use disorder
6. Sartori HE. Lithium orotate in the treatment of alcoholism and related conditions. Alcohol. 1986 Mar–Apr;3(2):97–100. doi: 10.1016/0741-8329(86)90018-2.
Dementia
7. Pereira da Silva AM, de Deus O, Ribeiro FV, Tudella GCN, Cabeça LS, Silva LL, Han ML, Franco JO, Costa JGP, Santos do Nascimento MDV, Andrade Fernandes JV, Franco ES, de Sousa Maia MB. Efficacy and safety of lithium for behavioral and cognitive symptoms in Alzheimer’s disease dementia: A systematic review with frequentist and Bayesian meta-analysis. Am J Geriatr Psychiatry. 2026 Mar;34(3):371–385. doi: 10.1016/j.jagp.2025.10.001. Epub 2025 Oct 4.
Magnesium References
25 references
Insomnia
1. Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. J Res Med Sci. 2012 Dec;17(12):1161–1169.
2. Carlos RM, Matias CN, Cavaca ML, Cardoso S, Santos DA, Giro R, Vaz JR, Pereira P, Vicente F, Leonardo-Mendonça RC, Ganhão-Arranhado S, Santos HO, Reiter RJ, Teixeira FJ. The effects of melatonin and magnesium in a novel supplement delivery system on sleep scores, body composition and metabolism in otherwise healthy individuals with sleep disturbances. Chronobiol Int. 2024 Jun;41(6):817–828. doi: 10.1080/07420528.2024.2353225. Epub 2024 May 14.
3. Hausenblas HA, Lynch T, Hooper S, Shrestha A, Rosendale D, Gu J. Magnesium-L-threonate improves sleep quality and daytime functioning in adults with self-reported sleep problems: A randomized controlled trial. Sleep Med X. 2024 Aug 17;8:100121. doi: 10.1016/j.sleepx.2024.100121.
4. Held K, Antonijevic IA, Künzel H, Uhr M, Wetter TC, Golly IC, Steiger A, Murck H. Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry. 2002 Jul;35(4):135–143. doi: 10.1055/s-2002-33195.
5. Khalid S, Bashir S, Mehboob R, Anwar T, Ali M, Hashim M, Waseem H, Basharat S. Effects of magnesium and potassium supplementation on insomnia and sleep hormones in patients with diabetes mellitus. Front Endocrinol (Lausanne). 2024 Oct 29;15:1370733. doi: 10.3389/fendo.2024.1370733.
Insomnia / Cognition
6. Lopresti AL, Smith SJ. The effects of magnesium L-threonate (Magtein®) on cognitive performance and sleep quality in adults: A randomised, double-blind, placebo-controlled trial. Front Nutr. 2026 Jan 12;12:1729164. doi: 10.3389/fnut.2025.1729164.
Cognition in healthy adults
7. Liu G, Weinger JG, Lu ZL, Xue F, Sadeghpour S. Efficacy and safety of MMFS-01, a synapse density enhancer, for treating cognitive impairment in older adults: A randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2016;49(4):971–990. doi: 10.3233/JAD-150538.
8. Zhang C, Hu Q, Li S, Dai F, Qian W, Hewlings S, Yan T, Wang Y. A Magtein®, magnesium L-threonate, -based formula improves brain cognitive functions in healthy Chinese adults. Nutrients. 2022 Dec 8;14(24):5235. doi: 10.3390/nu14245235.
Liver health in alcohol use disorder
9. Gullestad L, Dolva LO, Søyland E, Manger AT, Falch D, Kjekshus J. Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics. Alcohol Clin Exp Res. 1992 Oct;16(5):986–990. doi: 10.1111/j.1530-0277.1992.tb01906.x.
10. Poikolainen K, Alho H. Magnesium treatment in alcoholics: A randomized clinical trial. Subst Abuse Treat Prev Policy. 2008 Jan 25;3:1. doi: 10.1186/1747-597X-3-1.
Premenstrual syndrome
11. De Souza MC, Walker AF, Robinson PA, Bolland K. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: A randomized, double-blind, crossover study. J Womens Health Gend Based Med. 2000 Mar;9(2):131–139. doi: 10.1089/152460900318623.
12. Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazzani AR. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 1991 Aug;78(2):177–181.
13. Quaranta S, Buscaglia MA, Meroni MG, Colombo E, Cella S. Pilot study of the efficacy and safety of a modified-release magnesium 250 mg tablet (Sincromag) for the treatment of premenstrual syndrome. Clin Drug Investig. 2007;27(1):51–58. doi: 10.2165/00044011-200727010-00004.
Bruxism
14. Lehvilä P. Bruxism and magnesium. Literature review and case reports. Proc Finn Dent Soc. 1974 Dec;70(6):217–224.
15. Ploceniak C. Bruxisme et magnésium, mon expérience clinique depuis 1980 [Bruxism and magnesium, my clinical experiences since 1980]. Rev Stomatol Chir Maxillofac. 1990;91 Suppl 1:127. French.
Depression
16. Abiri B, Sarbakhsh P, Vafa M. Randomized study of the effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammation, and SIRT1 in obese women with mild to moderate depressive symptoms. Nutr Neurosci. 2022 Oct;25(10):2123–2135. doi: 10.1080/1028415X.2021.1945859. Epub 2021 Jul 2.
17. Afsharfar M, Shahraki M, Shakiba M, Asbaghi O, Dashipour A. The effects of magnesium supplementation on serum level of brain derived neurotrophic factor (BDNF) and depression status in patients with depression. Clin Nutr ESPEN. 2021 Apr;42:381–386. doi: 10.1016/j.clnesp.2020.12.022. Epub 2021 Jan 26.
18. Fard FE, Mirghafourvand M, Mohammad-Alizadeh Charandabi S, Farshbaf-Khalili A, Javadzadeh Y, Asgharian H. Effects of zinc and magnesium supplements on postpartum depression and anxiety: A randomized controlled clinical trial. Women Health. 2017 Oct;57(9):1115–1128. doi: 10.1080/03630242.2016.1235074. Epub 2016 Sep 12.
19. Mehdi SM, Atlas SE, Qadir S, Musselman D, Goldberg S, Woolger JM, Corredor R, Abbas MH, Arosemena L, Caccamo S, Campbell CS, Farooqi A, Gao J, Konefal J, Lages LC, Lantigua L, Lopez J, Padilla V, Rasul A, Ray AM, Simões HG, Tiozzo E, Lewis JE. Double-blind, randomized crossover study of intravenous infusion of magnesium sulfate versus 5% dextrose on depressive symptoms in adults with treatment-resistant depression. Psychiatry Clin Neurosci. 2017 Mar;71(3):204–211. doi: 10.1111/pcn.12480. Epub 2016 Dec 29.
20. Moabedi M, Aliakbari M, Erfanian S, Milajerdi A. Magnesium supplementation beneficially affects depression in adults with depressive disorder: A systematic review and meta-analysis of randomized clinical trials. Front Psychiatry. 2023 Dec 22;14:1333261. doi: 10.3389/fpsyt.2023.1333261.
21. Nazarinasab M, Behrouzian F, Abdi L, Sadegh Moghaddam AA, Sadeghi S. Investigating the effect of magnesium supplement in patients with major depressive disorder under selective serotonin reuptake inhibitor treatment. J Family Med Prim Care. 2022 Dec;11(12):7800–7805. doi: 10.4103/jfmpc.jfmpc_1164_22. Epub 2023 Jan 17.
22. Rajizadeh A, Mozaffari-Khosravi H, Yassini-Ardakani M, Dehghani A. Effect of magnesium supplementation on depression status in depressed patients with magnesium deficiency: A randomized, double-blind, placebo-controlled trial. Nutrition. 2017 Mar;35:56–60. doi: 10.1016/j.nut.2016.10.014. Epub 2016 Nov 9.
23. Ryszewska-Pokraśniewicz B, Mach A, Skalski M, Januszko P, Wawrzyniak ZM, Poleszak E, Nowak G, Pilc A, Radziwon-Zaleska M. Effects of magnesium supplementation on unipolar depression: A placebo-controlled study and review of the importance of dosing and magnesium status in the therapeutic response. Nutrients. 2018 Aug 3;10(8):1014. doi: 10.3390/nu10081014.
24. Strodl E, Bambling M, Parnam S, Ritchie G, Cramb S, Vitetta L. Probiotics and magnesium orotate for the treatment of major depressive disorder: A randomised double blind controlled trial. Sci Rep. 2024 Sep 6;14(1):20841. doi: 10.1038/s41598-024-71093-z.
25. Tarleton EK, Littenberg B, MacLean CD, Kennedy AG, Daley C. Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS One. 2017 Jun 27;12(6):e0180067. doi: 10.1371/journal.pone.0180067.
Zinc References
30 references
ADHD in zinc deficiency
1. Akhondzadeh S, Mohammadi MR, Khademi M. Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry. 2004 Apr 8;4:9. doi: 10.1186/1471-244X-4-9.
2. Arnold LE, Disilvestro RA, Bozzolo D, Bozzolo H, Crowl L, Fernandez S, Ramadan Y, Thompson S, Mo X, Abdel-Rasoul M, Joseph E. Zinc for attention-deficit/hyperactivity disorder: Placebo-controlled double-blind pilot trial alone and combined with amphetamine. J Child Adolesc Psychopharmacol. 2011 Feb;21(1):1–19. doi: 10.1089/cap.2010.0073.
3. Bilici M, Yildirim F, Kandil S, Bekaroğlu M, Yildirmiş S, Değer O, Ulgen M, Yildiran A, Aksu H. Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jan;28(1):181–190. doi: 10.1016/j.pnpbp.2003.09.034.
4. Noorazar SG, Malek A, Aghaei SM, Yasamineh N, Kalejahi P. The efficacy of zinc augmentation in children with attention deficit hyperactivity disorder under treatment with methylphenidate: A randomized controlled trial. Asian J Psychiatr. 2020 Feb;48:101868. doi: 10.1016/j.ajp.2019.101868. Epub 2019 Nov 5.
5. Salehi B, Mohammadbeigi A, Sheykholeslam H, Moshiri E, Dorreh F. Omega-3 and Zinc supplementation as complementary therapies in children with attention-deficit/hyperactivity disorder. J Res Pharm Pract. 2016 Jan–Mar;5(1):22–26. doi: 10.4103/2279-042X.176561.
6. Talebi S, Miraghajani M, Ghavami A, Mohammadi H. The effect of zinc supplementation in children with attention deficit hyperactivity disorder: A systematic review and dose-response meta‑analysis of randomized clinical trials. Crit Rev Food Sci Nutr. 2022;62(32):9093–9102. doi: 10.1080/10408398.2021.1940833. Epub 2021 Jun 29.
7. Zamora J, Velásquez A, Troncoso L, Barra P, Guajardo K, Castillo-Duran C. Zinc en la terapia del sindrome de déficit de atención e hiperactividad en niños. Un estudio controlado aleatorio preliminar [Zinc in the therapy of attention-deficit/hyperactivity disorder in children. A preliminary randomized controlled trial]. Arch Latinoam Nutr. 2011 Sep;61(3):242–246. Spanish.
Insomnia
8. Afzali A, Mojarrad LM, Goli S, Bagheri H, Mirhosseini S, Ebrahimi H. Effect of zinc supplement on sleep quality in older adults: A randomized clinical trial study. Acta Facultatis Medicae Naissensis. 2022;39(2):185–197. doi: 10.5937/afmnai39-33101.
9. Gholipour Baradari A, Alipour A, Mahdavi A, Sharifi H, Nouraei SM, Emami Zeydi A. The effect of zinc supplementation on sleep quality of ICU nurses: A double blinded randomized controlled trial. Workplace Health Saf. 2018 Apr;66(4):191–200. doi: 10.1177/2165079917734880. Epub 2017 Dec 14.
10. Jazinaki MS, Gheflati A, Moghadam MRSF, Hadi S, Razavidarmian M, Nezhad MY, Akhtari H, Nematizadeh M, Safarian M. Effects of zinc supplementation on sleep quality in humans: A systematic review of randomized controlled trials. Health Sci Rep. 2024;7(10):e70019. Published 2024 Oct 6. doi: 10.1002/hsr2.70019.
11. Rondanelli M, Opizzi A, Monteferrario F, Antoniello N, Manni R, Klersy C. The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: A double-blind, placebo-controlled clinical trial. J Am Geriatr Soc. 2011;59(1):82–90. doi: 10.1111/j.1532-5415.2010.03232.x.
12. Saito H, Cherasse Y, Suzuki R, Mitarai M, Ueda F, Urade Y. Zinc-rich oysters as well as zinc-yeast- and astaxanthin-enriched food improved sleep efficiency and sleep onset in a randomized controlled trial of healthy individuals. Mol Nutr Food Res. 2017;61(5):10.1002/mnfr.201600882. doi: 10.1002/mnfr.201600882. Epub 2017 Feb 27.
Major depressive disorder
13. Fard FE, Mirghafourvand M, Mohammad-Alizadeh Charandabi S, Farshbaf-Khalili A, Javadzadeh Y, Asgharian H. Effects of zinc and magnesium supplements on postpartum depression and anxiety: A randomized controlled clinical trial. Women Health. 2017 Oct;57(9):1115–1128. doi: 10.1080/03630242.2016.1235074. Epub 2016 Sep 12.
14. Nowak G, Siwek M, Dudek D, Zieba A, Pilc A. Effect of zinc supplementation on antidepressant therapy in unipolar depression: A preliminary placebo-controlled study. Pol J Pharmacol. 2003 Nov–Dec;55(6):1143–1147.
15. Ranjbar E, Shams J, Sabetkasaei M, M-Shirazi M, Rashidkhani B, Mostafavi A, Bornak E, Nasrollahzadeh J. Effects of zinc supplementation on efficacy of antidepressant therapy, inflammatory cytokines, and brain-derived neurotrophic factor in patients with major depression. Nutr Neurosci. 2014;17(2):65–71. doi: 10.1179/1476830513Y.0000000066. Epub 2013 Nov 26.
16. Salari S, Khomand P, Arasteh M, Yousefzamani B, Hassanzadeh K. Zinc sulphate: A reasonable choice for depression management in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial. Pharmacol Rep. 2015 Jun;67(3):606–609. doi: 10.1016/j.pharep.2015.01.002. Epub 2015 Jan 19.
17. Siwek M, Dudek D, Paul IA, Sowa-Kućma M, Zieba A, Popik P, Pilc A, Nowak G. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: A double blind, placebo-controlled study. J Affect Disord. 2009 Nov;118(1–3):187–195. doi: 10.1016/j.jad.2009.02.014. Epub 2009 Mar 10.
18. Solati Z, Jazayeri S, Tehrani-Doost M, Mahmoodianfard S, Gohari MR. Zinc monotherapy increases serum brain-derived neurotrophic factor (BDNF) levels and decreases depressive symptoms in overweight or obese subjects: A double-blind, randomized, placebo-controlled trial. Nutr Neurosci. 2015 May;18(4):162–168. doi: 10.1179/1476830513Y.0000000105. Epub 2014 Jan 7.
19. Swardfager W, Herrmann N, Mazereeuw G, Goldberger K, Harimoto T, Lanctôt KL. Zinc in depression: A meta-analysis. Biol Psychiatry. 2013 Dec 15;74(12):872–878. doi: 10.1016/j.biopsych.2013.05.008. Epub 2013 Jun 24.
20. Yosaee S, Soltani S, Esteghamati A, Motevalian SA, Tehrani-Doost M, Clark CCT, Jazayeri S. Effects of zinc, vitamin D, and their co-supplementation on mood, serum cortisol, and brain-derived neurotrophic factor in patients with obesity and mild to moderate depressive symptoms: A phase II, 12-wk, 2 × 2 factorial design, double-blind, randomized, placebo-controlled trial. Nutrition. 2020 Mar;71:110601. doi: 10.1016/j.nut.2019.110601. Epub 2019 Oct 15.
Premenstrual syndrome
21. Ahmadi M, Khansary S, Parsapour H, Alizamir A, Pirdehghan A. The effect of zinc supplementation on the improvement of premenstrual symptoms in female university students: A randomized clinical trial study. Biol Trace Elem Res. 2023 Feb;201(2):559–566. doi: 10.1007/s12011-022-03175-w. Epub 2022 Feb 28.
22. Haider S, Sajjad M, Zahid M. A systematic review and meta-analysis examining the role of zinc supplementation in ameliorating physical and psychological manifestations of premenstrual syndrome in young females. Eur J Obstet Gynecol Reprod Biol. 2025;312:114082. doi: 10.1016/j.ejogrb.2025.114082. Epub 2025 May 22.
23. Jafari F, Amani R, Tarrahi MJ. Effect of zinc supplementation on physical and psychological symptoms, biomarkers of inflammation, oxidative stress, and brain-derived neurotrophic factor in young women with premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res. 2020 Mar;194(1):89–95. doi: 10.1007/s12011-019-01757-9. Epub 2019 Jun 2.
24. Jafari F, Tarrahi MJ, Farhang A, Amani R. Effect of zinc supplementation on quality of life and sleep quality in young women with premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. Arch Gynecol Obstet. 2020 Sep;302(3):657–664. doi: 10.1007/s00404-020-05628-w. Epub 2020 Jun 8.
25. Sangestani G, Khatiban M, Marci R, Piva I. The positive effects of zinc supplements on the improvement of primary dysmenorrhea and premenstrual symptoms: A double-blind, randomized, controlled trial. Journal of Midwifery and Reproductive Health. 2015;3(3):378–384. doi: 10.22038/jmrh.2015.4463.
26. Siahbazi S, Behboudi-Gandevani S, Moghaddam-Banaem L, Montazeri A. Effect of zinc sulfate supplementation on premenstrual syndrome and health-related quality of life: Clinical randomized controlled trial. J Obstet Gynaecol Res. 2017 May;43(5):887–894. doi: 10.1111/jog.13299. Epub 2017 Feb 11.
Anorexia
27. Birmingham CL, Goldner EM, Bakan R. Controlled trial of zinc supplementation in anorexia nervosa. Int J Eat Disord. 1994;15(3):251–255.
28. Katz RL, Keen CL, Litt IF, Hurley LS, Kellams-Harrison KM, Glader LJ. Zinc deficiency in anorexia nervosa. J Adolesc Health Care. 1987 Sep;8(5):400–406. doi: 10.1016/0197-0070(87)90227-0.
29. Safai-Kutti S. Oral zinc supplementation in anorexia nervosa. Acta Psychiatr Scand Suppl. 1990;361:14–17.
Opioid use disorder
30. Amini Z, HeidariFarsani E. Investigating the effect of zinc supplementation on probability of relapse and mental health in patients with opioid use disorder undergoing methadone maintenance treatment. Subst Abuse Treat Prev Policy. 2023 Jan 6;18(1):1. doi: 10.1186/s13011-023-00514-5.
Acetyl-L-Carnitine References
18 references
Hepatic encephalopathy
1. Malaguarnera M, Bella R, Vacante M, Giordano M, Malaguarnera G, Gargante MP, Motta M, Mistretta A, Rampello L, Pennisi G. Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol. 2011 Jun;46(6):750–759. doi: 10.3109/00365521.2011.565067. Epub 2011 Mar 28.
2. Malaguarnera M, Gargante MP, Cristaldi E, Vacante M, Risino C, Cammalleri L, Pennisi G, Rampello L. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci. 2008 Nov;53(11):3018–3025. doi: 10.1007/s10620-008-0238-6. Epub 2008 Mar 21.
3. Malaguarnera M, Pistone G, Astuto M, Vecchio I, Raffaele R, Lo Giudice E, Rampello L. Effects of L-acetylcarnitine on cirrhotic patients with hepatic coma: Randomized double-blind, placebo-controlled trial. Dig Dis Sci. 2006;51(12):2242–2247. doi: 10.1007/s10620-006-9187-0. Epub 2006 Nov 1.
4. Malaguarnera M, Vacante M, Giordano M, Pennisi G, Bella R, Rampello L, Malaguarnera M, Li Volti G, Galvano F. Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: A randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2011 Apr;93(4):799–808. doi: 10.3945/ajcn.110.007393. Epub 2011 Feb 10.
5. Malaguarnera M, Vacante M, Motta M, Giordano M, Malaguarnera G, Bella R, Nunnari G, Rampello L, Pennisi G. Acetyl-L-carnitine improves cognitive functions in severe hepatic encephalopathy: A randomized and controlled clinical trial. Metab Brain Dis. 2011 Dec;26(4):281–289. doi: 10.1007/s11011-011-9260-z. Epub 2011 Aug 26.
Elevated ammonia on valproate
6. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. Am J Health Syst Pharm. 2012 Jan 1;69(1):35–39. doi: 10.2146/ajhp110049.
7. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009 Feb;47(2):101–111. doi: 10.1080/15563650902752376.
Major depressive disorder
8. Bella R, Biondi R, Raffaele R, Pennisi G. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res. 1990;10(6):355–360.
9. Bersani G, Meco G, Denaro A, Liberati D, Colletti C, Nicolai R, Bersani FS, Koverech A. L-Acetylcarnitine in dysthymic disorder in elderly patients: A double-blind, multicenter, controlled randomized study vs. fluoxetine. Eur Neuropsychopharmacol. 2013 Oct;23(10):1219–1225. doi: 10.1016/j.euroneuro.2012.11.013. Epub 2013 Feb 18.
10. Garzya G, Corallo D, Fiore A, Lecciso G, Petrelli G, Zotti C. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res. 1990;16(2):101–106.
11. Tempesta E, Casella L, Pirrongelli C, Janiri L, Calvani M, Ancona L. L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo. Drugs Exp Clin Res. 1987;13(7):417–423.
12. Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol. 2006 May;16(4):281–287. doi: 10.1016/j.euroneuro.2005.10.005. Epub 2005 Nov 28.
Alcohol use disorder
13. Martinotti G, Andreoli S, Reina D, Di Nicola M, Ortolani I, Tedeschi D, Fanella F, Pozzi G, Iannoni E, D'Iddio S, Prof LJ. Acetyl-L-carnitine in the treatment of anhedonia, melancholic and negative symptoms in alcohol dependent subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):953–958. doi: 10.1016/j.pnpbp.2011.01.013. Epub 2011 Jan 20.
14. Martinotti G, Reina D, Di Nicola M, Andreoli S, Tedeschi D, Ortolani I, Pozzi G, Iannoni E, D'Iddio S, Janiri L. Acetyl-L-carnitine for alcohol craving and relapse prevention in anhedonic alcoholics: A randomized, double-blind, placebo-controlled pilot trial. Alcohol Alcohol. 2010 Sep–Oct;45(5):449–455. doi: 10.1093/alcalc/agq039. Epub 2010 Jun 30.
Alzheimer's dementia
15. Hudson SA, Tabet N. Acetyl-L-carnitine for dementia. Cochrane Database of Systematic Reviews. 2003;2:CD003158. doi: 10.1002/14651858.CD003158.
Mild cognitive impairment
16. Malaguarnera G, Catania VE, Bertino G, Chisari LM, Castorina M, Bonfiglio C, Cauli O, Malaguarnera M. Acetyl-L-carnitine slows the progression from prefrailty to frailty in older subjects: A randomized interventional clinical trial. Curr Pharm Des. 2022;28(38):3158–3166. doi: 10.2174/1381612828666220830092815.
Sexual dysfunction in elderly men
17. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004 Apr;63(4):641–646. doi: 10.1016/j.urology.2003.11.009.
Schizophrenia
18. Bruno A, Pandolfo G, Crucitti M, Lorusso S, Zoccali RA, Muscatello MR. Acetyl-L-carnitine augmentation of clozapine in partial-responder schizophrenia: A 12-week, open-label uncontrolled preliminary study. Clin Neuropharmacol. 2016 Nov/Dec;39(6):277–280. doi: 10.1097/WNF.0000000000000170.
Creatine References
19 references
Cognition
1. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011 Apr;105(7):1100–1105. doi: 10.1017/S0007114510004733. Epub 2010 Dec 1.
2. Gordji-Nejad A, Matusch A, Kleedörfer S, Jayeshkumar Patel H, Drzezga A, Elmenhorst D, Binkofski F, Bauer A. Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation. Sci Rep. 2024 Feb 28;14(1):4937. doi: 10.1038/s41598-024-54249-9.
3. Li Z, Wang P, Yu Z, Cong Y, Sun H, Zhang J, Zhang J, Sun C, Zhang Y, Ju X. The effect of creatine and coenzyme Q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol. 2015;73(3–4):205–211. doi: 10.1159/000377676. Epub 2015 Mar 10.
4. McMorris T, Harris RC, Howard AN, Langridge G, Hall B, Corbett J, Dicks M, Hodgson C. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav. 2007 Jan 30;90(1):21–28. doi: 10.1016/j.physbeh.2006.08.024. Epub 2006 Oct 13.
5. McMorris T, Harris RC, Swain J, Corbett J, Collard K, Dyson RJ, Dye L, Hodgson C, Draper N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl). 2006 Mar;185(1):93–103. doi: 10.1007/s00213-005-0269-z. Epub 2006 Jan 17.
6. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003 Oct 22;270(1529):2147–2150. doi: 10.1098/rspb.2003.2492.
7. Rawson ES, Lieberman HR, Walsh TM, Zuber SM, Harhart JM, Matthews TC. Creatine supplementation does not improve cognitive function in young adults. Physiol Behav. 2008 Sep 3;95(1–2):130–134. doi: 10.1016/j.physbeh.2008.05.009. Epub 2008 May 15.
8. Sandkühler JF, Kersting X, Faust A, Königs EK, Altman G, Ettinger U, Lux S, Philipsen A, Müller H, Brauner J. The effects of creatine supplementation on cognitive performance-a randomised controlled study. BMC Med. 2023 Nov 15;21(1):440. doi: 10.1186/s12916-023-03146-5.
9. Toniolo RA, Fernandes FBF, Silva M, Dias RDS, Lafer B. Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2017 Dec 15;224:69–75. doi: 10.1016/j.jad.2016.11.029. Epub 2016 Nov 20.
Major depressive disorder
10. Hellem TL, Sung YH, Shi XF, Pett MA, Latendresse G, Morgan J, Huber RS, Kuykendall D, Lundberg KJ, Renshaw PF. Creatine as a novel treatment for depression in females using methamphetamine: A pilot study. J Dual Diagn. 2015;11(3–4):189–202. doi: 10.1080/15504263.2015.1100471.
11. Kondo DG, Forrest LN, Shi X, Sung YH, Hellem TL, Huber RS, Renshaw PF. Creatine target engagement with brain bioenergetics: A dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids. 2016 Aug;48(8):1941–1954. doi: 10.1007/s00726-016-2194-3. Epub 2016 Feb 23.
12. Lyoo IK, Yoon S, Kim TS, Hwang J, Kim JE, Won W, Bae S, Renshaw PF. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry. 2012 Sep;169(9):937–945. doi: 10.1176/appi.ajp.2012.12010009.
13. Nemets B, Levine J. A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression. Int Clin Psychopharmacol. 2013 May;28(3):127–133. doi: 10.1097/YIC.0b013e32835ff20f.
14. Sherpa NN, De Giorgi R, Ostinelli EG, Choudhury A, Dolma T, Dorjee S. Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial in an under-resourced area. Eur Neuropsychopharmacol. 2025 Jan;90:28–35. doi: 10.1016/j.euroneuro.2024.10.004. Epub 2024 Nov 1.
Traumatic brain injury
15. Sakellaris G, Nasis G, Kotsiou M, Tamiolaki M, Charissis G, Evangeliou A. Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study. Acta Paediatr. 2008 Jan;97(1):31–34. doi: 10.1111/j.1651-2227.2007.00529.x. Epub 2007 Dec 3. PMID: 18053002;
Long COVID
16. Slankamenac J, Ranisavljev M, Todorovic N, Ostojic J, Stajer V, Candow DG, Ratgeber L, Betlehem J, Acs P, Ostojic SM. Eight-week creatine-glucose supplementation alleviates clinical features of long COVID. J Nutr Sci Vitaminol (Tokyo). 2024;70(2):174–178. doi: 10.3177/jnsv.70.174.
PTSD
17. Amital D, Vishne T, Roitman S, Kotler M, Levine J. Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder. J Clin Psychiatry. 2006 May;67(5):836–837. doi: 10.4088/jcp.v67n0521c.
Treatment-resistant depression
18. Roitman S, Green T, Osher Y, Karni N, Levine J. Creatine monohydrate in resistant depression: A preliminary study. Bipolar Disord. 2007 Nov;9(7):754–758. doi: 10.1111/j.1399-5618.2007.00532.x.
19. Kious BM, Sabic H, Sung YH, Kondo DG, Renshaw P. An open-label pilot study of combined augmentation with creatine monohydrate and 5-hydroxytryptophan for selective serotonin reuptake inhibitor- or serotonin-norepinephrine reuptake inhibitor-resistant depression in adult women. J Clin Psychopharmacol. 2017 Oct;37(5):578–583. doi: 10.1097/JCP.0000000000000754.
5-Hydroxytryptophan References
11 references
Sleep quality in older adults
1. Sutanto CN, Xia X, Heng CW, Tan YS, Lee DPS, Fam J, Kim JE. The impact of 5-hydroxytryptophan supplementation on sleep quality and gut microbiota composition in older adults: A randomized controlled trial. Clin Nutr. 2024 Mar;43(3):593–602. doi: 10.1016/j.clnu.2024.01.010. Epub 2024 Jan 17.
Sleep quality / mood in Parkinson’s disease
2. Meloni M, Figorilli M, Carta M, Tamburrino L, Cannas A, Sanna F, Defazio G, Puligheddu M. Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease. Sleep Breath. 2022 Sep;26(3):1023–1031. doi: 10.1007/s11325-021-02417-w. Epub 2021 Aug 17.
3. Meloni M, Puligheddu M, Carta M, Cannas A, Figorilli M, Defazio G. Efficacy and safety of 5-hydroxytryptophan on depression and apathy in Parkinson’s disease: A preliminary finding. Eur J Neurol. 2020 May;27(5):779–786. doi: 10.1111/ene.14179. Epub 2020 Mar 13.
Sleep terrors in children
4. Bruni O, Ferri R, Miano S, Verrillo E. L-5-hydroxytryptophan treatment of sleep terrors in children. Eur J Pediatr. 2004 Jul;163(7):402–407. doi: 10.1007/s00431-004-1444-7. Epub 2004 May 14.
OCD
5. Yousefzadeh F, Sahebolzamani E, Sadri A, Mortezaei A, Aqamolaei A, Mortazavi SH, Shalbafan MR, Ghaffari S, Alikhani R, Mousavi SB, Naderi S, Shamabadi A, Jalilevand S, Akhondzadeh S. 5-hydroxytryptophan as adjuvant therapy in treatment of moderate to severe obsessive-compulsive disorder: A double-blind randomized trial with placebo control. Int Clin Psychopharmacol. 2020 Sep;35(5):254–262. doi: 10.1097/YIC.0000000000000321.
Major depressive disorder
6. Angst J, Woggon B, Schoepf J. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr (1970). 1977 Oct 11;224(2):175–186.
7. Nolen WA, van de Putte JJ, Dijken WA, Kamp JS. L-5–HTP in depression resistant to re-uptake inhibitors. An open comparative study with tranylcypromine. Br J Psychiatry. 1985 Jul;147:16–22. doi: 10.1192/bjp.147.1.16.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198. doi: 10.1002/14651858.CD003198.
Non-specific anxiety
9. Kahn RS, Westenberg HG, Verhoeven WM, Gispen-de Wied CC, Kamerbeek WD. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol. 1987 Jan;2(1):33–45. doi: 10.1097/00004850-198701000-00003.
LSD-induced psychosis
10. Abraham HD. L-5-hydroxytryptophan for LSD-induced psychosis. Am J Psychiatry. 1983 Apr;140(4):456–458. doi: 10.1176/ajp.140.4.456.
Stress from unreciprocated romantic love
11. Emanuele E, Bertona M, Minoretti P, Geroldi D. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress. Neuro Endocrinol Lett. 2010;31(5):663–666.
L-Arginine References
19 references
Erectile dysfunction in men
1. Abu El-Hamd M, Hegazy EM. Comparison of the clinical efficacy of daily use of L-arginine, tadalafil and combined L-arginine with tadalafil in the treatment of elderly patients with erectile dysfunction. Andrologia. 2020 Aug;52(7):e13640. doi: 10.1111/and.13640. Epub 2020 May 22.
2. Aoki H, Nagao J, Ueda T, Strong JM, Schonlau F, Yu-Jing S, Lu Y, Horie S. Clinical assessment of a supplement of Pycnogen®l and L-arginine in Japanese patients with mild to moderate erectile dysfunction. Phytother Res. 2012 Feb;26(2):204–207. doi: 10.1002/ptr.3462. Epub 2011 May 27.
3. Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: Results of a double-blind, randomized, placebo-controlled study. BJU Int. 1999 Feb;83(3):269–273. doi: 10.1046/j.1464-410x.1999.00906.x.
4. El Taieb M, Hegazy E, Ibrahim A. Daily oral L-arginine plus tadalafil in diabetic patients with erectile dysfunction: A double-blinded, randomized, controlled clinical trial. J Sex Med. 2019 Sep;16(9):1390–1397. doi: 10.1016/j.jsxm.2019.06.009. Epub 2019 Jul 17.
5. Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int. 1999;63(4):220–223. doi: 10.1159/000030454.
6. Lebret T, Hervé JM, Gorny P, Worcel M, Botto H. Efficacy and safety of a novel combination of L-arginine glutamate and yohimbine hydrochloride: A new oral therapy for erectile dysfunction. Eur Urol. 2002 Jun;41(6):608–613. doi: 10.1016/s0302-2838(02)00175-6.
7. Ledda A, Belcaro G, Cesarone MR, Dugall M, Schönlau F. Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double-blind, placebo-controlled, parallel-arm study. BJU Int. 2010 Oct;106(7):1030–1033. doi: 10.1111/j.1464-410X.2010.09213.x. Epub 2010 Feb 22.
8. Menafra D, de Angelis C, Garifalos F, Mazzella M, Galdiero G, Piscopo M, Castoro M, Verde N, Pivonello C, Simeoli C, Auriemma RS, Colao A, Pivonello R. Long-term high-dose L-arginine supplementation in patients with vasculogenic erectile dysfunction: A multicentre, double-blind, randomized, placebo-controlled clinical trial. J Endocrinol Invest. 2022 May;45(5):941–961. doi: 10.1007/s40618-021-01704-3. Epub 2022 Jan 1.
9. Stanislavov R, Nikolova V, Rohdewald P. Improvement of erectile function with Prelox: A randomized, double-blind, placebo-controlled, crossover trial. Int J Impot Res. 2008 Mar–Apr;20(2):173–180. doi: 10.1038/sj.ijir.3901597. Epub 2007 Aug 16.
Sexual dysfunction in women
10. Ito TY, Trant AS, Polan ML. A double-blind placebo-controlled study of ArginMax, a nutritional supplement for enhancement of female sexual function. J Sex Marital Ther. 2001 Oct–Dec;27(5):541–549. doi: 10.1080/713846828.
11. Ito TY, Polan ML, Whipple B, Trant AS. The enhancement of female sexual function with ArginMax, a nutritional supplement, among women differing in menopausal status. J Sex Marital Ther. 2006 Oct–Dec;32(5):369–378. doi: 10.1080/00926230600834901.
12. Meston CM, Worcel M. The effects of yohimbine plus L-arginine glutamate on sexual arousal in postmenopausal women with sexual arousal disorder. Arch Sex Behav. 2002 Aug;31(4):323–332. doi: 10.1023/a:1016220225392.
13. Torkaman P, Meybodi AM, Kheradmand A, Eiliaei S, Ardakani MT. Effect of L-arginine compared to placebo on sexual function in women with major depressive disorder: A randomized controlled trial. BMC Psychiatry. 2024 May 14;24(1):358. doi: 10.1186/s12888-024-05781-5.
Cognition in healthy adults
14. Gills JL, Campitelli A, Jones M, Paulson S, Myers JR, Madero EN, Glenn JM, Komorowski J, Gray M. Acute inositol-stabilized arginine silicate improves cognitive outcomes in healthy adults. Nutrients. 2021 Nov 26;13(12):4272. doi: 10.3390/nu13124272.
15. Kalman D, Harvey PD, Perez Ojalvo S, Komorowski J. Randomized prospective double-blind studies to evaluate the cognitive effects of inositol-stabilized arginine silicate in healthy physically active adults. Nutrients. 2016 Nov 18;8(11):736. doi: 10.3390/nu8110736. PMID: 27869715; PMCID: PMC5133120.
16. Sowinski R, Gonzalez D, Xing D, Yoo C, Jenkins V, Nottingham K, Dickerson B, Humphries M, Leonard M, Ko J, Faries M, Kephart W, Rasmussen CJ, Kreider RB. Effects of inositol-enhanced bonded arginine silicate ingestion on cognitive and executive function in gamers. Nutrients. 2021 Oct 24;13(11):3758. doi: 10.3390/nu13113758.
Long COVID
17. Tosato M, Calvani R, Picca A, Ciciarello F, Galluzzo V, Coelho-Júnior HJ, Di Giorgio A, Di Mario C, Gervasoni J, Gremese E, Leone PM, Nesci A, Paglionico AM, Santoliquido A, Santoro L, Santucci L, Tolusso B, Urbani A, Marini F, Marzetti E, Landi F; Gemelli against COVID-19 Post-Acute Care Team. Effects of L-arginine plus vitamin C supplementation on physical performance, endothelial function, and persistent fatigue in adults with long COVID: A single-blind randomized controlled trial. Nutrients. 2022 Nov 23;14(23):4984. doi: 10.3390/nu14234984.
Non-specific anxiety / stress
18. Jezova D, Makatsori A, Smriga M, Morinaga Y, Duncko R. Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety. Nutr Neurosci. 2005 Jun;8(3):155–160. doi: 10.1080/10284150500162937.
19. Smriga M, Ando T, Akutsu M, Furukawa Y, Miwa K, Morinaga Y. Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans. Biomed Res. 2007 Apr;28(2):85–90. doi: 10.2220/biomedres.28.85.
L-Carnosine References
8 references
ADHD
1. Ghajar A, Aghajan-Nashtaei F, Afarideh M, Mohammadi MR, Akhondzadeh S. L-carnosine as adjunctive therapy in children and adolescents with attention-deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled clinical trial. J Child Adolesc Psychopharmacol. 2018 Jun;28(5):331–338. doi: 10.1089/cap.2017.0157. Epub 2018 Feb 22.
Major depressive disorder
2. Araminia B, Shalbafan M, Mortezaei A, Shirazi E, Ghaffari S, Sahebolzamani E, Mortazavi SH, Shariati B, Ardebili ME, Aqamolaei A, Naderi S, Akhondzadeh S. L-carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. J Affect Disord. 2020 Apr 15;267:131–136. doi: 10.1016/j.jad.2020.02.020. Epub 2020 Feb 7.
3. Kabthymer RH, Feehan J, Mousa A, Aldini G, de Courten M, Cameron J, de Courten B. The effect of carnosine supplementation on depressive symptoms and health-related quality of life in individuals with prediabetes and well-controlled type 2 diabetes: A randomized controlled trial. Food Sci Nutr. 2026 Feb 25;14(3):e71514. doi: 10.1002/fsn3.71514.
Schizophrenia (negative symptoms)
4. Ghajar A, Khoaie-Ardakani MR, Shahmoradi Z, Alavi AR, Afarideh M, Shalbafan MR, Ghazizadeh-Hashemi M, Akhondzadeh S. L-carnosine as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: A double-blind, randomized placebo-controlled trial. Psychiatry Res. 2018 Apr;262:94–101. doi: 10.1016/j.psychres.2018.02.012. Epub 2018 Feb 3.
5. Tharoor H, Maran S, Chandan AK, Pari M, Rao S, Durairaj J. Cognitive and negative symptoms in schizophrenia with L-carnosine adjuvant therapy - a randomized double-blind placebo-controlled study. Pharmacol Res Perspect. 2023 Apr;11(2):e01074. doi: 10.1002/prp2.1074.
Cognition in young adults
6. O’Toole TE, Amraotkar AR, Gao H, Sears CG, Rai SN, Basner M, Bhatnagar A. Carnosine supplementation improves cognitive outcomes in younger participants of the NEAT trial. Neurotherapeutics. 2025 Mar;22(2):e00541. doi: 10.1016/j.neurot.2025.e00541. Epub 2025 Feb 6.
Binge eating disorder / Bulimia
7. Sakae K, Suka M, Yanagisawa H. Polaprezinc (zinc-L-carnosine complex) as an add-on therapy for binge eating disorder and bulimia nervosa, and the possible involvement of zinc deficiency in these conditions: A pilot study. J Clin Psychopharmacol. 2020 Nov/Dec;40(6):599–606. doi: 10.1097/JCP.0000000000001284.
8. Sakae K, Yanagisawa H. Zinc-L-carnosine complex (polaprezinc) for the treatment of binge eating: Three case reports. J Clin Psychopharmacol. 2017 Dec;37(6):734–736. doi: 10.1097/JCP.0000000000000784.
L-Lysine References
5 references
Schizophrenia
1. Wass C, Klamer D, Katsarogiannis E, Pålsson E, Svensson L, Fejgin K, Bogren IB, Engel JA, Rembeck B. L-lysine as adjunctive treatment in patients with schizophrenia: A single-blinded, randomized, cross-over pilot study. BMC Med. 2011 Apr 18;9:40. doi: 10.1186/1741-7015-9-40.
2. Zeinoddini A, Ahadi M, Farokhnia M, Rezaei F, Tabrizi M, Akhondzadeh S. L-lysine as an adjunct to risperidone in patients with chronic schizophrenia: A double-blind, placebo-controlled, randomized trial. J Psychiatr Res. 2014 Dec;59:125–131. doi: 10.1016/j.jpsychires.2014.08.016. Epub 2014 Sep 6.
Non-specific anxiety / stress
3. Jezova D, Makatsori A, Smriga M, Morinaga Y, Duncko R. Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety. Nutr Neurosci. 2005 Jun;8(3):155–160. doi: 10.1080/10284150500162937.
4. Smriga M, Ando T, Akutsu M, Furukawa Y, Miwa K, Morinaga Y. Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans. Biomed Res. 2007 Apr;28(2):85–90. doi: 10.2220/biomedres.28.85.
5. Smriga M, Ghosh S, Mouneimne Y, Pellett PL, Scrimshaw NS. Lysine fortification reduces anxiety and lessens stress in family members in economically weak communities in Northwest Syria. Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8285–8288. doi: 10.1073/pnas.0402550101. Epub 2004 May 24.
L-Serine References
1 reference
Autism
1. Kim HW, Kim JH, Chung US, Kim JI, Shim SH, Park TW, Lee MS, Hwang JW, Park EJ, Hwang SK, Joung YS. AST-001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial. Psychiatry Clin Neurosci. 2025;79(1):21–28. doi: 10.1111/pcn.13757. Epub 2024 Oct 18. Erratum in: Psychiatry Clin Neurosci. 2025 Aug;79(8):501–503. doi: 10.1111/pcn.13857.
N-Acetylcysteine References
44 references
Schizophrenia (negative symptoms)
1. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361–368. doi: 10.1016/j.biopsych.2008.03.004. Epub 2008 Apr 23.
2. Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y, Francis MM. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 2018 Sep;199:395–402. doi: 10.1016/j.schres.2018.03.012. Epub 2018 Mar 24.
3. Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, Ferrari C, Cousins A, Alameda L, Gholam-Rezaee M, Golay P, Jenni R, Woo TW, Keshavan MS, Eap CB, Wojcik J, Cuenod M, Buclin T, Gruetter R, Do KQ. N-acetylcysteine in a double-blind randomized placebo-controlled trial: Toward biomarker-guided treatment in early psychosis. Schizophr Bull. 2018 Feb 15;44(2):317–327. doi: 10.1093/schbul/sbx093.
4. Farokhnia M, Azarkolah A, Adinehfar F, Khodaie-Ardakani MR, Hosseini SM, Yekehtaz H, Tabrizi M, Rezaei F, Salehi B, Sadeghi SM, Moghadam M, Gharibi F, Mirshafiee O, Akhondzadeh S. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: A randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013 Nov–Dec;36(6):185–192. doi: 10.1097/WNF.0000000000000001.
5. Neill E, Rossell SL, Yolland C, Meyer D, Galletly C, Harris A, Siskind D, Berk M, Bozaoglu K, Dark F, Dean OM, Francis PS, Liu D, Phillipou A, Sarris J, Castle DJ. N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: A double-blind, randomized, placebo-controlled trial targeting negative symptoms. Schizophr Bull. 2022 Nov 18;48(6):1263–1272. doi: 10.1093/schbul/sbac065.
6. Pyatoykina AS, Zhilyaeva TV, Semennov IV, Mishanov GA, Blagonravova AS, Mazo GE. Dvoinoe slepoe randomizirovannoe platsebo-kontroliruemoe issledovanie primeneniya N-atsetiltsisteina pri shizofrenii: predvaritel'nye rezul'taty [The double-blind randomized placebo-controlled trial of N-acetylcysteine use in schizophrenia: preliminary results]. Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(9):66–71. Russian. doi: 10.17116/jnevro202012009166.
7. Rapado-Castro M, Dodd S, Bush AI, Malhi GS, Skvarc DR, On ZX, Berk M, Dean OM. Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med. 2017 Apr;47(5):866–876. doi: 10.1017/S0033291716002932. Epub 2016 Nov 29.
8. Sepehrmanesh Z, Heidary M, Akasheh N, Akbari H, Heidary M. Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Mar 2;82:289–296. doi: 10.1016/j.pnpbp.2017.11.001. Epub 2017 Nov 7.
9. Yang YS, Maddock RJ, Zhang H, Lee J, Hellemann G, Marder SR, Green MF. N-acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study. Psychiatry Res Neuroimaging. 2022 Sep;325:111515. doi: 10.1016/j.pscychresns.2022.111515. Epub 2022 Jun 23.
Cannabis use disorder
10. Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, McRae-Clark AL, Brady KT. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012 Aug;169(8):805–812. doi: 10.1176/appi.ajp.2012.12010055. Erratum in: Am J Psychiatry. 2012 Aug 1;169(8):869.
11. Gray KM, Sonne SC, McClure EA, Ghitza UE, Matthews AG, McRae-Clark AL, Carroll KM, Potter JS, Wiest K, Mooney LJ, Hasson A, Walsh SL, Lofwall MR, Babalonis S, Lindblad RW, Sparenborg S, Wahle A, King JS, Baker NL, Tomko RL, Haynes LF, Vandrey RG, Levin FR. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Drug Alcohol Depend. 2017 Aug 1;177:249–257. doi: 10.1016/j.drugalcdep.2017.04.020. Epub 2017 Jun 10.
12. Gray KM, Tomko RL, Baker NL, McClure EA, McRae-Clark AL, Squeglia LM. N-acetylcysteine for youth cannabis use disorder: Randomized controlled trial main findings. Neuropsychopharmacology. 2025 Apr;50(5):731–738. doi: 10.1038/s41386-025-02061-y. Epub 2025 Feb 5.
13. Sharma R, Tikka SK, Bhute AR, Bastia BK. N-acetyl cysteine in the treatment of cannabis use disorder: A systematic review of clinical trials. Addict Behav. 2022 Jun;129:107283. doi: 10.1016/j.addbeh.2022.107283. Epub 2022 Feb 16.
Gambling disorder
14. Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: A pilot study. Biol Psychiatry. 2007 Sep 15;62(6):652–657. doi: 10.1016/j.biopsych.2006.11.021. Epub 2007 Apr 18.
15. Grant JE, Odlaug BL, Chamberlain SR, Potenza MN, Schreiber LR, Donahue CB, Kim SW. A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers. J Clin Psychiatry. 2014 Jan;75(1):39–45. doi: 10.4088/JCP.13m08411.
Mood in opioid use disorders
16. Padoei F, Mamsharifi P, Hazegh P, Boroumand H, Ostadmohammady F, Abbaszadeh-Mashkani S, Banafshe HR, Matini AH, Ghaderi A, Dehkohneh SG. The therapeutic effect of N-acetylcysteine as an add-on to methadone maintenance therapy medication in outpatients with substance use disorders: A randomized, double-blind, placebo-controlled clinical trial. Brain Behav. 2023 Jan;13(1):e2823. doi: 10.1002/brb3.2823. Epub 2022 Nov 30.
Nicotine use disorder
17. Arancini L, Mohebbi M, Berk M, Dean OM, Bortolasci CC, Spolding B, Zazula R, Dodd S. A placebo-controlled, randomised pilot trial of N-acetylcysteine or placebo for cessation of tobacco smoking. Eur Neuropsychopharmacol. 2021 Dec;53:120–126. doi: 10.1016/j.euroneuro.2021.10.002. Epub 2021 Oct 31.
18. Froeliger B, McConnell PA, Stankeviciute N, McClure EA, Kalivas PW, Gray KM. The effects of N-acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. 2015 Nov 1;156:234–242. doi: 10.1016/j.drugalcdep.2015.09.021. Epub 2015 Sep 26.
20. McClure EA, Wahlquist AE, Tomko RL, Baker NL, Carpenter MJ, Bradley ED, Cato PA, Gipson CD, Gray KM. Evaluating N-acetylcysteine for early and end-of-treatment abstinence in adult cigarette smokers. Drug Alcohol Depend. 2021 Aug 1;225:108815. doi: 10.1016/j.drugalcdep.2021.108815. Epub 2021 Jun 18.
21. Prado E, Maes M, Piccoli LG, Baracat M, Barbosa DS, Franco O, Dodd S, Berk M, Vargas Nunes SO. N-acetylcysteine for therapy-resistant tobacco use disorder: A pilot study. Redox Rep. 2015 Sep;20(5):215–222. doi: 10.1179/1351000215Y.0000000004. Epub 2015 Mar 2.
22. Schulte M, Goudriaan AE, Kaag AM, Kooi DP, van den Brink W, Wiers RW, Schmaal L. The effect of N-acetylcysteine on brain glutamate and gamma-aminobutyric acid concentrations and on smoking cessation: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2017 Oct;31(10):1377–1379. doi: 10.1177/0269881117730660. Epub 2017 Sep 19.
Nicotine use disorder / Gambling disorder
19. Grant JE, Odlaug BL, Chamberlain SR, Potenza MN, Schreiber LR, Donahue CB, Kim SW. A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers. J Clin Psychiatry. 2014 Jan;75(1):39–45. doi: 10.4088/JCP.13m08411.
OCD
23. Afshar H, Roohafza H, Mohammad-Beigi H, Haghighi M, Jahangard L, Shokouh P, Sadeghi M, Hafezian H. N-acetylcysteine add-on treatment in refractory obsessive-compulsive disorder: A randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2012 Dec;32(6):797–803. doi: 10.1097/JCP.0b013e318272677d.
24. Costa DLC, Diniz JB, Requena G, Joaquim MA, Pittenger C, Bloch MH, Miguel EC, Shavitt RG. Randomized, double-blind, placebo-controlled trial of N-acetylcysteine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2017 Jul;78(7):e766–e773. doi: 10.4088/JCP.16m11101.
25. Ghanizadeh A, Mohammadi MR, Bahraini S, Keshavarzi Z, Firoozabadi A, Alavi Shoshtari A. Efficacy of N-acetylcysteine augmentation on obsessive compulsive disorder: A multicenter randomized double blind placebo controlled clinical trial. Iran J Psychiatry. 2017 Apr;12(2):134–141.
26. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: Randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016 Apr;41(2):214–219. doi: 10.1111/jcpt.12370. Epub 2016 Mar 2.
27. Sarris J, Byrne G, Castle D, Bousman C, Oliver G, Cribb L, Blair-West S, Brakoulias V, Camfield D, Ee C, Chamoli S, Boschen M, Dean OM, Dowling N, Menon R, Murphy J, Metri NJ, Nguyen TP, Wong A, Jordan R, Karamacoska D, Rossell SL, Berk M, Ng CH. N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jul 13;117:110550. doi: 10.1016/j.pnpbp.2022.110550. Epub 2022 Mar 15.
28. Sarris J, Oliver G, Camfield DA, Dean OM, Dowling N, Smith DJ, Murphy J, Menon R, Berk M, Blair-West S, Ng CH. N-acetyl cysteine (NAC) in the treatment of obsessive-compulsive disorder: A 16-week, double-blind, randomised, placebo-controlled study. CNS Drugs. 2015 Sep;29(9):801–809. doi: 10.1007/s40263-015-0272-9.
Trichotillomania
29. Bloch MH, Panza KE, Grant JE, Pittenger C, Leckman JF. N-acetylcysteine in the treatment of pediatric trichotillomania: A randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013 Mar;52(3):231–240. doi: 10.1016/j.jaac.2012.12.020.
30. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: A double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009 Jul;66(7):756–763. doi: 10.1001/archgenpsychiatry.2009.60.
Bipolar depression
31. Bauer IE, Green C, Colpo GD, Teixeira AL, Selvaraj S, Durkin K, Zunta-Soares GB, Soares JC. A double-blind, randomized, placebo-controlled study of aspirin and N-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018 Dec 4;80(1):18m12200. doi: 10.4088/JCP.18m12200.
32. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15;64(6):468–475. doi: 10.1016/j.biopsych.2008.04.022. Epub 2008 Jun 5.
33. Berk M, Turner A, Malhi GS, Ng CH, Cotton SM, Dodd S, Samuni Y, Tanious M, McAulay C, Dowling N, Sarris J, Owen L, Waterdrinker A, Smith D, Dean OM. A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: Mitochondrial agents, N-acetylcysteine, and placebo. BMC Med. 2019 Jan 25;17(1):18. doi: 10.1186/s12916-019-1257-1. Erratum in: BMC Med. 2019 Feb 17;17(1):35. doi: 10.1186/s12916-019-1280-2.
34. Ellegaard PK, Licht RW, Nielsen RE, Dean OM, Berk M, Poulsen HE, Mohebbi M, Nielsen CT. The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study. J Affect Disord. 2019 Feb 15;245:1043–1051. doi: 10.1016/j.jad.2018.10.083. Epub 2018 Oct 6.
35. Hu CC, Xie J. N-acetylcysteine add on treatment for depressive symptoms in bipolar disorder: A comparative trial. Clin Educ Gen Pract. 2012;10:515–517. Chinese.
36. Porcu M, Urbano MR, Verri WA Jr, Barbosa DS, Baracat M, Vargas HO, Machado RCBR, Pescim RR, Nunes SOV. Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein. Psychiatry Res. 2018;263:268–274. doi: 10.1016/j.psychres.2018.02.056. Epub 2018 Mar 13.
Self-injury
37. Hans D, Rengel A, Hans J, Bassett D, Hood S. N-acetylcysteine as a novel rapidly acting anti-suicidal agent: A pilot naturalistic study in the emergency setting. PLoS One. 2022 Jan 28;17(1):e0263149. doi: 10.1371/journal.pone.0263149.
38. Kandel H, Cruz AR, Thom RP, McDougle CJ. N-acetylcysteine for nonsuicidal self-injurious behavior in 3 adults with Williams syndrome: A case series. J Clin Psychopharmacol. 2025 May–Jun 01;45(3):277–281. doi: 10.1097/JCP.0000000000001976. Epub 2025 Feb 27.
39. Marler S, Sanders KB, Veenstra-VanderWeele J. N-acetylcysteine as treatment for self-injurious behavior in a child with autism. J Child Adolesc Psychopharmacol. 2014 May;24(4):231–234. doi: 10.1089/cap.2013.0137. Epub 2014 May 9.
40. Sahasrabudhe SA, Silamongkol T, Park YW, Colette A, Eberly LE, Klimes-Dougan B, Coles LD, Cloyd JC, Öz G, Mueller BA, Kartha RV, Cullen KR. Identifying biological signatures of N-acetylcysteine for non-suicidal self-injury in adolescents and young adults. J Psychiatr Brain Sci. 2021;6:e210007. doi: 10.20900/jpbs.20210007. Epub 2021 Apr 29.
Renal
41. Efrati S, Averbukh M, Berman S, Feldman L, Dishy V, Kachko L, Weissgarten J, Golik A, Averbukh Z. N-acetylcysteine ameliorates lithium-induced renal failure in rats. Nephrol Dial Transplant. 2005 Jan;20(1):65–70. doi: 10.1093/ndt/gfh573. Epub 2004 Nov 16.
42. Hernández-Cruz EY, Aparicio-Trejo OE, Hammami FA, Bar-Shalom D, Tepel M, Pedraza-Chaverri J, Scholze A. N-acetylcysteine in kidney disease: Molecular mechanisms, pharmacokinetics, and clinical effectiveness. Kidney Int Rep. 2024 Jul 20;9(10):2883–2903. doi: 10.1016/j.ekir.2024.07.020.
43. Prabu OG, Islami NN, Mellenia J, Nugroho P, Rajabto W, Shatri H. N-acetylcysteine role in maintaining renal function in cancer patients with cisplatin-based chemotherapy. Int J Nephrol Renovasc Dis. 2025 Nov 27;18:337–348. doi: 10.2147/IJNRD.S563298.
44. Scholze A, Rinder C, Beige J, Riezler R, Zidek W, Tepel M. Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure. Circulation. 2004 Jan 27;109(3):369–374. doi: 10.1161/01.CIR.0000109492.65802.AD. Epub 2004 Jan 19.
SAMe References
16 references
Major depressive disorder
1. Alkema A, Schalkwijk W, Bohte E, Draisma L, Hoppe A, Koch C, Refuge V, Romberg B, Luykx JJ, Jans JJM, Cahn W, Regeer E, Boks MPM. S-adenosylmethionine as an epigenetic treatment of depression in adults with childhood trauma. Epigenomics. 2026 Apr;18(4):437–449. doi: 10.1080/17501911.2026.2645001. Epub 2026 Apr 24.
2. Bell KM, Plon L, Bunney WE, Potkin SG. S-adenosylmethionine treatment of depression: A controlled clinical trial. Am J Psychiatry. 1988;145(9):1110–1114.
3. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in accelerating the onset of action of imipramine. Psychiatry Res. 1992;44(3):257–262. doi: 10.1016/0165-1781(92)90029-3.
4. De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res. 1992;52(3):478–485. doi: 10.1016/S0011-393X(05)80424-2.
5. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular SAMe in major depression: Comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002;76(5):1172S–1176S.
6. Janicak PG, Lipinski J, Davis JM, Comaty JE, Waternaux C, Cohen B, Altman E, Sharma RP. S-adenosylmethionine in depression. A literature review and preliminary report. Ala J Med Sci. 1988 Jul;25(3):306–313.
7. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: A randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990 May;147(5):591–595. doi: 10.1176/ajp.147.5.591.
8. Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, Baer L, Dording CM, Clain AJ, Durham K, Walker R, Ludington E, Fava M. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. J Clin Psychiatry. 2014 Apr;75(4):370–376. doi: 10.4088/JCP.13m08591.
9. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002 Dec;5(4):287–294. doi: 10.1017/S1461145702003085.
10. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. Am J Psychiatry. 2010 Aug;167(8):942–948. doi: 10.1176/appi.ajp.2009.09081198. Epub 2010 Jul 1.
11. Saccarello A, Montarsolo P, Massardo I, Picciotto R, Pedemonte A, Castagnaro R, Brasesco PC, Guida V, Picco P, Fioravanti P, Montisci R, Schiavetti I, Vanelli A. Oral administration of S-adenosylmethionine (SAMe) and Lactobacillus plantarum HEAL9 improves the mild-to-moderate symptoms of depression. Prim Care Companion CNS Disord. 2020;22(4):19m02578.
12. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of SAMe in depressed postmenopausal women. Psychother Psychosom. 1993;59(1):34–40. doi: 10.1159/000288642.
13. Sarris J, Byrne GJ, Bousman C, Stough C, Murphy J, MacDonald P, Adams L, Nazareth S, Oliver G, Cribb L, Savage K, Menon R, Chamoli S, Berk M, Ng C, Mischoulon D. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial. Eur Neuropsychopharmacol. 2018;28(10):1126–1136. doi: 10.1016/j.euroneuro.2018.07.098.
14. Sarris J, Murphy J, Stough C, Mischoulon D, Bousman C, MacDonald P, Adams L, Nazareth S, Oliver G, Cribb L, Savage K, Menon R, Chamoli S, Berk M, Ng CH, Byrne GJ. S-adenosylmethionine (SAMe) monotherapy for depression: An 8-week double-blind, randomised, controlled trial. Psychopharmacology (Berl). 2020;237(1):209–218. doi: 10.1007/s00213-019-05358-1.
15. Targum SD, Cameron BR, Ferreira L, MacDonald ID. An augmentation study of MSI-195 (S-adenosylmethionine) in major depressive disorder. J Psychiatr Res. 2018;107:86–96.
16. Ullah H, Di Minno A, Esposito C, El-Seedi HR, Khalifa SAM, Baldi A, Greco A, Santonastaso S, Cioffi V, Sperandeo R, Sacchi R, Daglia M. Efficacy of a food supplement based on S-adenosyl methionine and probiotic strains in subjects with subthreshold depression and mild-to-moderate depression: A monocentric, randomized, cross-over, double-blind, placebo-controlled clinical trial. Biomed Pharmacother. 2022 Dec;156:113930. doi: 10.1016/j.biopha.2022.113930. Epub 2022 Oct 27.
Sarcosine References
11 references
Schizophrenia
1. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: A randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry. 2005 Nov;62(11):1196–1204. doi: 10.1001/archpsyc.62.11.1196.
2. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry. 2006 Sep 15;60(6):645–649. doi: 10.1016/j.biopsych.2006.04.005. Epub 2006 Jun 14.
3. Lane HY, Lin CH, Huang YJ, Liao CH, Chang YC, Tsai GE. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol. 2010 May;13(4):451–460. doi: 10.1017/S1461145709990939. Epub 2009 Nov 4.
4. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai GE. Sarcosine (N-methylglycine) treatment for acute schizophrenia: A randomized, double-blind study. Biol Psychiatry. 2008 Jan 1;63(1):9–12. doi: 10.1016/j.biopsych.2007.04.038. Epub 2007 Jul 20.
5. Lin CY, Liang SY, Chang YC, Ting SY, Kao CL, Wu YH, Tsai GE, Lane HY. Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial. World J Biol Psychiatry. 2017 Aug;18(5):357–368. doi: 10.3109/15622975.2015.1117654. Epub 2015 Dec 22.
6. Strzelecki D, Kałużyńska O, Wysokiński A. BDNF serum levels in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study). Psychiatry Res. 2016;242:54–60. PMID: 27262086. [PULSAR trial—primary clinical results reported across multiple publications]
7. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004 Mar 1;55(5):452–456. doi: 10.1016/j.biopsych.2003.09.012.
Major depressive disorder
8. Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, Tun R, Huang KH, Chang YC, Lane HY, Tsai GE. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry. 2013 Nov 15;74(10):734–741. doi: 10.1016/j.biopsych.2013.02.020. Epub 2013 Apr 3.
Major depressive disorder (augmentation)
9. Padhan M, Mohapatra D, Mishra BR, Maiti R, Jena M. Efficacy and safety of add-on sarcosine in patients with major depressive disorder: A randomized controlled trial. J Psychiatr Res. 2024 Oct;178:298–304. doi: 10.1016/j.jpsychires.2024.08.026. Epub 2024 Aug 22.
ADHD (oppositional symptoms, augmentation)
10. Tzang RF, Chang YC, Tsai GE, Lane HY. Sarcosine treatment for oppositional defiant disorder symptoms of attention deficit hyperactivity disorder children. J Psychopharmacol. 2016 Oct;30(10):976–982. doi: 10.1177/0269881116658986. Epub 2016 Jul 21.
OCD
11. Wu PL, Tang HS, Lane HY, Tsai CA, Tsai GE. Sarcosine therapy for obsessive compulsive disorder: A prospective, open-label study. J Clin Psychopharmacol. 2011 Jun;31(3):369–374. doi: 10.1097/JCP.0b013e3182189878.
Omega-3 References
155 references
Aggression / irritability
1. Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146–154. doi: 10.1001/archgenpsychiatry.2009.192.
2. Bègue L, Zaalberg A, Shankland R, et al. Omega-3 supplements reduce self-reported physical aggression in healthy adults. Psychiatry Res. 2018;261:307-311. doi:10.1016/j.psychres.2017.12.038
3. Bos DJ, Oranje B, Veerhoek ES, et al. Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015;40(10):2298-2306. doi:10.1038/npp.2015.73
4. Bozzatello P, Rocca P, Bellino S. Combination of Omega-3 Fatty Acids and Valproic Acid in Treatment of Borderline Personality Disorder: A Follow-Up Study. Clin Drug Investig. 2018;38(4):367-372. doi:10.1007/s40261-017-0617-x
5. Buydens-Branchey L, Branchey M. Long-chain n-3 polyunsaturated fatty acids decrease feelings of anger in substance abusers. Psychiatry Res. 2008;157(1-3):95-104. doi:10.1016/j.psychres.2007.01.004
6. Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002;159(9):1596-1598. doi:10.1176/appi.ajp.159.9.1596
7. Heres S, Hamann J, Kissling W, Leucht S. Attitudes of psychiatrists toward antipsychotic depot medication. J Clin Psychiatry. 2006;67(12):1948-1953. doi:10.4088/jcp.v67n1216
8. Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158(12):2071-2074. doi:10.1176/appi.ajp.158.12.2071
9. Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder MJ. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Br J Psychiatry. 2002;181:22-28. doi:10.1192/bjp.181.1.22
10. Gustafsson PA, Birberg-Thornberg U, Duchén K, et al. EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD. Acta Paediatr. 2010;99(10):1540-1549. doi:10.1111/j.1651-2227.2010.01871.x
11. Hamazaki T, Sawazaki S, Itomura M, et al. The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study. J Clin Invest. 1996;97(4):1129-1133. doi:10.1172/JCI118507
12. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder - a placebo-controlled double-blind study. Eur J Clin Nutr. 2004;58(3):467-473. doi:10.1038/sj.ejcn.1601830
13. Itomura M, Hamazaki K, Sawazaki S, et al. The effect of fish oil on physical aggression in schoolchildren--a randomized, double-blind, placebo-controlled trial. J Nutr Biochem. 2005;16(3):163-171. doi:10.1016/j.jnutbio.2004.10.009
14. Long SJ, Benton D. A double-blind trial of the effect of docosahexaenoic acid and vitamin and mineral supplementation on aggression, impulsivity, and stress. Hum Psychopharmacol. 2013;28(3):238-247. doi:10.1002/hup.2313
15. Mazahery H, Conlon CA, Beck KL, et al. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with autism spectrum disorder. J Steroid Biochem Mol Biol. 2019;187:9-16. doi:10.1016/j.jsbmb.2018.10.017
16. Pawełczyk T, Grancow-Grabka M, Kotlicka-Antczak M, Trafalska E, Pawełczyk A. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016;73:34-44. doi:10.1016/j.jpsychires.2015.11.013
17. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59(10):913-919. doi:10.1001/archpsyc.59.10.913
18. Raine A, Fung ALC, Gao Y, Lee TMC. Omega-3 supplementation, child antisocial behavior, and psychopathic personality: a randomized, double-blind, placebo-controlled, stratified, parallel group trial. Eur Child Adolesc Psychiatry. 2021;30(2):303-312. doi:10.1007/s00787-020-01513-8
19. Raine A, Portnoy J, Liu J, Mahoomed T, Hibbeln JR. Reduction in behavior problems with omega-3 supplementation in children aged 8-16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. J Child Psychol Psychiatry. 2015;56(5):509-520. doi:10.1111/jcpp.12314
20. Raine A, Cheney RA, Ho R, et al. Nutritional supplementation to reduce child aggression: a randomized, stratified, single-blind, factorial trial. J Child Psychol Psychiatry. 2016;57(9):1038-1046. doi:10.1111/jcpp.12565
21. Raine A, Ang RP, Choy O, et al. Omega-3 (ω-3) and social skills interventions for reactive aggression and childhood externalizing behavior problems: a randomized, stratified, double-blind, placebo-controlled, factorial trial. Psychol Med. 2019;49(2):335-344. doi:10.1017/S0033291718000983
22. Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr. 2007;28(2):82-91. doi:10.1097/01.DBP.0000267558.88457.a5
23. Tammam JD, Steinsaltz D, Bester DW, Semb-Andenaes T, Stein JF. A randomised double-blind placebo-controlled trial investigating the behavioural effects of vitamin, mineral and n-3 fatty acid supplementation in typically developing adolescent schoolchildren. Br J Nutr. 2016;115(2):361-373. doi:10.1017/S0007114515004390
24. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 2001 Aug;139(2):189–196. doi: 10.1067/mpd.2001.116050.
25. Zaalberg A, Nijman H, Bulten E, Stroosma L, van der Staak C. Effects of nutritional supplements on aggression, rule-breaking, and psychopathology among young adult prisoners. Aggress Behav. 2010 Mar–Apr;36(2):117–126. doi: 10.1002/ab.20335.
Aggression / irritability / Borderline personality disorder
26. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: A double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan;160(1):167–169. doi: 10.1176/appi.ajp.160.1.167.
Major depressive disorder
27. Açık M, Çakıroğlu FP, Tekin A, Egeli A. The effect of fish oil versus krill oil intervention on clinical symptoms and cardiometabolic risk factors in patients with MDD. J Affect Disord. 2025;380:171–180.
28. Amminger GP, Rice S, Davey CG, Quinn AL, Hermens DF, Zmicerevska N, Nichles A, Hickie I, Incerti L, Weller A, Joseph S, Hilton Z, Pugh C, Rayner M, Reid N, Ratheesh A, Yung AR, Yuen HP, Mackinnon A, Hetrick S, Parker A, Street R, Berger M, Berk M, McGorry PD, Lin A. The addition of fish oil to cognitive behavioral case management for youth depression: A randomized, double-blind, placebo-controlled, multicenter clinical trial. Biol Psychiatry. 2024 Mar 1;95(5):426–433. doi: 10.1016/j.biopsych.2023.06.015. Epub 2023 Jun 22.
29. Berger G, Häberling I, Emery S, Albermann M, Baumgartner N, Nalani K, Strumberger M, Wöckel L, Erb S, Bachmann S, Müller-Knapp U, Contin-Waldvogel B, Yamini A, Rhiner B, Drechsler R, Held U, Reeve K, Heinz P, Pauli D, Schmeck K, Hersberger M, Walitza S; Omega-3 pMDD Study Group. Omega-3 fatty acids in pediatric major depressive disorder: A randomized clinical trial. JAMA Netw Open. 2026 Jan 2;9(1):e2548703. doi: 10.1001/jamanetworkopen.2025.48703.
30. Bot M, Pouwer F, Assies J, Jansen EH, Diamant M, Snoek FJ, Beekman AT, de Jonge P. Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: A randomized, double-blind placebo-controlled study. J Affect Disord. 2010 Oct;126(1–2):282–286. doi: 10.1016/j.jad.2010.04.008. Epub 2010 May 14.
31. Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC, Harris WS. A randomized placebo-controlled trial of omega-3 and sertraline in depressed patients with or at risk for coronary heart disease. J Clin Psychiatry. 2019 Jun 4;80(4):19m12742. doi: 10.4088/JCP.19m12742.
32. Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC, Harris WS. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: A randomized controlled trial. JAMA. 2009 Oct 21;302(15):1651–1657. doi: 10.1001/jama.2009.1487.
33. Chang JP, Chang SS, Yang HT, Chen HT, Chien YC, Yang B, Su H, Su KP. Omega-3 polyunsaturated fatty acids in cardiovascular diseases comorbid major depressive disorder - results from a randomized controlled trial. Brain Behav Immun. 2020 Mar;85:14–20. doi: 10.1016/j.bbi.2019.03.012. Epub 2019 Mar 19.
34. Coryell W et al. (unpublished data, referenced in Cochrane 2021)
35. Fristad MA, Vesco AT, Young AS, Healy KZ, Nader ES, Gardner W, Seidenfeld AM, Wolfson HL, Arnold LE. Pilot randomized controlled trial of omega-3 and individual-family psychoeducational psychotherapy for children and adolescents with depression. J Clin Child Adolesc Psychol. 2019;48(sup1):S105–S118. doi: 10.1080/15374416.2016.1233500. Epub 2016 Nov 7.
36. Gabbay V, Freed RD, Alonso CM, Senger S, Stadterman J, Davison BA, Klein RG. A double-blind placebo-controlled trial of omega-3 fatty acids as a monotherapy for adolescent depression. J Clin Psychiatry. 2018 Jun 26;79(4):17m11596. doi: 10.4088/JCP.17m11596.
37. Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol. 2012 Feb;32(1):61–64. doi: 10.1097/JCP.0b013e31823f3b5f.
38. Gharekhani A, Khatami MR, Dashti-Khavidaki S, Razeghi E, Noorbala AA, Hashemi-Nazari SS, Mansournia MA. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in maintenance hemodialysis patients: A randomized, placebo-controlled clinical trial. Eur J Clin Pharmacol. 2014 Jun;70(6):655–665. doi: 10.1007/s00228-014-1666-1. Epub 2014 Mar 20.
39. González A, Mata S, Sánchez P, González D, Urbina M, Fazzino F, Lima L. Ácidos grasos omega-3 como coadyuvantes del tratamiento antidepresivo y sus efectos sobre el factor neurotrófico derivado del cerebro en suero y en células mononucleares [Omega-3 fatty acids as adjunctive of antidepressant therapy and its effects on brain-derived neurotrophic factor in serum, monocytes and lymphocytes]. Archivos Venezolanos de Farmacología y Terapéutica. 2011;30(4):72–78. Spanish.
40. Grenyer BF, Crowe T, Meyer B, Owen AJ, Grigonis-Deane EM, Caputi P, Howe PR. Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1393–1396. doi: 10.1016/j.pnpbp.2007.06.004. Epub 2007 Jun 19.
41. Jahangard L, Sadeghi A, Ahmadpanah M, Holsboer-Trachsler E, Sadeghi Bahmani D, Haghighi M, Brand S. Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation. J Psychiatr Res. 2018 Dec;107:48–56. doi: 10.1016/j.jpsychires.2018.09.016. Epub 2018 Oct 1.
42. Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine. Aust N Z J Psychiatry. 2008 Mar;42(3):192–198. doi: 10.1080/00048670701827275.
43. Jiang W, Whellan DJ, Adams KF, Babyak MA, Boyle SH, Wilson JL, Patel CB, Rogers JG, Harris WS, O'Connor CM. Long-chain omega-3 fatty acid supplements in depressed heart failure patients: Results of the OCEAN trial. JACC Heart Fail. 2018 Oct;6(10):833–843. doi: 10.1016/j.jchf.2018.03.011. Epub 2018 Aug 8.
44. Keshavarz SA, Mostafavi SA, Akhondzadeh S, Mohammadi MR, Hosseini S, Eshraghian MR, Chamari M. Omega-3 supplementation effects on body weight and depression among dieter women with co-morbidity of depression and obesity compared with the placebo: A randomized clinical trial. Clin Nutr ESPEN. 2018 Jun;25:37–43. doi: 10.1016/j.clnesp.2018.03.001. Epub 2018 Mar 17.
45. Lespérance F, Frasure-Smith N, St-André E, Turecki G, Lespérance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: A randomized controlled trial. J Clin Psychiatry. 2011 Aug;72(8):1054–1062. doi: 10.4088/JCP.10m05966blu. Epub 2010 Jun 15.
46. Li S, Li R, Hu X, Zhang Y, Wang D, Gao Y, Wang J, Wang Q, Song C, Huang S, Zhang E, Zhang J, Xia Z, Wan C. Omega-3 supplementation improves depressive symptoms, cognitive function and niacin skin flushing response in adolescent depression. J Affect Disord. 2024 Jan 15;345:394–403. doi: 10.1016/j.jad.2023.10.151. Epub 2023 Oct 30.
47. Lucas M, Asselin G, Mérette C, Poulin MJ, Dodin S. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women. Am J Clin Nutr. 2009 Feb;89(2):641–651. doi: 10.3945/ajcn.2008.26749. Epub 2008 Dec 30.
48. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003 May;160(5):996–998. doi: 10.1176/appi.ajp.160.5.996.
49. Masoumi SZ, Kazemi F, Tavakolian S, Rahimi A, Oshvandi K, Soltanian A, Shobeiri F. Effect of citalopram in combination with omega-3 on depression in post-menopausal women. J Clin Diagn Res. 2016 Oct;10(10):QC01–QC05. doi: 10.7860/JCDR/2016/19487.8597. Epub 2016 Oct 1.
50. Mazereeuw G, Herrmann N, Oh PI, Ma DW, Wang CT, Kiss A, Lanctôt KL. Omega-3 fatty acids, depressive symptoms, and cognitive performance in patients with coronary artery disease. J Clin Psychopharmacol. 2016 Oct;36(5):436–444. doi: 10.1097/JCP.0000000000000565.
51. McNamara RK, Jandacek R, Rider T, Tso P, Chu WJ, Weber WA, Welge JA, Strawn JR, Adler CM, DelBello MP. Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study. Nutr Neurosci. 2016 May;19(4):145-55. doi: 10.1179/1476830514Y.0000000135. Epub 2016 Mar 2.
52. Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH. Omega-3 fatty acids for major depressive disorder with high inflammation: A randomized dose-finding clinical trial. J Clin Psychiatry. 2022 Aug 22;83(5):21m14074. doi: 10.4088/JCP.21m14074.
53. Mischoulon D, Nierenberg AA, Schettler PJ, Kinkead BL, Fehling K, Martinson MA, Hyman Rapaport M. A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. J Clin Psychiatry. 2015 Jan;76(1):54–61. doi: 10.4088/JCP.14m08986.
54. Mischoulon D, Papakostas GI, Dording CM, Farabaugh AH, Sonawalla SB, Agoston AM, Smith J, Beaumont EC, Dahan LE, Alpert JE, Nierenberg AA, Fava M. A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J Clin Psychiatry. 2009 Dec;70(12):1636–1644. doi: 10.4088/JCP.08m04603. Epub 2009 Aug 25.
55. Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, Shariati-Bafghi SE. Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: A randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2013 Jul;23(7):636–644. doi: 10.1016/j.euroneuro.2012.08.003. Epub 2012 Aug 19.
56. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002 Mar;159(3):477–479. doi: 10.1176/appi.ajp.159.3.477.
57. Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH. Omega-3 treatment of childhood depression: A controlled, double-blind pilot study. Am J Psychiatry. 2006 Jun;163(6):1098–1100. doi: 10.1176/ajp.2006.163.6.1098.
58. Paduchová Z, Katrenčíková B, Vaváková M, Laubertová L, Nagyová Z, Garaiova I, Ďuračková Z, Trebatická J. The effect of omega-3 fatty acids on thromboxane, brain-derived neurotrophic factor, homocysteine, and vitamin D in depressive children and adolescents: randomized controlled trial. Nutrients. 2021 Mar 27;13(4):1095. doi: 10.3390/nu13041095.
59. Park Y, Park YS, Kim SH, Oh DH, Park YC. Supplementation of n-3 polyunsaturated fatty acids for major depressive disorder: A randomized, double-blind, 12-week, placebo-controlled trial in Korea. Ann Nutr Metab. 2015;66(2–3):141–148. doi: 10.1159/000377640. Epub 2015 Mar 24.
60. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002 Oct;59(10):913–919. doi: 10.1001/archpsyc.59.10.913.
61. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: A proof-of-concept study. Mol Psychiatry. 2016 Jan;21(1):71–79. doi: 10.1038/mp.2015.22. Epub 2015 Mar 24.
62. Rondanelli M, Giacosa A, Opizzi A, Pelucchi C, La Vecchia C, Montorfano G, Negroni M, Berra B, Politi P, Rizzo AM. Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: A double-blind, placebo-controlled, randomized clinical trial. J Am Coll Nutr. 2010 Feb;29(1):55–64. doi: 10.1080/07315724.2010.10719817.
63. Shinto L, Marracci G, Mohr DC, Bumgarner L, Murchison C, Senders A, Bourdette D. Omega-3 fatty acids for depression in multiple sclerosis: A randomized pilot study. PLoS One. 2016 Jan 22;11(1):e0147195. doi: 10.1371/journal.pone.0147195.
64. Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005 Mar;72(3):211–218. doi: 10.1016/j.plefa.2004.11.004.
65. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003 Aug;13(4):267–271. doi: 10.1016/s0924-977x(03)00032-4. Erratum in: Eur Neuropsychopharmacol. 2004 Mar;14(2):173.
66. Tajalizadekhoob Y, Sharifi F, Fakhrzadeh H, Mirarefin M, Ghaderpanahi M, Badamchizade Z, Azimipour S. The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: A double-blind, randomized, placebo-controlled study. Eur Arch Psychiatry Clin Neurosci. 2011 Dec;261(8):539–549. doi: 10.1007/s00406-011-0191-9. Epub 2011 Feb 12.
67. Tayama J, Ogawa S, Nakaya N, Sone T, Hamaguchi T, Takeoka A, Hamazaki K, Okamura H, Yajima J, Kobayashi M, Hayashida M, Shirabe S. Omega-3 polyunsaturated fatty acids and psychological intervention for workers with mild to moderate depression: A double-blind randomized controlled trial. J Affect Disord. 2019 Feb 15;245:364–370. doi: 10.1016/j.jad.2018.11.039. Epub 2018 Nov 6.
68. Trebatická J, Hradecká Z, Surovcová A, Katrenčíková B, Gushina I, Waczulikóvá I, Sušienková K, Garaiova I, Šuba J, Ďuráková Z. Omega-3 fatty-acids modulate symptoms of depressive disorder, serum levels of omega-3 fatty acids and omega-6/omega-3 ratio in children. Psychiatry Res. 2020 May;287:112911. doi: 10.1016/j.psychres.2020.112911. Epub 2020 Mar 7.
69. Wang J, Li S, Wang D, Gao Y, Wang Q, Wang T, Wang G, Peng D, Qiao Y, Zhou J, Feng L, Hu X, Wan C. Effects of omega-3 PUFAs on lipid profiles and antioxidant response in depressed adolescents: A metabolomic and lipidomic study. Redox Biol. 2025 May;82:103617. doi: 10.1016/j.redox.2025.103617. Epub 2025 Mar 25.
70. Wu SK, Yang KJ, Liu WC, Malau IA, Zailani H, Chang CH, Huang SY, Chang JP, Chiu WC, Su KP. The efficacy of omega-3 fatty acids as the monotherapy for depression: A randomized, double-blind, placebo-controlled pilot study. Nutrients. 2024 Oct 29;16(21):3688. doi: 10.3390/nu16213688.
71. Yang B, Lin L, Bazinet RP, Chien YC, Chang JP, Satyanarayanan SK, Su H, Su KP. Clinical efficacy and biological regulations of omega-3 PUFA-derived endocannabinoids in major depressive disorder. Psychother Psychosom. 2019;88(4):215–224. doi: 10.1159/000501158. Epub 2019 Jul 3.
72. Young AS, Arnold LE, Wolfson HL, Fristad MA. Psychoeducational psychotherapy and omega-3 supplementation improve co-occurring behavioral problems in youth with depression: Results from a pilot RCT. J Abnorm Child Psychol. 2017 Jul;45(5):1025–1037. doi: 10.1007/s10802-016-0203-3.
Mild cognitive impairment
73. Bo Y, Zhang X, Wang Y, You J, Cui H, Zhu Y, Pang W, Liu W, Jiang Y, Lu Q. The n-3 polyunsaturated fatty acids supplementation improved the cognitive function in the chinese elderly with mild cognitive impairment: A double-blind randomized controlled trial. Nutrients. 2017 Jan 10;9(1):54. doi: 10.3390/nu9010054.
74. Külzow N, Witte AV, Kerti L, Grittner U, Schuchardt JP, Hahn A, Flöel A. Impact of omega-3 fatty acid supplementation on memory functions in healthy older adults. J Alzheimers Dis. 2016;51(3):713–725. doi: 10.3233/JAD-150886.
75. Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2013 Feb;225(3):605–612. doi: 10.1007/s00213-012-2848-0. Epub 2012 Aug 30.
76. Phillips MA, Childs CE, Calder PC, Rogers PJ. No effect of omega-3 fatty acid supplementation on cognition and mood in individuals with cognitive impairment and probable Alzheimer's disease: A randomised controlled trial. Int J Mol Sci. 2015 Oct 16;16(10):24600–24613. doi: 10.3390/ijms161024600.
77. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, Howe PR. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: A 6-month randomised controlled trial. Br J Nutr. 2012 Jun;107(11):1682–1693. doi: 10.1017/S0007114511004788. Epub 2011 Sep 20.
78. Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov;24(11):3059–3068. doi: 10.1093/cercor/bht163. Epub 2013 Jun 24.
79. Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456–464. doi: 10.1016/j.jalz.2010.01.013.
80. Zhang YP, Miao R, Li Q, Wu T, Ma F. Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with mild cognitive impairment: A 12-month randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2017;55(2):497–507. doi: 10.3233/JAD-160439.
Anxiety
81. Aucoin M, LaChance L, van der Wurff I, McLaren M, Monteiro S, Miller S, Jenkins A, Sabri E, Cooley K. Dietary counseling plus omega-3 supplementation in the treatment of generalized anxiety disorder: Results of a randomized wait-list controlled pilot trial (the 'EASe-GAD Trial'). Nutr Neurosci. 2025 Jun;28(6):635–648. doi: 10.1080/1028415X.2024.2403901. Epub 2024 Sep 24.
82. Buydens-Branchey L, Branchey M, Hibbeln JR. Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):568–575. doi: 10.1016/j.pnpbp.2007.10.020. Epub 2007 Nov 1.
83. Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008 Mar;42(3):192–198. doi: 10.1080/00048670701827275.
84. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: A randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402–1408. doi: 10.1001/archneur.63.10.1402.
85. Fux M, Benjamin J, Nemets B. A placebo-controlled cross-over trial of adjunctive EPA in OCD. J Psychiatr Res. 2004 May–Jun;38(3):323–325. doi: 10.1016/S0022-3956(03)00077-3.
86. Gabbay V, Babb JS, Klein RG, et al. A double-blind, placebo-controlled trial of ω-3 fatty acids in Tourette's disorder. Pediatrics. 2012;129(6):e1493-e1500. doi:10.1542/peds.2011-3384
87. Gharekhani A, Khatami MR, Dashti-Khavidaki S, et al. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in maintenance hemodialysis patients: a randomized, placebo-controlled clinical trial. Eur J Clin Pharmacol. 2014;70(6):655-665. doi:10.1007/s00228-014-1666-1
88. Haberka M, Mizia-Stec K, Mizia M, Gieszczyk K, Chmiel A, Sitnik-Warchulska K, Gąsior Z. Effects of n-3 polyunsaturated fatty acids on depressive symptoms, anxiety and emotional state in patients with acute myocardial infarction. Pharmacol Rep. 2013;65(1):59–68. doi: 10.1016/s1734-1140(13)70964-2.
89. Jahangard L, Sadeghi A, Ahmadpanah M, et al. Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation among outpatients with major depressive disorders - Results from a double-blind, randomized and placebo-controlled clinical trial. J Psychiatr Res. 2018;107:48-56. doi:10.1016/j.jpsychires.2018.09.016
90. Keshavarz SA, Mostafavi SA, Akhondzadeh S, Mohammadi MR, Hosseini S, Eshraghian MR, Chamari M. Omega-3 supplementation effects on body weight and depression among dieter women with co-morbidity of depression and obesity compared with the placebo: A randomized clinical trial. Clin Nutr ESPEN. 2018 Jun;25:37–43. doi: 10.1016/j.clnesp.2018.03.001. Epub 2018 Mar 17.
91. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial. Brain Behav Immun. 2011 Nov;25(8):1725–1734. doi: 10.1016/j.bbi.2011.07.229. Epub 2011 Jul 19.
92. Lespérance F, Frasure-Smith N, St-André E, Turecki G, Lespérance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry. 2011;72(8):1054-1062. doi:10.4088/JCP.10m05966blu
93. Matsuoka Y, Nishi D, Hamazaki K, et al. Docosahexaenoic acid for selective prevention of posttraumatic stress disorder among severely injured patients: a randomized, placebo-controlled trial. J Clin Psychiatry. 2015;76(8):e1015-e1022. doi:10.4088/JCP.14m09260
94. Milte CM, Parletta N, Buckley JD, Coates AM, Young RM, Howe PR. Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: a randomized controlled trial. Nutrition. 2012;28(6):670-677. doi:10.1016/j.nut.2011.12.009
95. Nishi D, Koido Y, Nakaya N, et al. Fish oil for attenuating posttraumatic stress symptoms among rescue workers after the great east Japan earthquake: a randomized controlled trial. Psychother Psychosom. 2012;81(5):315-317. doi:10.1159/000336811
96. Piperoglou M, Hopwood M, Norman TR. Adjunctive docosahexaenoic acid in residual symptoms of depression and anxiety. J Clin Psychopharmacol. 2023 Nov–Dec 01;43(6):493–497. doi: 10.1097/JCP.0000000000001767. Epub 2023 Oct 25.
97. Rocha Filho EA, Lima JC, Pinho Neto JS, Montarroyos U. Essential fatty acids for premenstrual syndrome and their effect on prolactin and total cholesterol levels: A randomized, double blind, placebo-controlled study. Reprod Health. 2011 Jan 17;8:2. doi: 10.1186/1742-4755-8-2.
98. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(4):267-271. doi:10.1016/s0924-977x(03)00032-4
99. Wang L, Liu T, Guo J, Zhao T, Tang H, Wang F, Dong F, Chen J, Tang M. N-3 PUFA supplementation alleviates anxiety symptoms by manipulating erythrocyte fatty acid levels in depression. Eur J Nutr. 2024 Sep;63(6):2271–2279. doi: 10.1007/s00394-024-03421-y. Epub 2024 May 17.
100. Widenhorn-Müller K, Schwanda S, Scholz E, Spitzer M, Bode H. Effect of supplementation with long-chain ω-3 polyunsaturated fatty acids on behavior and cognition in children with attention deficit/hyperactivity disorder (ADHD): a randomized placebo-controlled intervention trial. Prostaglandins Leukot Essent Fatty Acids. 2014;91(1-2):49-60. doi:10.1016/j.plefa.2014.04.004
101. Yehuda S, Rabinovitz S, Mostofsky DI. Mixture of essential fatty acids lowers test anxiety. Nutr Neurosci. 2005;8(4):265-267. doi:10.1080/10284150500445795
Anxiety / Borderline personality disorder
102. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: A double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan;160(1):167–169. doi: 10.1176/appi.ajp.160.1.167.
Borderline personality disorder
103. Amminger GP, Chanen AM, Ohmann S, Klier CM, Mossaheb N, Bechdolf A, Nelson B, Thompson A, McGorry PD, Yung AR, Schäfer MR. Omega-3 fatty acid supplementation in adolescents with borderline personality disorder and ultra-high risk criteria for psychosis: A post hoc subgroup analysis of a double-blind, randomized controlled trial. Can J Psychiatry. 2013 Jul;58(7):402–408. doi: 10.1177/070674371305800705.
104. Bellino S, Bozzatello P, Rocca G, Bogetto F. Efficacy of omega-3 fatty acids in the treatment of borderline personality disorder: A study of the association with valproic acid. J Psychopharmacol. 2014 Feb;28(2):125–132. doi: 10.1177/0269881113510072. Epub 2013 Nov 5.
105. Hallahan B, Hibbeln JR, Davis JM, Garland MR. Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br J Psychiatry. 2007 Feb;190:118–122. doi: 10.1192/bjp.bp.106.022707.
106. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: A double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan;160(1):167–169. doi: 10.1176/appi.ajp.160.1.167.
Metabolic syndrome on antipsychotics
107. Behdani F, Roudbaraki SN, Saberi-Karimian M, Tayefi M, Hebrani P, Akhavanrezayat A, Amlashi SV, Ferns GA, Ghayour-Mobarhan M. Assessment of the efficacy of omega-3 fatty acids on metabolic and inflammatory parameters in patients with schizophrenia taking clozapine and sodium valproate. Psychiatry Res. 2018 Mar;261:243–247. doi: 10.1016/j.psychres.2017.12.028. Epub 2017 Dec 12.
108. Bentsen H, Osnes K, Refsum H, Solberg DK, Bøhmer T. A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry. 2013;3(12):e335. Published 2013 Dec 17. doi:10.1038/tp.2013.110
109. Berger GE, Proffitt TM, McConchie M, Yuen H, Wood SJ, Amminger GP, Brewer W, McGorry PD. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry. 2007 Dec;68(12):1867–1875. doi: 10.4088/jcp.v68n1206.
110. Emsley R, Niehaus DJ, Oosthuizen PP, Koen L, Ascott-Evans B, Chiliza B, van Rensburg SJ, Smit RM. Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo-controlled trial. Psychiatry Res. 2008 Dec 15;161(3):284–291. doi: 10.1016/j.psychres.2007.06.029. Epub 2008 Oct 29.
111. Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001 Dec;158(12):2071–2074. doi: 10.1176/appi.ajp.158.12.2071.
112. Freeman MP, McInerney K, Sosinsky AZ, Kwiatkowski MA, Cohen LS. Omega-3 fatty acids for atypical antipsychotic-associated hypertriglyceridemia. Ann Clin Psychiatry. 2015 Aug;27(3):197–202.
113. Jamilian H, Solhi H, Jamilian M. Randomized, placebo-controlled clinical trial of omega-3 as supplemental treatment in schizophrenia. Glob J Health Sci. 2014;6(7 Spec No):103-108. Published 2014 Sep 18. doi:10.5539/gjhs.v6n7p103
114. Pawełczyk T, Grancow-Grabka M, Kotlicka-Antczak M, Trafalska E, Pawełczyk A. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016 Feb;73:34–44. doi: 10.1016/j.jpsychires.2015.11.013. Epub 2015 Nov 25.
115. Peet M, Horrobin DF; E-E Multicentre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res. 2002 Jan–Feb;36(1):7–18. doi: 10.1016/s0022-3956(01)00048-6.
116. Tang W, Wang Y, Xu F, Fan W, Zhang Y, Fan K, Wang W, Zhang Y, Zhang C. Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome. Brain Behav Immun. 2020 Aug;88:529–534. doi: 10.1016/j.bbi.2020.04.034. Epub 2020 Apr 15.
117. Xu F, Fan W, Wang W, Tang W, Yang F, Zhang Y, Cai J, Song L, Zhang C. Effects of omega-3 fatty acids on metabolic syndrome in patients with schizophrenia: A 12-week randomized placebo-controlled trial. Psychopharmacology (Berl). 2019 Apr;236(4):1273–1279. doi: 10.1007/s00213-018-5136-9. Epub 2018 Dec 5.
Bipolar disorder
118. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: Randomised double-blind placebo-controlled study. Br J Psychiatry. 2006 Jan;188:46–50. doi: 10.1192/bjp.188.1.46.
119. Fristad MA, Young AS, Vesco AT, Nader ES, Healy KZ, Gardner W, Wolfson HL, Arnold LE. A randomized controlled trial of individual family psychoeducational psychotherapy and omega-3 fatty acids in youth with subsyndromal bipolar disorder. J Child Adolesc Psychopharmacol. 2015 Dec;25(10):764–774. doi: 10.1089/cap.2015.0132.
120. Gholipour D, Shahraki M, Shakiba M, Shamsi-Goushki A. Supplementation of omega-3 increases serum levels of brain-derived neurotrophic factor and decreases depression status in patients with bipolar disorder. J Hum Nutr Diet. 2025 Jun;38(3):e70076. doi: 10.1111/jhn.70076.
121. Gracious BL, Chirieac MC, Costescu S, Finucane TL, Youngstrom EA, Hibbeln JR. Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder. Bipolar Disord. 2010 Mar;12(2):142–154. doi: 10.1111/j.1399-5618.2010.00799.x.
122. Keck PE Jr, Mintz J, McElroy SL, Freeman MP, Suppes T, Frye MA, Altshuler LL, Kupka R, Nolen WA, Leverich GS, Denicoff KD, Grunze H, Duan N, Post RM. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry. 2006 Nov 1;60(9):1020–1022. doi: 10.1016/j.biopsych.2006.03.056. Epub 2006 Jun 30.
123. McPhilemy G, Byrne F, Waldron M, Hibbeln JR, Davis J, McDonald C, Hallahan B. A 52-week prophylactic randomised control trial of omega-3 polyunsaturated fatty acids in bipolar disorder. Bipolar Disord. 2021 Nov;23(7):697–706. doi: 10.1111/bdi.13037. Epub 2021 Jan 10.
124. Murphy BL, Stoll AL, Harris PQ, Ravichandran C, Babb SM, Carlezon WA Jr, Cohen BM. Omega-3 fatty acid treatment, with or without cytidine, fails to show therapeutic properties in bipolar disorder: a double-blind, randomized add-on clinical trial. J Clin Psychopharmacol. 2012 Oct;32(5):699–703. doi: 10.1097/JCP.0b013e318266854c.
125. Saunders EFH, Mukherjee D, Myers T, Wasserman E, Hameed A, Bassappa Krishnamurthy V, MacIntosh B, Domenichiello A, Ramsden CE, Wang M. Adjunctive dietary intervention for bipolar disorder: A randomized, controlled, parallel-group, modified double-blinded trial of a high n-3 plus low n-6 diet. Bipolar Disord. 2022 Mar;24(2):171–184. doi: 10.1111/bdi.13112. Epub 2021 Aug 2.
126. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999 May;56(5):407–412. doi: 10.1001/archpsyc.56.5.407.
127. Vesco AT, Young AS, Arnold LE, Fristad MA. Omega-3 supplementation associated with improved parent-rated executive function in youth with mood disorders. J Child Psychol Psychiatry. 2018 Jun;59(6):628–636. doi: 10.1111/jcpp.12830. Epub 2017 Oct 24.
128. Wozniak J, Faraone SV, Chan J, Tarko L, Hernandez M, Davis J, Woodworth KY, Biederman J. A randomized clinical trial of high eicosapentaenoic acid omega-3 fatty acids and inositol as monotherapy and in combination in the treatment of pediatric bipolar spectrum disorders: A pilot study. J Clin Psychiatry. 2015 Nov;76(11):1548–1555. doi: 10.4088/JCP.14m09267. Erratum in: J Clin Psychiatry. 2016 Sep;77(9):e1153. PMID: 26646031.
129. Zailani H, Wu SK, Yang KJ, Malau IA, Liao HF, Chung YL, Chang JP, Chiu WC, Su KP. Omega-3 polyunsaturated fatty acids in the prevention of relapse in patients with stable bipolar disorder: A 6-month pilot randomized controlled trial. Psychiatry Res. 2024 Jan;331:115633. doi: 10.1016/j.psychres.2023.115633. Epub 2023 Nov 26.
ADHD
130. Bos DJ, Oranje B, Veerhoek ES, Van Diepen RM, Weusten JM, Demmelmair H, Koletzko B, de Sain-van der Velden MG, Eilander A, Hoeksma M, Durston S. Reduced symptoms of inattention after dietary omega-3 fatty acid supplementation in boys with and without attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2015 Sep;40(10):2298–2306. doi: 10.1038/npp.2015.73. Epub 2015 Mar 19.
131. Carucci S, Romaniello R, Demuru G, Curatolo P, Grelloni C, Masi G, Liboni F, Mereu A, Contu P, Lamberti M, Gagliano A, Zuddas A. Omega-3/6 supplementation for mild to moderate inattentive ADHD: A randomised, double-blind, placebo-controlled efficacy study in Italian children. Eur Arch Psychiatry Clin Neurosci. 2022 Dec;272(8):1453–1467. doi: 10.1007/s00406-022-01428-2. Epub 2022 Jun 7.
132. Chang JP, Su KP, Mondelli V, Satyanarayanan SK, Yang HT, Chiang YJ, Chen HT, Pariante CM. High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels. Transl Psychiatry. 2019 Nov 20;9(1):303. doi: 10.1038/s41398-019-0633-0.
133. Crippa A, Tesei A, Sangiorgio F, Salandi A, Trabattoni S, Grazioli S, Agostoni C, Molteni M, Nobile M. Behavioral and cognitive effects of docosahexaenoic acid in drug-naïve children with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled clinical trial. Eur Child Adolesc Psychiatry. 2019 Apr;28(4):571–583. doi: 10.1007/s00787-018-1223-z. Epub 2018 Sep 24.
134. Gustafsson PA, Birberg-Thornberg U, Duchén K, Landgren M, Malmberg K, Pelling H, Strandvik B, Karlsson T. EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD. Acta Paediatr. 2010 Oct;99(10):1540–1549. doi: 10.1111/j.1651-2227.2010.01871.x. Epub 2010 Jun 8.
135. Milte CM, Parletta N, Buckley JD, Coates AM, Young RM, Howe PR. Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: a randomized controlled trial. Nutrition. 2012 Jun;28(6):670–677. doi: 10.1016/j.nut.2011.12.009. Epub 2012 Apr 25.
136. Mohammadzadeh S, Baghi N, Yousefi F, Yousefzamani B. Effect of omega-3 plus methylphenidate as an alternative therapy to reduce attention deficit-hyperactivity disorder in children. Korean J Pediatr. 2019 Sep;62(9):360–366. doi: 10.3345/kjp.2018.06982. Epub 2019 May 20.
137. Perera H, Jeewandara KC, Seneviratne S, Guruge C. Combined omega-3 and omega-6 supplementation in children with attention-deficit hyperactivity disorder (ADHD) refractory to methylphenidate treatment: A double-blind, placebo-controlled study. J Child Neurol. 2012 Jun;27(6):747–753. doi: 10.1177/0883073811435243.
138. Rodríguez C, García T, Areces D, Fernández E, García-Noriega M, Domingo JC. Supplementation with high-content docosahexaenoic acid triglyceride in attention-deficit hyperactivity disorder: A randomized double-blind placebo-controlled trial. Neuropsychiatr Dis Treat. 2019 May 8;15:1193–1209. doi: 10.2147/NDT.S206020.
139. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 2001 Aug;139(2):189–196. doi: 10.1067/mpd.2001.116050.
140. Widenhorn-Müller K, Schwanda S, Scholz E, Spitzer M, Bode H. Effect of supplementation with long-chain ω-3 polyunsaturated fatty acids on behavior and cognition in children with attention deficit/hyperactivity disorder (ADHD): A randomized placebo-controlled intervention trial. Prostaglandins Leukot Essent Fatty Acids. 2014 Jul–Aug;91(1–2):49–60. doi: 10.1016/j.plefa.2014.04.004. Epub 2014 May 28.
Autism
141. Amminger GP, Berger GE, Schäfer MR, Klier C, Friedrich MH, Feucht M. Omega-3 fatty acids supplementation in children with autism: A double-blind randomized, placebo-controlled pilot study. Biol Psychiatry. 2007 Feb 15;61(4):551–553. doi: 10.1016/j.biopsych.2006.05.007. Epub 2006 Aug 22.
142. Bent S, Bertoglio K, Ashwood P, Bostrom A, Hendren RL. A pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorder. J Autism Dev Disord. 2011 May;41(5):545–554. doi: 10.1007/s10803-010-1078-8.
143. Bent S, Hendren RL, Zandi T, Law K, Choi JE, Widjaja F, Kalb L, Nestle J, Law P. Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism. J Am Acad Child Adolesc Psychiatry. 2014 Jun;53(6):658–666. doi: 10.1016/j.jaac.2014.01.018. Epub 2014 Mar 12.
144. Doaei S, Bourbour F, Teymoori Z, Jafari F, Kalantari N, Abbas Torki S, Ashoori N, Nemat Gorgani S, Gholamalizadeh M. The effect of omega-3 fatty acids supplementation on social and behavioral disorders of children with autism: A randomized clinical trial. Pediatr Endocrinol Diabetes Metab. 2021;27(1):12–18. doi: 10.5114/pedm.2020.101806.
145. Keim SA, Gracious B, Boone KM, Klebanoff MA, Rogers LK, Rausch J, Coury DL, Sheppard KW, Husk J, Rhoda DA. Omega-3 and omega-6 fatty acid supplementation may reduce autism symptoms based on parent report in preterm toddlers. J Nutr. 2018 Feb 1;148(2):227–235. doi: 10.1093/jn/nxx047.
146. Mankad D, Dupuis A, Smile S, Roberts W, Brian J, Lui T, Genore L, Zaghloul D, Iaboni A, Marcon PM, Anagnostou E. A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. Mol Autism. 2015 Mar 21;6:18. doi: 10.1186/s13229-015-0010-7.
147. Mazahery H, Conlon CA, Beck KL, Mugridge O, Kruger MC, Stonehouse W, Camargo CA Jr, Meyer BJ, Tsang B, Jones B, von Hurst PR. A randomised-controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of core symptoms of autism spectrum disorder in children. J Autism Dev Disord. 2019 May;49(5):1778–1794. doi: 10.1007/s10803-018-3860-y.
148. Parellada M, Llorente C, Calvo R, Gutierrez S, Lázaro L, Graell M, Guisasola M, Dorado ML, Boada L, Romo J, Dulin E, Sanz I, Arango C, Moreno C. Randomized trial of omega-3 for autism spectrum disorders: Effect on cell membrane composition and behavior. Eur Neuropsychopharmacol. 2017 Dec;27(12):1319–1330. doi: 10.1016/j.euroneuro.2017.08.426. Epub 2017 Sep 19.
149. Voigt RG, Mellon MW, Katusic SK, Weaver AL, Matern D, Mellon B, Jensen CL, Barbaresi WJ. Dietary docosahexaenoic acid supplementation in children with autism. J Pediatr Gastroenterol Nutr. 2014 Jun;58(6):715–722. doi: 10.1097/MPG.0000000000000260.
150. Yui K, Koshiba M, Nakamura S, Kobayashi Y. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: A double-blind, placebo-controlled, randomized trial. J Clin Psychopharmacol. 2012 Apr;32(2):200–206. doi: 10.1097/JCP.0b013e3182485791.
Premenstrual syndrome
151. Behboudi-Gandevani S, Hariri FZ, Moghaddam-Banaem L. The effect of omega 3 fatty acid supplementation on premenstrual syndrome and health-related quality of life: A randomized clinical trial. J Psychosom Obstet Gynaecol. 2018 Dec;39(4):266–272. doi: 10.1080/0167482X.2017.1348496. Epub 2017 Jul 14.
152. Harel Z, Biro FM, Kottenhahn RK, Rosenthal SL. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. Am J Obstet Gynecol. 1996 Apr;174(4):1335–1338. doi: 10.1016/s0002-9378(96)70681-6.
153. Rocha Filho EA, Lima JC, Pinho Neto JS, Montarroyos U. Essential fatty acids for premenstrual syndrome and their effect on prolactin and total cholesterol levels: A randomized, double blind, placebo-controlled study. Reprod Health. 2011 Jan 17;8:2. doi: 10.1186/1742-4755-8-2.
Prevention of psychosis in adolescents at high risk
154. Chen C, Deng Y, Li Y, Zhang M, Yu T, Xie K, Bao W, Li P, Sun L, Zhang T, Zhu Y, Zhang B. Network meta-analysis indicates superior effects of omega-3 polyunsaturated fatty acids in preventing the transition to psychosis in individuals at clinical high-risk. Int J Neuropsychopharmacol. 2024 Mar 1;27(3):pyae014. doi: 10.1093/ijnp/pyae014.
Cardiovascular Disease
155. Reference: Malik A, Ramadan A, Vemuri B, et al. ω-3 Ethyl ester results in better cognitive function at 12 and 30 months than control in cognitively healthy subjects with coronary artery disease: a secondary analysis of a randomized clinical trial. Am J Clin Nutr. 2021;113(5):1168-1176.
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Back to categories
Schizotypal personality traits
156. Raine A, Gur RC, Gur RE, Richmond TS, Hibbeln J, Liu J. Omega-3 supplementation reduces schizotypal personality in children: A randomized controlled trial. Schizophr Bull. 2024 Aug 27;50(5):1117–1126. doi: 10.1093/schbul/sbae009.
Palmitoylethanolamide References
7 references
Autism (irritability and hyperactivity)
1. Khalaj M, Saghazadeh A, Shirazi E, Shalbafan MR, Alavi K, Shooshtari MH, Laksari FY, Hosseini M, Mohammadi MR, Akhondzadeh S. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018 Aug;103:104–111. doi: 10.1016/j.jpsychires.2018.04.022. Epub 2018 May 1.
Bipolar mania (augmentation)
2. Abedini T, Hosseyni R, Ghannadi F, Moghaddam HS, Ardakani MK, Talaei A, Akhondzadeh S. Efficacy and safety of palmitoylethanolamide as an adjunctive treatment for acute mania: A randomized, double-blind, placebo-controlled trial. Psychiatry Clin Neurosci. 2022 Oct;76(10):505–511. doi: 10.1111/pcn.13441. Epub 2022 Jul 19.
Frontotemporal dementia (with luteolin)
3. Assogna M, Di Lorenzo F, Bonnì S, Borghi I, Cerulli Irelli E, Mencarelli L, Maiella M, Minei M, Esposito R, Casula EP, Pezzopane V, D'Acunto A, Porrazzini F, Candeo F, Ferraresi M, Motta C, Ferrari C, Caltagirone C, Martorana A, Koch G. Phase 2 study of palmitoylethanolamide combined with luteoline in frontotemporal dementia patients. Brain Commun. 2025 Mar 5;7(2):fcaf080. doi: 10.1093/braincomms/fcaf080.
Major depressive disorder
4. Ghazizadeh-Hashemi M, Ghajar A, Shalbafan MR, Ghazizadeh-Hashemi F, Afarideh M, Malekpour F, Ghaleiha A, Ardebili ME, Akhondzadeh S. Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. J Affect Disord. 2018 May;232:127–133. doi: 10.1016/j.jad.2018.02.057. Epub 2018 Feb 21.
PTSD (augmentation of CBT)
5. Steardo L Jr, D'Angelo M, Di Stefano V, Monaco F, Fornaro M, Steardo L. Targeting PTSD with ultramicronized palmitoylethanolamide: Results from a randomized trial integrating pharmacotherapy and cognitive behavioral therapy. J Psychiatr Res. 2026 Jan;192:439–450. doi: 10.1016/j.jpsychires.2025.10.071. Epub 2025 Nov 8.
Schizophrenia (negative symptoms)
6. Salehi A, Namaei P, TaghaviZanjani F, Bagheri S, Moradi K, Khodaei Ardakani MR, Akhondzadeh S. Adjuvant palmitoylethanolamide therapy with risperidone improves negative symptoms in patients with schizophrenia: A randomized, double-blinded, placebo-controlled trial. Psychiatry Res. 2022 Oct;316:114737. doi: 10.1016/j.psychres.2022.114737. Epub 2022 Jul 27.
Long COVID (depression, with luteolin)
7. Merolla A, De Lorenzo R, Paolazzi G, Critelli S, Palladini M, Damanti S, Vitali G, Canti V, Cilla M, Martinenghi S, Falbo E, Ferrante M, Castellani J, Pacioni G, Magnaghi C, Fumagalli A, Mazza MG, Benedetti F, Rovere-Querini P. Micronized/ultramicronized palmitoylethanolamide improves depression and fatigue in coronavirus disease 2019 (COVID-19) survivors. Int Clin Psychopharmacol. 2024 Nov 1;39(6):361–368. doi: 10.1097/YIC.0000000000000537. Epub 2024 Feb 22.
Phosphatidylserine References
15 references
Mild cognitive impairment
1. Crook TH, Tinklenberg J, Yesavage J, Petrie W, Nunzi MG, Massari DC. Effects of phosphatidylserine in age-associated memory impairment. Neurology. 1991 May;41(5):644–649. doi: 10.1212/wnl.41.5.644.
2. Duan H, Xu N, Yang T, Wang M, Zhang C, Zhao J, Li Z, Chen Y, Yan J, Zhang M, Li W, Yue Z, Ma F, He R, Huang G. Effects of a food supplement containing phosphatidylserine on cognitive function in Chinese older adults with mild cognitive impairment: A randomized double-blind, placebo-controlled trial. J Affect Disord. 2025 Jan 15;369:35–42. doi: 10.1016/j.jad.2024.09.131. Epub 2024 Sep 22.
3. Richter Y, Herzog Y, Lifshitz Y, Hayun R, Zchut S. The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints: a pilot study. Clin Interv Aging. 2013;8:557–563. doi: 10.2147/CIA.S40348. Epub 2013 May 21.
4. Vakhapova V, Cohen T, Richter Y, Herzog Y, Kam Y, Korczyn AD. Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: Results from an open-label extension study. Dement Geriatr Cogn Disord. 2014;38(1–2):39–45. doi: 10.1159/000357793. Epub 2014 Feb 20.
5. Vakhapova V, Cohen T, Richter Y, Herzog Y, Korczyn AD. Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: A double-blind placebo-controlled trial. Dement Geriatr Cogn Disord. 2010;29(5):467–474. doi: 10.1159/000310330. Epub 2010 Jun 3.
Alzheimer's dementia (early phase)
6. Crook T, Petrie W, Wells C, Massari DC. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull. 1992;28(1):61–66.
7. Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand. 1986 Feb;73(2):136–140. doi: 10.1111/j.1600-0404.1986.tb03254.x.
8. Engel RR, Satzger W, Günther W, Kathmann N, Bove D, Gerke S, Münch U, Hippius H. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol. 1992 Jun;2(2):149–155. doi: 10.1016/0924-977x(92)90025-4.
Alzheimer's dementia (early phase) / Depressive symptoms in dementia
9. Moré MI, Freitas U, Rutenberg D. Positive effects of soy lecithin-derived phosphatidylserine plus phosphatidic acid on memory, cognition, daily functioning, and mood in elderly patients with Alzheimer's disease and dementia. Adv Ther. 2014 Dec;31(12):1247–1262. doi: 10.1007/s12325-014-0165-1. Epub 2014 Nov 21.
ADHD (in children)
10. Hirayama S, Terasawa K, Rabeler R, Hirayama T, Inoue T, Tatsumi Y, Purpura M, Jäger R. The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: A randomised, double-blind, placebo-controlled clinical trial. J Hum Nutr Diet. 2014 Apr;27 Suppl 2:284–291. doi: 10.1111/jhn.12090. Epub 2013 Mar 17.
11. Manor I, Magen A, Keidar D, Rosen S, Tasker H, Cohen T, Richter Y, Zaaroor-Regev D, Manor Y, Weizman A. The effect of phosphatidylserine containing omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children: A double-blind placebo-controlled trial, followed by an open-label extension. Eur Psychiatry. 2012 Jul;27(5):335–342. doi: 10.1016/j.eurpsy.2011.05.004. Epub 2011 Jul 31.
12. Shen Z, Jia S, Li X, Jiang X, Zhang H, Fang Y. The effect of phosphatidylserine on behavioral problems in children with attention deficit hyperactivity disorder. Front Psychiatry. 2026 Mar 25;17:1661725. doi: 10.3389/fpsyt.2026.1661725.
13. Vaisman N, Kaysar N, Zaruk-Adasha Y, Pelled D, Brichon G, Zwingelstein G, Bodennec J. Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: Effect of dietary n-3 fatty acids containing phospholipids. Am J Clin Nutr. 2008 May;87(5):1170–1180. doi: 10.1093/ajcn/87.5.1170.
Major depressive disorder in older adults
14. Komori T. The effects of phosphatidylserine and omega-3 fatty acid-containing supplement on late life depression. Ment Illn. 2015 Apr 1;7(1):5647. doi: 10.4081/mi.2015.5647.
15. Maggioni M, Picotti GB, Bondiolotti GP, Panerai A, Cenacchi T, Nobile P, Brambilla F. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand. 1990 Mar;81(3):265–270. doi: 10.1111/j.1600-0447.1990.tb06494.x.
Citicoline References
25 references
Cocaine / meth use disorder
1. Brown ES, Gorman AR, Hynan LS. A randomized, placebo-controlled trial of citicoline add-on therapy in outpatients with bipolar disorder and cocaine dependence. J Clin Psychopharmacol. 2007 Oct;27(5):498–502. doi: 10.1097/JCP.0b013e31814db4c4.
2. Brown ES, Gabrielson B. A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. J Affect Disord. 2012 Dec 20;143(1–3):257–260. doi: 10.1016/j.jad.2012.05.006. Epub 2012 Sep 11.
3. Brown ES, Todd JP, Hu LT, Schmitz JM, Carmody TJ, Nakamura A, Sunderajan P, Rush AJ, Adinoff B, Bret ME, Holmes T, Lo A. A randomized, double-blind, placebo-controlled trial of citicoline for cocaine dependence in bipolar I disorder. Am J Psychiatry. 2015 Oct;172(10):1014–1021. doi: 10.1176/appi.ajp.2015.14070857. Epub 2015 May 22.
4. Jeong H, Yoon S, Sung YH, Kim J, Lyoo IK, Yurgelun-Todd DA, Renshaw PF. Effects of cytidine-5’-diphosphate choline on gray matter volumes in methamphetamine-dependent patients: A randomized, double-blind, placebo-controlled study. J Psychiatr Res. 2021 Nov;143:215–221. doi: 10.1016/j.jpsychires.2021.09.006. Epub 2021 Sep 2.
5. Licata SC, Penetar DM, Ravichandran C, Rodolico J, Palmer C, Berko J, Geaghan T, Looby A, Peters E, Ryan E, Renshaw PF, Lukas SE. Effects of daily treatment with citicoline: A double-blind, placebo-controlled study in cocaine-dependent volunteers. J Addict Med. 2011 Mar;5(1):57–64. doi: 10.1097/ADM.0b013e3181d80c93.
6. Renshaw PF, Daniels S, Lundahl LH, Rogers V, Lukas SE. Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: A preliminary report. Psychopharmacology (Berl). 1999 Feb;142(2):132–138. doi: 10.1007/s002130050871.
7. Yoon SJ, Lyoo IK, Kim HJ, Kim TS, Sung YH, Kim N, Lukas SE, Renshaw PF. Neurochemical alterations in methamphetamine-dependent patients treated with cytidine-5’-diphosphate choline: A longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology. 2010 Apr;35(5):1165–1173. doi: 10.1038/npp.2009.221. Epub 2009 Dec 30.
Vascular dementia / post-stroke
8. Alvarez-Sabín J, Ortega G, Jacas C, Santamarina E, Maisterra O, Ribo M, Molina C, Quintana M, Román GC. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146–154. doi: 10.1159/000346602. Epub 2013 Feb 7.
9. Barbagallo Sangiorgi G, Barbagallo M, Giordano M, Meli M, Panzarasa R. Alpha-glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial. Ann N Y Acad Sci. 1994 Jun 30;717:253–269. doi: 10.1111/j.1749-6632.1994.tb12095.x.
10. Capurso A, Capurso S, Panza F, Solfrizzi V, Mastroianni F, Giaquinto S, Denaro A. Efficacy of cytidine diphosphate choline in patients affected by chronic cerebrovascular disease. Clinical Drug Investigation 1996;12(1):26‐38
11. Cohen RA, Browndyke JN, Moser DJ, Paul RH, Gordon N, Sweet L. Long-term citicoline (cytidine diphosphate choline) use in patients with vascular dementia: Neuroimaging and neuropsychological outcomes. Cerebrovasc Dis. 2003;16(3):199–204. doi: 10.1159/000071116.
12. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005 Apr 18;2005(2):CD000269. doi: 10.1002/14651858.CD000269.pub3.
13. Sinforiani E, Trucco M, Pacchetti C, Gualtieri S. Assessment of CDP‐choline effects in patients with chronic cerebrovascular disease [Valutazione degli effetti della citicolina nella malattia cerebro‐vascolare cronica]. Minerva Medica 1986;77:51‐57.
14. Medariaga Aguirre LM, Espina Tamarigo JM, Pascual Lazaro A, Ortiz Tripol LG, Castro del Pozo JM. A double‐blind evaluation on a group of senile female patients, treated with CDP‐choline [Estudio double ciego sobre un grupo de enfermas seniles tratadas con CDP‐colina]. Revista de Psiquiatria y Psicologia Medica 1978;13:331‐342.
15. Motta L, Fichera G, Tiralosi G, Di Stefano A. CDP-choline in the treatment of chronic cerebrovasculopaties [La citicolina nel trattamento delle cerebrovasculopatie croniche]. Unpublished Lederle (Cyanamid Italia) report. 1985. (cited in Cochrane review, Fioravanti Yanagi 2005)
16. Piccoli F, Battistini N, Carbonin P, Currò Dossi B, Fiori L, La Bella V, Megna G, Salvioli G, Fioravanti M. CDP-choline in the treatment of chronic cerebrovasculopathies. Arch Gerontol Geriatr. 1994 May–Jun;18(3):161–168. doi: 10.1016/0167-4943(94)90010-8.
17. Senin U, Fioravanti M. Clinical controlled study vs placebo of CDP‐choline in a large group of aged patients with cerebrovascular dementia. Wyeth, Italy 2003. (cited in Cochrane review, Fioravanti Yanagi 2005)
Mild cognitive impairment
18. Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F. Citicoline and memory function in healthy older adults: A randomized, double-blind, placebo-controlled clinical trial. J Nutr. 2021 Aug 7;151(8):2153–2160. doi: 10.1093/jn/nxab119.
19. Nemkova SA, Semenov DV, Petrova EA, Zavadenko NN, Vozvyshaeva MY. Vliyanie preparata Rekognan na sostoyanie vysshikh psikhicheskikh funktsii u patsientov s legkimi kognitivnymi narusheniyami [The effect of the use of the drug recognan (citicoline) on the state of higher mental functions in patients with mild cognitive impairment]. Zh Nevrol Psikhiatr Im S S Korsakova. 2021;121(9):51–57. Russian. doi: 10.17116/jnevro202112109151.
20. Bonavita E. Studio clinico controllato sull’efficacia terapeutica della CDP-colina. 1983 (cited in Cochrane review, Fioravanti Yanagi 2005)
21. Angeli M. Studio clinico sull’impiego della CDP-colina in pazienti affetti da insufficienza mentale. 1985 (cited in Cochrane review, Fioravanti Yanagi 2005)
22. Falchi Delitata G, Falchi Delitata N, Casali R, Serlupi Crescenzi G, Attorri L, Lombardi R, Martinangeli A, Amici S, DeSantis M. Intermediate term, double‐blind vs. placebo study of CDP‐choline in cases with cognitive senile deterioration. Gazzetta Medica Italiana ‐ Archivio Scienze Mediche 1984;143:789‐810
23. Ostfeld I, Ben-Zeev T, Zamir A, Levi C, Gepner Y, Springer S, Hoffman JR. Role of beta-alanine supplementation on cognitive function, mood, and physical function in older adults; double-blind randomized controlled study. Nutrients. 2023 Feb 12;15(4):923. doi: 10.3390/nu15040923.
Major depressive disorder
24. Roohi-Azizi M, Arabzadeh S, Amidfar M, Salimi S, Zarindast MR, Talaei A, Akhondzadeh S. Citicoline combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2017 Jan/Feb;40(1):1–5. doi: 10.1097/WNF.0000000000000185.
Schizophrenia (negative symptoms)
25. Ghajar A, Gholamian F, Tabatabei-Motlagh M, Afarideh M, Rezaei F, Ghazizadeh-Hashemi M, Akhondzadeh S. Citicoline (CDP-choline) add-on therapy to risperidone for treatment of negative symptoms in patients with stable schizophrenia: A double-blind, randomized placebo-controlled trial. Hum Psychopharmacol. 2018 Jul;33(4):e2662. doi: 10.1002/hup.2662. Epub 2018 Jun 14.
Coenzyme Q10 References
13 references
Fatigue in medical illness
1. Cordero MD, Alcocer-Gómez E, de Miguel M, Culic O, Carrión AM, Alvarez-Suarez JM, Bullón P, Battino M, Fernández-Rodríguez A, Sánchez-Alcazar JA. Can coenzyme Q10 improve clinical and molecular parameters in fibromyalgia? Antioxid Redox Signal. 2013 Oct 20;19(12):1356–1361. doi: 10.1089/ars.2013.5260. Epub 2013 Apr 6.
2. Di Pierro F, Rossi A, Consensi A, Giacomelli C, Bazzichi L. Role for a water-soluble form of CoQ10 in female subjects affected by fibromyalgia. A preliminary study. Clin Exp Rheumatol. 2017 May–Jun;35 Suppl 105(3):20–27. Epub 2016 Dec 13.
3. Fukuda S, Nojima J, Kajimoto O, Yamaguti K, Nakatomi Y, Kuratsune H, Watanabe Y. Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome. Biofactors. 2016 Jul 8;42(4):431–440. doi: 10.1002/biof.1293. Epub 2016 Apr 29.
4. Golomb BA, Allison M, Koperski S, Koslik HJ, Devaraj S, Ritchie JB. Coenzyme Q10 benefits symptoms in Gulf War veterans: Results of a randomized double-blind study. Neural Comput. 2014 Nov;26(11):2594–2651. doi: 10.1162/NECO_a_00659. Epub 2014 Aug 22.
5. Karamali M, Gholizadeh M. The effects of coenzyme Q10 supplementation on metabolic profiles and parameters of mental health in women with polycystic ovary syndrome. Gynecol Endocrinol. 2022 Jan;38(1):45–49. doi: 10.1080/09513590.2021.1991910. Epub 2021 Oct 19.
6. Magalhães PLM, da Silva AMP, Maximiano MLB, Fernandes JVA, Amaral DC, Fortes AAT, Filho HNF, Silva LO, Teixeira BDDS, Franco ES, Maia MBS. Effects of coenzyme Q10 supplementation on depressive symptoms and fatigue: A systematic review and meta-analysis of randomized controlled trials. J Clin Psychopharmacol. 2026 Jan–Feb 01;46(1):93–100. doi: 10.1097/JCP.0000000000002112. Epub 2025 Nov 26.
7. Sanoobar M, Dehghan P, Khalili M, Azimi A, Seifar F. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial. Nutr Neurosci. 2016;19(3):138–143. doi: 10.1179/1476830515Y.0000000002. Epub 2015 Jan 20.
8. Sawaddiruk P, Apaijai N, Paiboonworachat S, Kaewchur T, Kasitanon N, Jaiwongkam T, Kerdphoo S, Chattipakorn N, Chattipakorn SC. Coenzyme Q10 supplementation alleviates pain in pregabalin-treated fibromyalgia patients via reducing brain activity and mitochondrial dysfunction. Free Radic Res. 2019 Aug;53(8):901–909. doi: 10.1080/10715762.2019.1645955. Epub 2019 Aug 7.
9. Tsai IC, Hsu CW, Chang CH, Tseng PT, Chang KV. Effectiveness of coenzyme Q10 supplementation for reducing fatigue: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022 Aug 24;13:883251. doi: 10.3389/fphar.2022.883251.
ADHD
10. Gamal F, El Agami O, Salamah A. Coenzyme Q10 in the treatment of attention deficit hyperactivity disorder in children: A randomized controlled trial. CNS Neurol Disord Drug Targets. 2022;21(8):717–723. doi: 10.2174/1871527320666211124093345.
Autism
11. Mousavinejad E, Ghaffari MA, Riahi F, Hajmohammadi M, Tiznobeyk Z, Mousavinejad M. Coenzyme Q10 supplementation reduces oxidative stress and decreases antioxidant enzyme activity in children with autism spectrum disorders. Psychiatry Res. 2018 Jul;265:62–69. doi: 10.1016/j.psychres.2018.03.061. Epub 2018 Apr 4.
Bipolar depression
12. Mehrpooya M, Yasrebifar F, Haghighi M, Mohammadi Y, Jahangard L. Evaluating the effect of coenzyme Q10 augmentation on treatment of bipolar depression: A double-blind controlled clinical trial. J Clin Psychopharmacol. 2018 Oct;38(5):460–466. doi: 10.1097/JCP.0000000000000938.
Major depressive disorder
13. Majmasanaye M, Mehrpooya M, Amiri H, Eshraghi A. Discovering the potential value of coenzyme Q10 as an adjuvant treatment in patients with depression. J Clin Psychopharmacol. 2024 May–Jun 01;44(3):232–239. doi: 10.1097/JCP.0000000000001845.
Inositol References
12 references
Bipolar (depression / manic / mixed)
1. Chengappa KN, Levine J, Gershon S, Mallinger AG, Hardan A, Vagnucci A, Pollock B, Luther J, Buttenfield J, Verfaille S, Kupfer DJ. Inositol as an add-on treatment for bipolar depression. Bipolar Disord. 2000 Mar;2(1):47–55. doi: 10.1034/j.1399-5618.2000.020107.x.
2. Eden Evins A, Demopulos C, Yovel I, Culhane M, Ogutha J, Grandin LD, Nierenberg AA, Sachs GS. Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disord. 2006 Apr;8(2):168–174. doi: 10.1111/j.1399-5618.2006.00303.x.
3. Wozniak J, Farrell A, DiSalvo M, Ceranoglu A, Uchida M, Vaudreuil C, Joshi G, Faraone SV, Cook E, Biederman J. A randomized, double-blind, controlled clinical trial of omega-3 fatty acids and inositol as monotherapies and in combination for the treatment of pediatric bipolar spectrum disorder in children age 5-12. Psychopharmacol Bull. 2022 Oct 27;52(4):31–51. doi: 10.64719/pb.4449.
Bulimia / Binge eating
4. Gelber D, Levine J, Belmaker RH. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord. 2001 Apr;29(3):345–348. doi: 10.1002/eat.1028.
Insomnia during pregnancy
5. Mashayekh-Amiri S, Delavar MA, Bakouei F, Faramarzi M, Esmaeilzadeh S. The impact of myo-inositol supplementation on sleep quality in pregnant women: A randomized, double-blind, placebo-controlled study. J Matern Fetal Neonatal Med. 2022 Sep;35(18):3415–3423. doi: 10.1080/14767058.2020.1818225. Epub 2020 Sep 15.
OCD
6. Fux M, Benjamin J, Belmaker RH. Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: A double-blind cross-over study. Int J Neuropsychopharmacol. 1999 Sep;2(3):193–195. doi: 10.1017/S1461145799001546.
7. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996 Sep;153(9):1219–1221. doi: 10.1176/ajp.153.9.1219.
Panic disorder
8. Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry. 1995 Jul;152(7):1084–1086. doi: 10.1176/ajp.152.7.1084.
9. Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol. 2001 Jun;21(3):335–339. doi: 10.1097/00004714-200106000-00014.
Premenstrual dysphoric disorder
10. Gianfranco C, Vittorio U, Silvia B, Francesco D. Myo-inositol in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2011 Oct;26(7):526–530. doi: 10.1002/hup.1241.
11. Nemets B, Talesnick B, Belmaker RH, Levine J. Myo-inositol has no beneficial effect on premenstrual dysphoric disorder. World J Biol Psychiatry. 2002 Jul;3(3):147–149. doi: 10.3109/15622970209150615.
Psoriasis on lithium
12. Allan SJ, Kavanagh GM, Herd RM, Savin JA. The effect of inositol supplements on the psoriasis of patients taking lithium: A randomized, placebo-controlled trial. Br J Dermatol. 2004 May;150(5):966–969. doi: 10.1111/j.1365-2133.2004.05822.x.
Melatonin References
52 references
Cognitive problems during ECT
1. Shahrokhi M, Soleimani R, Ahmadinia M, Rezapour A, Taatirad S, Jamali F, Mohamadabadi HJ, Qobadighadikolaei R. Melatonin as a neuroprotective adjunct in bipolar patients undergoing electroconvulsive therapy: A double-blind randomized controlled trial. Basic Clin Neurosci. 2026 Jan–Feb;17(1):97–112. doi: 10.32598/bcn.2026.8317.1. Epub 2026 Jan 1.
Delirium prevention
2. de Oliveira HM, Gallo Ruelas M, Parker T, Diaz CAV, Oliveira de Paula G, Zamora FV, Fruett da Costa PR. Pharmacologic modulation of circadian rhythms for delirium prevention: An age-stratified systematic review and meta-analysis. J Am Geriatr Soc. 2026 Jan 16. doi: 10.1111/jgs.70305. Epub ahead of print.
3. Shin HW, Kwak JS, Choi YJ, Kim JW, You HS, Shin HJ, Jang YK. Efficacy and safety of perioperative melatonin for postoperative delirium in patients undergoing surgery: A systematic review and meta-analysis. J Int Med Res. 2024 May;52(5):3000605241239854. doi: 10.1177/03000605241239854.
4. Wu X, Hu P, Wu H, Zhang K, Ying J. Melatonin supplementation reduces delirium incidence in critically ill patients: A systematic review and meta-analysis. Front Pharmacol. 2026;17:1728873. Published 2026 Jan 12. doi: 10.3389/fphar.2026.1728873.
Insomnia
5. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: A systematic review. CNS Drugs. 2019 Dec;33(12):1167–1186. doi: 10.1007/s40263-019-00680-w.
6. Bruno S, Cenerini G, Lo Giudice L, Cruz-Sanabria F, Benedetti D, Crippa A, Fiori S, Ferri R, Masi G, Faraguna U. Optimizing timing and dose of exogenous melatonin administration in neuropsychiatric pediatric populations: A meta-analysis on sleep outcomes. Sleep Med Rev. 2025 Dec;84:102158. doi: 10.1016/j.smrv.2025.102158. Epub 2025 Aug 30.
7. Cruz-Sanabria F, Bruno S, Crippa A, Frumento P, Scarselli M, Skene DJ, Faraguna U. Optimizing the time and dose of melatonin as a sleep-promoting drug: A systematic review of randomized controlled trials and dose-response meta-analysis. J Pineal Res. 2024 Aug;76(5):e12985. doi: 10.1111/jpi.12985.
8. Edemann-Callesen H, Andersen HK, Ussing A, Virring A, Jennum P, Debes NM, Laursen T, Baandrup L, Gade C, Dettmann J, Holm J, Krogh C, Birkefoss K, Tarp S, Händel MN. Use of melatonin in children and adolescents with idiopathic chronic insomnia: A systematic review, meta-analysis, and clinical recommendation. EClinicalMedicine. 2023 Jul 6;61:102048. doi: 10.1016/j.eclinm.2023.102048.
9. Maruani J, Reynaud E, Chambe J, Palagini L, Bourgin P, Geoffroy PA. Efficacy of melatonin and ramelteon for the acute and long-term management of insomnia disorder in adults: A systematic review and meta-analysis. J Sleep Res. 2023 Dec;32(6):e13939. doi: 10.1111/jsr.13939. Epub 2023 Jul 11.
10. Mdluli NT, Banda KJ, Chang YC. Melatonin for sleep and cognitive outcomes in older adults with cognitive impairment: A meta-analysis of randomised controlled trials. Age Ageing. 2025 Oct 30;54(11):afaf333. doi: 10.1093/ageing/afaf333.
11. Seo K, Kim JH, Han D. Effects of melatonin supplementation on sleep quality in breast cancer patients: A systematic review and meta-analysis. Healthcare (Basel). 2023 Feb 24;11(5):675. doi: 10.3390/healthcare11050675.
12. van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: A meta-analysis. Sleep. 2010 Dec;33(12):1605–1614. doi: 10.1093/sleep/33.12.1605.
13. Woodford EC, McLay L, France KG, Blampied NM, Gibbs R, Swan CE, Eggleston M. Endogenous melatonin and sleep in individuals with rare genetic neurodevelopmental disorders (RGND): A systematic review. Sleep Med Rev. 2021 Jun;57:101433. doi: 10.1016/j.smrv.2021.101433. Epub 2021 Jan 17.
14. Yang H, Lu F, Zhao X. Factors influencing the effect of melatonin on sleep quality in children with autism spectrum disorder: A systematic review and meta-analysis. Sleep Breath. 2025 Aug 6;29(4):262. doi: 10.1007/s11325-025-03432-x.
15. Yousef O, Abouelmagd ME, Khaddam H, Shbani A, Yousef R, Meshref M, Hanafi I. The effectiveness of melatonin for sleep disturbances in Parkinson's disease: Systematic review and meta-analysis. J Sleep Res. 2026 Feb;35(1):e70097. doi: 10.1111/jsr.70097. Epub 2025 Jun 30.
Jet lag
17. Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, Folkard S. Some effects of jet lag and their alleviation by melatonin. Ergonomics. 1987;30:1379–1393. doi: 10.1080/00140138708966031.
18. Arendt J, Aldhous M, Marks V. Alleviation of jet lag by melatonin: Preliminary results of controlled double blind trial. Br Med J (Clin Res Ed). 1986 May 3;292(6529):1170. doi: 10.1136/bmj.292.6529.1170.
19. Beaumont M, Batéjat D, Piérard C, Van Beers P, Denis JB, Coste O, Doireau P, Chauffard F, French J, Lagarde D. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol (1985). 2004 Jan;96(1):50–58. doi: 10.1152/japplphysiol.00940.2002. Epub 2003 Sep 5.
20. Burke TM, Markwald RR, Chinoy ED, Snider JA, Bessman SC, Jung CM, Wright KP Jr. Combination of light and melatonin time cues for phase advancing the human circadian clock. Sleep. 2013 Nov 1;36(11):1617–1624. doi: 10.5665/sleep.3110.
21. Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: Confirmatory result using a simplified protocol. Biol Psychiatry. 1992 Oct 15;32(8):705–711. doi: 10.1016/0006-3223(92)90300-o.
22. Edwards BJ, Atkinson G, Waterhouse J, Reilly T, Godfrey R, Budgett R. Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones. Ergonomics. 2000 Oct;43(10):1501–1513. doi: 10.1080/001401300750003934.
23. Jamieson AO, Zammit GK, Rosenberg RS, Davis JR, Walsh JK. Zolpidem reduces the sleep disturbance of jet lag. Sleep Med. 2001 Sep;2(5):423–430. doi: 10.1016/s1389-9457(00)00073-3.
24. Nickelsen T, Samel A, Vejvoda M, Wenzel J, Smith B, Gerzer R. Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial. Chronobiol Int. 2002;19(5):915-936. doi:10.1081/cbi-120014108
25. Paul MA, Miller JC, Gray GW, Love RJ, Lieberman HR, Arendt J. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). 2010 Feb;208(3):377–386. doi: 10.1007/s00213-009-1737-7. Epub 2009 Dec 15.
26. Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. BMJ. 1989 Mar 18;298(6675):705–707. doi: 10.1136/bmj.298.6675.705.
27. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry. 1993 Apr 1;33(7):526–530. doi: 10.1016/0006-3223(93)90007-z.
28. Spitzer RL, Terman M, Williams JB, Terman JS, Malt UF, Singer F, Lewy AJ. Jet lag: Clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psychiatry. 1999 Sep;156(9):1392–1396. doi: 10.1176/ajp.156.9.1392.
29. Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001;72(7):638-646.
30. Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int. 1998 Nov;15(6):655–666. doi: 10.3109/07420529808993201.
Shift work
16. Aeschbach D, Lockyer BJ, Dijk DJ, Lockley SW, Nuwayser ES, Nichols LD, Czeisler CA. Use of transdermal melatonin delivery to improve sleep maintenance during daytime. Clin Pharmacol Ther. 2009 Oct;86(4):378–382. doi: 10.1038/clpt.2009.109. Epub 2009 Jul 15.
31. Bjorvatn B, Stangenes K, Oyane N, Forberg K, Lowden A, Holsten F, Akerstedt T. Randomized placebo-controlled field study of the effects of bright light and melatonin in adaptation to night work. Scand J Work Environ Health. 2007 Jun;33(3):204–214. doi: 10.5271/sjweh.1129.
32. Cavallo A, Ris MD, Succop P, Jaskiewicz J. Melatonin treatment of pediatric residents for adaptation to night shift work. Ambul Pediatr. 2005 May–Jun;5(3):172–177. doi: 10.1367/A04-124R.1.
33. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int. 1993 Oct;10(5):315–320. doi: 10.3109/07420529309064485.
34. Hannemann J, Laing A, Middleton B, Schwedhelm E, Marx N, Federici M, Kastner M, Skene DJ, Böger R. Effect of oral melatonin treatment on insulin resistance and diurnal blood pressure variability in night shift workers. Pharmacol Res. 2024 Jan;199:107011. doi: 10.1016/j.phrs.2023.107011. Epub 2023 Nov 27.
35. James M, Tremea MO, Jones JS, Krohmer JR. Can melatonin improve adaptation to night shift? Am J Emerg Med. 1998 Jul;16(4):367–370. doi: 10.1016/s0735-6757(98)90129-2.
36. Jockovich M, Cosentino D, Cosentino L, Wears RL, Seaberg DC. Effect of exogenous melatonin on mood and sleep efficiency in emergency medicine residents working night shifts. Acad Emerg Med. 2000 Aug;7(8):955–958. doi: 10.1111/j.1553-2712.2000.tb02082.x.
37. Jorgensen KM, Witting MD. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med. 1998 Jun;31(6):699–704. doi: 10.1016/s0196-0644(98)70227-6.
38. Marqueze EC, Nogueira LFR, Vetter C, Skene DJ, Cipolla-Neto J, Moreno CRC. Exogenous melatonin decreases circadian misalignment and body weight among early types. J Pineal Res. 2021 Sep;71(2):e12750. doi: 10.1111/jpi.12750. Epub 2021 Jun 20.
39. Sadeghniiat-Haghighi K, Aminian O, Pouryaghoub G, Yazdi Z. Efficacy and hypnotic effects of melatonin in shift-work nurses: Double-blind, placebo-controlled crossover trial. J Circadian Rhythms. 2008 Oct 29;6:10. doi: 10.1186/1740-3391-6-10.
40. Sadeghniiat-Haghighi K, Bahrami H, Aminian O, Meysami A, Khajeh-Mehrizi A. Melatonin therapy in shift workers with difficulty falling asleep: A randomized, double-blind, placebo-controlled crossover field study. Work. 2016 Sep 27;55(1):225–230. doi: 10.3233/WOR-162376.
41. Saraiva SP, D'Aurea CVR, Luz CSS, Amaral FG, Cipolla-Neto J, Marqueze EC, Moreno CRC. Low-dose melatonin, climacteric symptoms and sleep in female shift workers: A randomized controlled trial. J Pineal Res. 2026 Mar;78(2):e70140. doi: 10.1111/jpi.70140.
42. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001 Sep;10(3):181–192. doi: 10.1046/j.1365-2869.2001.00256.x.
43. Wright SW, Lawrence LM, Wrenn KD, Haynes ML, Welch LW, Schlack HM. Randomized clinical trial of melatonin after night-shift work: Efficacy and neuropsychologic effects. Ann Emerg Med. 1998 Sep;32(3 Pt 1):334–340. doi: 10.1016/s0196-0644(98)70010-1.
44. Yoon IY, Song BG. Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers. Chronobiol Int. 2002 Sep;19(5):903–913. doi: 10.1081/cbi-120014571.
Metabolic effects on antipsychotics
45. Agahi M, Akasheh N, Ahmadvand A, Akbari H, Izadpanah F. Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial. Diabetes Metab Syndr. 2018 Jan–Mar;12(1):9–15. doi: 10.1016/j.dsx.2017.08.004. Epub 2017 Aug 18.
46. Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, Ashrafi M, Modabbernia MJ. Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: Randomized double-blind placebo-controlled study. J Psychiatr Res. 2014 Jun;53:133–140. doi: 10.1016/j.jpsychires.2014.02.013. Epub 2014 Feb 24.
47. Mostafavi SA, Solhi M, Mohammadi MR, Akhondzadeh S. Melatonin for reducing weight gain following administration of atypical antipsychotic olanzapine for adolescents with bipolar disorder: A randomized, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2017 Jun;27(5):440–444. doi: 10.1089/cap.2016.0046. Epub 2017 Mar 24.
48. Romo-Nava F, Alvarez-Icaza González D, Fresán-Orellana A, Saracco Alvarez R, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga C, Heinze G, Buijs RM. Melatonin attenuates antipsychotic metabolic effects: An eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014 Jun;16(4):410–421. doi: 10.1111/bdi.12196. Epub 2014 Mar 17.
Major depressive disorder
49. Fava M, Targum SD, Nierenberg AA, Bleicher LS, Carter TA, Wedel PC, Hen R, Gage FH, Barlow C. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): A possible role for neurogenesis in drug discovery. J Psychiatr Res. 2012 Dec;46(12):1553–1563. doi: 10.1016/j.jpsychires.2012.08.013. Epub 2012 Sep 19.
Alzheimer's dementia
50. Sumsuzzman DM, Choi J, Jin Y, Hong Y. Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer's disease and insomnia: A systematic review and meta-analysis of randomized controlled trials. Neurosci Biobehav Rev. 2021 Aug;127:459–473. doi: 10.1016/j.neubiorev.2021.04.034. Epub 2021 May 3.
Bipolar mania
51. Moghaddam HS, Bahmani S, Bayanati S, Mahdavinasa M, Rezaei F, Akhondzadeh S. Efficacy of melatonin as an adjunct in the treatment of acute mania: A double-blind and placebo-controlled trial. Int Clin Psychopharmacol. 2020 Mar;35(2):81–88. doi: 10.1097/YIC.0000000000000298.
52. Quested DJ, Gibson JC, Sharpley AL, Cordey JH, Economou A, De Crescenzo F, Voysey M, Lawson J, Rendell JM, Al-Taiar H, Lennox A, Ahmad F, Geddes JR. Melatonin In Acute Mania Investigation (MIAMI-UK). A randomized controlled trial of add-on melatonin in bipolar disorder. Bipolar Disord. 2021 Mar;23(2):176–185. doi: 10.1111/bdi.12196. Epub 2020 Jul 3.
Probiotics References
140 references
ADHD / Borderline personality disorder
1. Arteaga-Henríquez G, Ramos-Sayalero C, Ibañez-Jimenez P, Karina Rosales-Ortiz S, Kilencz T, Schiweck C, Schnorr I, Siegl A, Arias-Vasquez A, Bitter I, Fadeuilhe C, Ferrer M, Lavebratt C, Matura S, Reif A, Réthelyi JM, Richarte V, Rommelse N, Antoni Ramos-Quiroga J. Efficacy of a synbiotic in the management of adults with attention-deficit and hyperactivity disorder and/or borderline personality disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial. Brain Behav Immun. 2024 Aug;120:360–371. doi: 10.1016/j.bbi.2024.06.012. Epub 2024 Jun 15. Erratum in: Brain Behav Immun. 2024 Oct;121:404–405. doi: 10.1016/j.bbi.2024.08.019.
12. Skott E, Yang LL, Stiernborg M, Söderström Å, Rȕegg J, Schalling M, Forsell Y, Giacobini M, Lavebratt C. Effects of a synbiotic on symptoms, and daily functioning in attention deficit hyperactivity disorder - a double-blind randomized controlled trial. Brain Behav Immun. 2020 Oct;89:9–19. doi: 10.1016/j.bbi.2020.05.056. Epub 2020 Jun 1.
ADHD
2. Elhossiny RM, Elshahawy HH, Mohamed HM, Abdelmageed RI. Assessment of probiotic strain Lactobacillus acidophilus LB supplementation as adjunctive management of attention-deficit hyperactivity disorder in children and adolescents: A randomized controlled clinical trial. BMC Psychiatry. 2023 Nov 9;23(1):823. doi: 10.1186/s12888-023-05324-4.
3. Ghanaatgar M, Taherzadeh S, Ariyanfar S, Jahromi SR, Martami F, Gharaei JM, Teimourpour A, Shahrivar Z. Probiotic supplement as an adjunctive therapy with Ritalin for treatment of attention-deficit hyperactivity disorder symptoms in children: A double-blind placebo-controlled randomized clinical trial. Nutr Food Sci. 2022;53(1):19–34. doi: 10.1108/NFS-12-2021-0388.
4. Kumperscak HG, Gricar A, Ülen I, Micetic-Turk D. A pilot randomized control trial with the probiotic strain Lactobacillus rhamnosus GG (LGG) in ADHD: Children and adolescents report better health-related quality of life. Front Psychiatry. 2020 Mar 17;11:181. doi: 10.3389/fpsyt.2020.00181.
5. Lawrence K, Fibert P, Toribio-Mateas M, Gregory AM, Hobbs J, Quadt F, Wright S, Cotter PD, Patel S, Myrissa K. Effects of kefir on symptoms, sleep, and gut microbiota in children with ADHD: A randomised controlled trial. BMC Psychiatry. 2025 Nov 24;25(1):1117. doi: 10.1186/s12888-025-07568-8.
6. Levy Schwartz M, Magzal F, Yehuda I, Tamir S. Exploring the impact of probiotics on adult ADHD management through a double-blind RCT. Sci Rep. 2024 Nov 5;14(1):26830. doi: 10.1038/s41598-024-73874-y.
7. Parhiz A, Samani P, Kamali M, Shekari Y, Naghshi N, Faghihshojaei N, Tejareh F, Lahiji NP, Nori A, Aminifard A, Bahmani P, Doaei S, Rabipour F, Gholamalizadeh M. Probiotic supplementation and executive function in children with attention-deficit/hyperactivity disorder. Neuropsychopharmacol Rep. 2026 Mar;46(1):e70084. doi: 10.1002/npr2.70084. Erratum in: Neuropsychopharmacol Rep. 2026 Jun;46(2):e70130. doi: 10.1002/npr2.70130.
8. Pärtty A, Kalliomäki M, Wacklin P, Salminen S, Isolauri E. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: A randomized trial. Pediatr Res. 2015 Jun;77(6):823–828. doi: 10.1038/pr.2015.51. Epub 2015 Mar 11.
10. Sangsefidi ZS, Sangsefidi ZS, Moharreri F, Heydari Yazdi AS, Eslami S, Emadzadeh B, Ghorani B, Sarabi-Jamab M, Farahmand A, Modiri Dovom A, Ghanaei A, Emadzadeh M. Effect of probiotics as an adjunctive therapy with Ritalin among ADHD children and adolescents: A triple-blind randomized controlled trial. Nutr Neurosci. 2025 Apr;28(4):522–531. doi: 10.1080/1028415X.2024.2391655. Epub 2024 Aug 20.
11. Sepehrmanesh Z, Shahzeidi A, Mansournia MA, Ghaderi A, Ahmadvand A. Clinical and metabolic reaction to probiotic supplement in children suffering attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled experiment. Int Arch Health Sci. 2021;8(2):90. doi: 10.4103/iahs.iahs_112_20.
13. Trezzi S, Scaccabarozzi G, Nossa R, Piazza C, Bianchi AR, Rosi E, Tizzoni F, Mauri M, Camillo L, Baragetti A, Molteni M, Campanella V, Mauro L, Cremonesi P, Severgnini M, Monroy MM, Castiglioni B, Sparvoli F, Pisano S, Pozzi M, Crippa A, Nobile M. Behavioural, cognitive, and neurophysiological effects of a synbiotic supplementation enriched with pigmented corn extract or cornstarch in drug-naïve children with attention-deficit hyperactivity disorder: A randomised, double-blind, comparison-controlled clinical trial. Clin Nutr ESPEN. 2025 Feb;65:408–417. doi: 10.1016/j.clnesp.2024.12.016. Epub 2024 Dec 20.
ADHD / Autism
9. Rojo-Marticella M, Arija V, Canals-Sans J. Effect of probiotics on the symptomatology of autism spectrum disorder and/or attention deficit/hyperactivity disorder in children and adolescents: Pilot study. Res Child Adolesc Psychopathol. 2025 Feb;53(2):163–178. doi: 10.1007/s10802-024-01278-7. Epub 2025 Jan 11.
Anxiety
14. Colica C, Avolio E, Bollero P, Costa de Miranda R, Ferraro S, Sinibaldi Salimei P, De Lorenzo A, Di Renzo L. Evidences of a new psychobiotic formulation on body composition and anxiety. Mediators Inflamm. 2017;2017:5650627. doi: 10.1155/2017/5650627. Epub 2017 Sep 24.
15. Eskandarzadeh S, Effatpanah M, Khosravi-Darani K, Askari R, Hosseini AF, Reisian M, Jazayeri S. Efficacy of a multispecies probiotic as adjunctive therapy in generalized anxiety disorder: A double blind, randomized, placebo-controlled trial. Nutr Neurosci. 2021 Feb;24(2):102–108. doi: 10.1080/1028415X.2019.1598669. Epub 2019 Sep 13.
16. Freijy TM, Cribb L, Oliver G, Metri NJ, Opie RS, Jacka FN, Hawrelak JA, Rucklidge JJ, Ng CH, Sarris J. Effects of a high-prebiotic diet versus probiotic supplements versus synbiotics on adult mental health: The "Gut Feelings" randomised controlled trial. Front Neurosci. 2023 Feb 6;16:1097278. doi: 10.3389/fnins.2022.1097278.
17. Gualtieri P, Marchetti M, Cioccoloni G, De Lorenzo A, Romano L, Cammarano A, Colica C, Condò R, Di Renzo L. Psychobiotics regulate the anxiety symptoms in carriers of allele A of IL-1-beta gene: A randomized, placebo-controlled clinical trial. Mediators Inflamm. 2020 Jan 7;2020:2346126. doi: 10.1155/2020/2346126.
18. Johnstone N, Milesi C, Burn O, van den Bogert B, Nauta A, Hart K, Sowden P, Burnet PWJ, Cohen Kadosh K. Anxiolytic effects of a galacto-oligosaccharides prebiotic in healthy females (18-25 years) with corresponding changes in gut bacterial composition. Sci Rep. 2021 Apr 15;11(1):8302. doi: 10.1038/s41598-021-87865-w.
19. Lew LC, Hor YY, Yusoff NAA, Choi SB, Yusoff MSB, Roslan NS, Ahmad A, Mohammad JAM, Abdullah MFIL, Zakaria N, Wahid N, Sun Z, Kwok LY, Zhang H, Liong MT. Probiotic Lactobacillus plantarum P8 alleviated stress and anxiety while enhancing memory and cognition in stressed adults: A randomised, double-blind, placebo-controlled study. Clin Nutr. 2019 Oct;38(5):2053–2064. doi: 10.1016/j.clnu.2018.09.010. Epub 2018 Sep 19.
20. Marotta A, Sarno E, Del Casale A, Pane M, Mogna L, Amoruso A, Felis GE, Fiorio M. Effects of probiotics on cognitive reactivity, mood, and sleep quality. Front Psychiatry. 2019 Mar 27;10:164. doi: 10.3389/fpsyt.2019.00164.
21. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel JM. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011 Mar;105(5):755–764. doi: 10.1017/S0007114510004319. Epub 2010 Oct 26.
22. Nishida K, Sawada D, Kawai T, Kuwano Y, Fujiwara S, Rokutan K. Para-psychobiotic Lactobacillus gasseri CP2305 ameliorates stress-related symptoms and sleep quality. J Appl Microbiol. 2017 Dec;123(6):1561–1570. doi: 10.1111/jam.13594. Epub 2017 Nov 7.
23. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: A pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017 Aug;153(2):448–459.e8. doi: 10.1053/j.gastro.2017.05.003. Epub 2017 May 5.
24. Romijn AR, Rucklidge JJ, Kuijer RG, Frampton C. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017 Aug;51(8):810–821. doi: 10.1177/0004867416686694. Epub 2017 Jan 10.
25. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl). 2015 May;232(10):1793–1801. doi: 10.1007/s00213-014-3810-0. Epub 2014 Dec 3.
26. Slykerman RF, Li E, Mitchell EA. Probiotics for Reduction of Examination Stress in Students (PRESS) study: A randomized, double-blind, placebo-controlled trial of the probiotic Lacticaseibacillus rhamnosus HN001. PLoS One. 2022 Jun 8;17(6):e0267778. doi: 10.1371/journal.pone.0267778.
27. Srivastava S, Basak U, Naghibi M, Vijayakumar V, Parihar R, Patel J, Jadon PS, Pandit A, Dargad RR, Khanna S, Kumar S, Day R. A randomized double-blind, placebo-controlled trial to evaluate the safety and efficacy of live Bifidobacterium longum CECT 7347 (ES1) and heat-treated Bifidobacterium longum CECT 7347 (HT-ES1) in participants with diarrhea-predominant irritable bowel syndrome. Gut Microbes. 2024 Jan–Dec;16(1):2338322. doi: 10.1080/19490976.2024.2338322. Epub 2024 Apr 17.
28. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015 Aug;48:258–264. doi: 10.1016/j.bbi.2015.04.003. Epub 2015 Apr 7.
29. Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, Suda K, Kawai M, Hoshi R, Watanabe O, Igarashi T, Kuwano Y, Miyazaki K, Rokutan K. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil. 2016 Jul;28(7):1027–1036. doi: 10.1111/nmo.12804. Epub 2016 Feb 20.
30. Tran N, Zhebrak M, Yacoub C, Pelletier J, Hawley D. The gut-brain relationship: Investigating the effect of multispecies probiotics on anxiety in a randomized placebo-controlled trial of healthy young adults. J Affect Disord. 2019 Jun 1;252:271–277. doi: 10.1016/j.jad.2019.04.043. Epub 2019 Apr 8.
Autism
31. Arnold LE, Luna RA, Williams K, Chan J, Parker RA, Wu Q, Hollway JA, Jeffs A, Lu F, Coury DL, Hayes C, Savidge T. Probiotics for gastrointestinal symptoms and quality of life in autism: A placebo-controlled pilot trial. J Child Adolesc Psychopharmacol. 2019 Nov;29(9):659–669. doi: 10.1089/cap.2018.0156. Epub 2019 Aug 30.
32. Grimaldi R, Gibson GR, Vulevic J, Giallourou N, Castro-Mejía JL, Hansen LH, Leigh Gibson E, Nielsen DS, Costabile A. A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome. 2018 Aug 2;6(1):133. doi: 10.1186/s40168-018-0523-3.
33. Guidetti C, Salvini E, Viri M, Deidda F, Amoruso A, Visciglia A, Drago L, Calgaro M, Vitulo N, Pane M, Caucino AC. Randomized double-blind crossover study for evaluating a probiotic mixture on gastrointestinal and behavioral symptoms of autistic children. J Clin Med. 2022 Sep 6;11(18):5263. doi: 10.3390/jcm11185263.
34. Hrnciarova J, Kubelkova K, Bostik V, Rychlik I, Karasova D, Babak V, Datkova M, Simackova K, Macela A. Modulation of gut microbiome and autism symptoms of ASD children supplemented with biological response modifier: A randomized, double-blinded, placebo-controlled pilot study. Nutrients. 2024 Jun 21;16(13):1988. doi: 10.3390/nu16131988.
35. Li Y, Hu W, Lin B, Ma T, Zhang Z, Hu W, Zhou R, Kwok LY, Sun Z, Zhu C, Zhang H. Omic characterizing and targeting gut dysbiosis in children with autism spectrum disorder: Symptom alleviation through combined probiotic and medium-carbohydrate diet intervention - a pilot study. Gut Microbes. 2024 Jan–Dec;16(1):2434675. doi: 10.1080/19490976.2024.2434675. Epub 2024 Dec 4.
36. Li YQ, Sun YH, Liang YP, Zhou F, Yang J, Jin SL. Effect of probiotics combined with applied behavior analysis in the treatment of children with autism spectrum disorder: A prospective randomized controlled trial. Zhongguo Dang Dai Er Ke Za Zhi. 2021 Nov 15;23(11):1103–1110. English, Chinese. doi: 10.7499/j.issn.1008-8830.2108085.
37. Liu YW, Liong MT, Chung YE, Huang HY, Peng WS, Cheng YF, Lin YS, Wu YY, Tsai YC. Effects of Lactobacillus plantarum PS128 on children with autism spectrum disorder in Taiwan: A randomized, double-blind, placebo-controlled trial. Nutrients. 2019 Apr 11;11(4):820. doi: 10.3390/nu11040820.
38. Mazzone L, Dooling SW, Volpe E, Uljarević M, Waters JL, Sabatini A, Arturi L, Abate R, Riccioni A, Siracusano M, Pereira M, Engstrand L, Cristofori F, Adduce D, Francavilla R, Costa-Mattioli M, Hardan AY. Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial. Cell Host Microbe. 2024 Jan 10;32(1):106–116.e6. doi: 10.1016/j.chom.2023.11.021. Epub 2023 Dec 18.
39. Narula Khanna H, Roy S, Shaikh A, Chhabra R, Uddin A. Impact of probiotic supplements on behavioural and gastrointestinal symptoms in children with autism spectrum disorder: A randomised controlled trial. BMJ Paediatr Open. 2025 Mar 4;9(1):e003045. doi: 10.1136/bmjpo-2024-003045.
40. Niu M, Li Q, Zhang J, Wen F, Dang W, Duan G, Li H, Ruan W, Yang P, Guan C, Tian H, Gao X, Zhang S, Yuan F, Han Y. Characterization of intestinal microbiota and probiotics treatment in children with autism spectrum disorders in China. Front Neurol. 2019 Nov 5;10:1084. doi: 10.3389/fneur.2019.01084.
42. Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, Tancredi R, Billeci L, Mastromarino P, Grossi E, Gastaldelli A, Morales MA, Muratori F. Effects of probiotic supplementation on gastrointestinal, sensory and core symptoms in autism spectrum disorders: A randomized controlled trial. Front Psychiatry. 2020 Sep 25;11:550593. doi: 10.3389/fpsyt.2020.550593.
43. Wang Y, Li N, Yang JJ, Zhao DM, Chen B, Zhang GQ, Chen S, Cao RF, Yu H, Zhao CY, Zhao L, Ge YS, Liu Y, Zhang LH, Hu W, Zhang L, Gai ZT. Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharmacol Res. 2020 Jul;157:104784. doi: 10.1016/j.phrs.2020.104784. Epub 2020 Apr 17.
Autism / ADHD
41. Rojo-Marticella M, Arija V, Canals-Sans J. Effect of probiotics on the symptomatology of autism spectrum disorder and/or attention deficit/hyperactivity disorder in children and adolescents: Pilot study. Res Child Adolesc Psychopathol. 2025 Feb;53(2):163–178. doi: 10.1007/s10802-024-01278-7. Epub 2025 Jan 11.
Major depressive disorder
44. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, Jafari P, Akbari H, Taghizadeh M, Memarzadeh MR, Asemi Z, Esmaillzadeh A. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition. 2016 Mar;32(3):315–320. doi: 10.1016/j.nut.2015.09.003. Epub 2015 Sep 28.
45. Baião R, Capitão LP, Higgins C, Browning M, Harmer CJ, Burnet PWJ. Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: A randomised, double-blind, placebo-controlled study. Psychol Med. 2023 Jun;53(8):3437–3447. doi: 10.1017/S003329172100550X. Epub 2022 Feb 7.
46. Chahwan B, Kwan S, Isik A, van Hemert S, Burke C, Roberts L. Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms. J Affect Disord. 2019 Jun 15;253:317–326. doi: 10.1016/j.jad.2019.04.097. Epub 2019 May 9.
47. Gawlik-Kotelnicka O, Margulska A, Płeska K, Skowrońska A, Strzelecki D. Metabolic status influences probiotic efficacy for depression-PRO-DEMET randomized clinical trial results. Nutrients. 2024 May 3;16(9):1389. doi: 10.3390/nu16091389.
48. Ghorbani Z, Nazari S, Etesam F, Nourimajd S, Ahmadpanah M, Jahromi SR. The effect of synbiotic as an adjuvant therapy to fluoxetine in moderate depression: A randomized multicenter trial. Arch Neurosci. 2018;5(2):e60507. doi: 10.5812/archneurosci.60507.
49. Heidarzadeh-Rad N, Gökmen-Özel H, Kazemi A, Almasi N, Djafarian K. Effects of a psychobiotic supplement on serum brain-derived neurotrophic factor levels in depressive patients: A post hoc analysis of a randomized clinical trial. J Neurogastroenterol Motil. 2020 Sep 30;26(4):486–495. doi: 10.5056/jnm20079.
50. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clin Nutr. 2019 Apr;38(2):522–528. doi: 10.1016/j.clnu.2018.04.010. Epub 2018 Apr 24.
51. Majeed M, Nagabhushanam K, Arumugam S, Majeed S, Ali F. Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: A randomised, double-blind, placebo controlled, multi-centre, pilot clinical study. Food Nutr Res. 2018 Jul 4;62. doi: 10.29219/fnr.v62.1218.
52. Miyaoka T, Kanayama M, Wake R, Hashioka S, Hayashida M, Nagahama M, Okazaki S, Yamashita S, Miura S, Miki H, Matsuda H, Koike M, Izuhara M, Araki T, Tsuchie K, Azis IA, Arauchi R, Abdullah RA, Oh-Nishi A, Horiguchi J. Clostridium butyricum MIYAIRI 588 as adjunctive therapy for treatment-resistant major depressive disorder: A prospective open-label trial. Clin Neuropharmacol. 2018 Sep/Oct;41(5):151–155. doi: 10.1097/WNF.0000000000000299.
53. Mörkl S, Narrath M, Schlotmann D, Sallmutter MT, Putz J, Lang J, Brandstätter A, Pilz R, Karl Lackner H, Goswami N, Steuber B, Tatzer J, Lackner S, Holasek S, Painold A, Jauk E, Wenninger J, Horvath A, Spicher N, Barth A, Butler MI, Wagner-Skacel J. Multi-species probiotic supplement enhances vagal nerve function - results of a randomized controlled trial in patients with depression and healthy controls. Gut Microbes. 2025 Dec;17(1):2492377. doi: 10.1080/19490976.2025.2492377. Epub 2025 Apr 29.
54. Nikolova VL, Cleare AJ, Young AH, Stone JM. Acceptability, tolerability, and estimates of putative treatment effects of probiotics as adjunctive treatment in patients with depression: A randomized clinical trial. JAMA Psychiatry. 2023 Aug 1;80(8):842–847. doi: 10.1001/jamapsychiatry.2023.1817.
55. Reininghaus EZ, Platzer M, Kohlhammer-Dohr A, Hamm C, Mörkl S, Bengesser SA, Fellendorf FT, Lahousen-Luxenberger T, Leitner-Afschar B, Schöggl H, Amberger-Otti D, Wurm W, Queissner R, Birner A, Falzberger VS, Painold A, Fitz W, Wagner-Skacel J, Brunnmayr M, Rieger A, Maget A, Unterweger R, Schwalsberger K, Reininghaus B, Lenger M, Bastiaanssen TFS, Dalkner N. PROVIT: Supplementary probiotic treatment and vitamin B7 in depression-a randomized controlled trial. Nutrients. 2020 Nov 8;12(11):3422. doi: 10.3390/nu12113422.
56. Rudzki L, Ostrowska L, Pawlak D, Małus A, Pawlak K, Waszkiewicz N, Szulc A. Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study. Psychoneuroendocrinology. 2019 Feb;100:213–222. doi: 10.1016/j.psyneuen.2018.10.010. Epub 2018 Oct 16.
57. Schaub AC, Schneider E, Vazquez-Castellanos JF, Schweinfurth N, Kettelhack C, Doll JPK, Yamanbaeva G, Mählmann L, Brand S, Beglinger C, Borgwardt S, Raes J, Schmidt A, Lang UE. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: A randomized controlled trial. Transl Psychiatry. 2022 Jun 3;12(1):227. doi: 10.1038/s41398-022-01977-z.
58. Söderberg Veibäck G, Lindahl J, Suneson K, Tjernberg J, Ståhl D, Landberg R, Asp M, Kjellberg A, Falknäs F, Sjöberg K, Lavebratt C, Wolkowitz OM, Lindqvist D. Add-on probiotics for inflammatory depression - a double-blind randomized placebo-controlled trial. Brain Behav Immun. 2025 Oct;129:348–358. doi: 10.1016/j.bbi.2025.06.002. Epub 2025 Jun 6.
59. Strodl E, Bambling M, Parnam S, Ritchie G, Cramb S, Vitetta L. Probiotics and magnesium orotate for the treatment of major depressive disorder: A randomised double blind controlled trial. Sci Rep. 2024 Sep 6;14(1):20841. doi: 10.1038/s41598-024-71093-z.
60. Taghavi SA, Sadri M, Hashemimohammadabad M, Hashemimohammadabad N, Hashemimohammadabad Z, Bazarganipour F. Adjuvant administration probiotic effects on sexual function in depressant men undergoing selective serotonin reuptake inhibitor treatment: A double-blinded randomized controlled trial. J Sex Med. 2026 Apr 9;23(5):qdag043. doi: 10.1093/jsxmed/qdag043.
61. Tian P, Chen Y, Zhu H, et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: A randomized clinical trial. Brain Behav Immun. 2022;100:233-241. doi:10.1016/j.bbi.2021.11.023
62. Zhang X, Chen S, Zhang M, Ren F, Ren Y, Li Y, Liu N, Zhang Y, Zhang Q, Wang R. Effects of fermented milk containing Lacticaseibacillus paracasei strain shirota on constipation in patients with depression: A randomized, double-blind, placebo-controlled trial. Nutrients. 2021 Jun 29;13(7):2238. doi: 10.3390/nu13072238.
Mild cognitive impairment
63. Aljumaah MR, Bhatia U, Roach J, Gunstad J, Azcarate Peril MA. The gut microbiome, mild cognitive impairment, and probiotics: A randomized clinical trial in middle-aged and older adults. Clin Nutr. 2022 Nov;41(11):2565–2576. doi: 10.1016/j.clnu.2022.09.012. Epub 2022 Sep 28.
64. Asaoka D, Xiao J, Takeda T, Yanagisawa N, Yamazaki T, Matsubara Y, Sugiyama H, Endo N, Higa M, Kasanuki K, Ichimiya Y, Koido S, Ohno K, Bernier F, Katsumata N, Nagahara A, Arai H, Ohkusa T, Sato N. Effect of probiotic Bifidobacterium breve in improving cognitive function and preventing brain atrophy in older patients with suspected mild cognitive impairment: Results of a 24-week randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2022;88(1):75–95. doi: 10.3233/JAD-220148.
65. Chung YC, Jin HM, Cui Y, Kim DS, Jung JM, Park JI, Jung ES, Choi EK, Chae SW. Fermented milk of Lactobacillus helveticus IDCC3801 improves cognitive functioning during cognitive fatigue tests in healthy older adults. J Funct Foods. 2014;10:465–474. doi: 10.1016/j.jff.2014.07.007.
66. Eastwood J, van Hemert S, Stolaki M, Williams C, Walton G, Lamport D. Exploring the acute and chronic effects of a multistrain probiotic supplement on cognitive function and mood in healthy older adults: A randomized controlled trial. Am J Clin Nutr. 2025 Jun;121(6):1268–1280. doi: 10.1016/j.ajcnut.2025.04.002. Epub 2025 Apr 11.
67. Fei Y, Wang R, Lu J, Peng S, Yang S, Wang Y, Zheng K, Li R, Lin L, Li M. Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment. Geriatr Nurs. 2023 May–Jun;51:167–175. doi: 10.1016/j.gerinurse.2023.03.006. Epub 2023 Mar 28.
68. Gao S, Dai H, Hao Q, Song J, Ji K, Xu H, Chen G, Lu J. Effect of perioperative probiotic intervention on postoperative cognitive dysfunction in elderly patients: a randomized double-blinded and placebo-controlled trial. J Transl Med. 2025 Jun 10;23(1):637. doi: 10.1186/s12967-025-06584-2.
69. Hwang YH, Park S, Paik JW, Chae SW, Kim DH, Jeong DG, Ha E, Kim M, Hong G, Park SH, Jung SJ, Lee SM, Na KH, Kim J, Chung YC. Efficacy and safety of Lactobacillus Plantarum C29-fermented soybean (DW2009) in individuals with mild cognitive impairment: A 12-week, multi-center, randomized, double-blind, placebo-controlled clinical trial. Nutrients. 2019 Feb 1;11(2):305. doi: 10.3390/nu11020305.
70. Jung SJ, Cho K, Jung ES, Son D, Byun JS, Kim SI, Chae SW, Yang JC, Lee SO, Lim S. Augmenting cognitive function in the elderly with mild cognitive impairment using probiotic Lacticaseibacillus rhamnosus CBT-LR5: A 12-week randomized, double-blind, parallel-group non-comparative study. Nutrients. 2025 Feb 14;17(4):691. doi: 10.3390/nu17040691.
71. Kim BH, Kwon M, Yim SV, Park JW, Lee CN, Chae SW, Choi JG, Park SC, Sohn MW, Choi SZ, Lee JS. Efficacy and safety of MT104, a dietary supplement based on Cuscuta seeds and heat-killed probiotics, on cognitive function in patients with mild cognitive impairment: A 12-week, multicenter, randomized, double-blind, placebo-controlled clinical trial. J Med Food. 2025 Aug;28(8):812–823. doi: 10.1089/jmf.2024.k.0267. Epub 2025 Jun 25.
72. Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, Shin DM. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: A randomized, double-blind, placebo-controlled, multicenter trial. J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):32–40. doi: 10.1093/gerona/glaa090.
73. Kobayashi Y, Kuhara T, Oki M, Xiao JZ. Effects of Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: A randomised, double-blind, placebo-controlled trial. Benef Microbes. 2019 May 28;10(5):511–520. doi: 10.3920/BM2018.0170. Epub 2019 May 15.
74. Louzada ER, Ribeiro SML. Synbiotic supplementation, systemic inflammation, and symptoms of brain disorders in elders: A secondary study from a randomized clinical trial. Nutr Neurosci. 2020 Feb;23(2):93–100. doi: 10.1080/1028415X.2018.1477349. Epub 2018 May 23.
75. Ruiz-Gonzalez C, Cardona D, Rueda-Ruzafa L, Rodriguez-Arrastia M, Ropero-Padilla C, Roman P. Cognitive and emotional effect of a multi-species probiotic containing Lactobacillus rhamnosus and Bifidobacterium lactis in healthy older adults: A double-blind randomized placebo-controlled crossover trial. Probiotics Antimicrob Proteins. 2025 Oct;17(5):3525–3537. doi: 10.1007/s12602-024-10315-2. Epub 2024 Jun 27.
76. Shi S, Zhang Q, Sang Y, Ge S, Wang Q, Wang R, He J. Probiotic Bifidobacterium longum BB68S improves cognitive functions in healthy older adults: A randomized, double-blind, placebo-controlled trial. Nutrients. 2022 Dec 22;15(1):51. doi: 10.3390/nu15010051.
77. Tomizawa M, Sato T, Segawa S, Iio SI, Takara T. Effect of probiotic drinks containing 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one on cognitive function of middle-aged and older individuals. J Nutr Sci Vitaminol (Tokyo). 2025;71(3):223–229. doi: 10.3177/jnsv.71.223.
78. Wang P, Yin X, Chen G, Li L, Le Y, Xie Z, Ouyang W, Tong J. Perioperative probiotic treatment decreased the incidence of postoperative cognitive impairment in elderly patients following non-cardiac surgery: A randomised double-blind and placebo-controlled trial. Clin Nutr. 2021 Jan;40(1):64–71. doi: 10.1016/j.clnu.2020.05.001. Epub 2020 May 11.
79. Xiao J, Katsumata N, Bernier F, Ohno K, Yamauchi Y, Odamaki T, Yoshikawa K, Ito K, Kaneko T. Probiotic Bifidobacterium breve in Improving cognitive functions of older adults with suspected mild cognitive impairment: A randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2020;77(1):139–147. doi: 10.3233/JAD-200488. Erratum in: J Alzheimers Dis. 2026 Feb;109(4):1985. doi: 10.1177/13872877251407772.
Alzheimer's dementia
80. Agahi A, Hamidi GA, Daneshvar R, Hamdieh M, Soheili M, Alinaghipour A, Esmaeili Taba SM, Salami M. Does severity of Alzheimer's disease contribute to its responsiveness to modifying gut microbiota? A double blind clinical trial. Front Neurol. 2018 Aug 15;9:662. doi: 10.3389/fneur.2018.00662. Erratum in: Front Neurol. 2019 Feb 05;10:31. doi: 10.3389/fneur.2019.00031.
81. Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, Hamidi GA, Salami M. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: A randomized, double-blind and controlled trial. Front Aging Neurosci. 2016 Nov 10;8:256. doi: 10.3389/fnagi.2016.00256.
82. Hsu YC, Huang YY, Tsai SY, Kuo YW, Lin JH, Ho HH, Chen JF, Hsia KC, Sun Y. Efficacy of probiotic supplements on brain-derived neurotrophic factor, inflammatory biomarkers, oxidative stress and cognitive function in patients with Alzheimer's dementia: A 12-week randomized, double-blind active-controlled study. Nutrients. 2023 Dec 20;16(1):16. doi: 10.3390/nu16010016.
83. Loffredo L, Alfano AR, Ettorre E, Desideri G, Carnevale R, Forte M, Maglione V, Bartimoccia S, Castellani V, Totè CM, Pignatelli P, Violi F; Neurodegenerative Disease study group. Effect of the probiotic Escherichia coli Nissle 1917 on serum levels of NADPH oxidase-2 and lipopolysaccharide in patients with Alzheimer's disease. J Alzheimers Dis. 2025 Jul;106(2):774–782. doi: 10.1177/13872877251345157. Epub 2025 Jul 1.
84. Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E, Tajabadi-Ebrahimi M, Asemi Z. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: A randomized, double-blind, controlled trial. Clin Nutr. 2019 Dec;38(6):2569–2575. doi: 10.1016/j.clnu.2018.11.034. Epub 2018 Dec 10.
Mild depressive symptoms
85. Benton D, Williams C, Brown A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr. 2007 Mar;61(3):355–361. doi: 10.1038/sj.ejcn.1602546. Epub 2006 Dec 6.
86. Browne PD, Bolte AC, Besseling-van der Vaart I, Claassen E, de Weerth C. Probiotics as a treatment for prenatal maternal anxiety and depression: A double-blind randomized pilot trial. Sci Rep. 2021 Feb 4;11(1):3051. doi: 10.1038/s41598-021-81204-9.
87. Eastwood J, van Hemert S, Stolaki M, Williams C, Walton G, Lamport D. Exploring the acute and chronic effects of a multistrain probiotic supplement on cognitive function and mood in healthy older adults: a randomized controlled trial. Am J Clin Nutr. 2025 Jun;121(6):1268–1280. doi: 10.1016/j.ajcnut.2025.04.002. Epub 2025 Apr 11.
88. El-Heis S, Barton SJ, Chang HF, Nield H, Cox V, Galani S, Cutfield W, Chan SY, Godfrey KM; NiPPeR Study Group. Maternal mood, anxiety and mental health functioning after combined myo-inositol, probiotics, micronutrient supplementation from preconception: Findings from the NiPPeR RCT. Psychiatry Res. 2024 Apr;334:115813. doi: 10.1016/j.psychres.2024.115813. Epub 2024 Feb 23.
89. Erlita D, Shatri H, Fauzi A, Abdullah M, Putranto R, Ginanjar E, Hasan I, Rachman A. The Role of Probiotics in Depression and Quality of Life in Patients with Irritable Bowel Syndrome. Acta Med Indones. 2025 Oct;57(4):485–492.
90. Haghighat N, Rajabi S, Mohammadshahi M. Effect of synbiotic and probiotic supplementation on serum brain-derived neurotrophic factor level, depression and anxiety symptoms in hemodialysis patients: A randomized, double-blinded, clinical trial. Nutr Neurosci. 2021 Jun;24(6):490–499. doi: 10.1080/1028415X.2019.1646975. Epub 2019 Aug 4.
91. Hulkkonen P, Kataja EL, Vahlberg T, Koivuniemi E, Houttu N, Pellonperä O, Mokkala K, Karlsson H, Laitinen K. The efficacy of probiotics and/or n-3 long-chain polyunsaturated fatty acids intervention on maternal prenatal and postnatal depressive and anxiety symptoms among overweight and obese women. J Affect Disord. 2021 Jun 15;289:21–30. doi: 10.1016/j.jad.2021.04.006. Epub 2021 Apr 20.
92. Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, Shin DM. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: A randomized, double-blind, placebo-controlled, multicenter trial. J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):32–40. doi: 10.1093/gerona/glaa090.
93. Komorniak N, Kaczmarczyk M, Łoniewski I, Martynova-Van Kley A, Nalian A, Wroński M, Kaseja K, Kowalewski B, Folwarski M, Stachowska E. Analysis of the efficacy of diet and short-term probiotic intervention on depressive symptoms in patients after bariatric surgery: A randomized double-blind placebo controlled pilot study. Nutrients. 2023 Nov 24;15(23):4905. doi: 10.3390/nu15234905.
94. Marques CG, Dos Santos Quaresma MVL, França Ferracini CB, Alves Carrilho FB, Nakamoto FP, Lucin GA, Oumatu Magalhães AC, Mendes GL, Alvares LA, Thomatieli-Santos RV. Effect of caloric restriction with probiotic supplementation on body composition, quality of life, and psychobiological factors of obese men: A randomized, double-blinded placebo-controlled clinical trial. Clin Nutr. 2025 Feb;45:234–249. doi: 10.1016/j.clnu.2024.12.031. Epub 2024 Dec 31.
95. Moludi J, Alizadeh M, Mohammadzad MHS, Davari M. The effect of probiotic supplementation on depressive symptoms and quality of life in patients after myocardial infarction: Results of a preliminary double-blind clinical trial. Psychosom Med. 2019 Nov/Dec;81(9):770–777. doi: 10.1097/PSY.0000000000000749.
96. Moludi J, Khedmatgozar H, Nachvak SM, Abdollahzad H, Moradinazar M, Sadeghpour Tabaei A. The effects of co-administration of probiotics and prebiotics on chronic inflammation, and depression symptoms in patients with coronary artery diseases: A randomized clinical trial. Nutr Neurosci. 2022 Aug;25(8):1659–1668. doi: 10.1080/1028415X.2021.1889451. Epub 2021 Feb 28.
97. Mosavat SH, Sahraian A, Kalani M, Namjoyan F, Ghasemi Y. Effect of probiotic supplement on improvement of depressive symptoms in patients with substance-induced depressive disorder: A randomized, double-blind, placebo-controlled clinical trial. BMC Psychiatry. 2026 Mar 13;26(1):334. doi: 10.1186/s12888-026-07903-7.
98. Moschonis G, Sarapis K, Resciniti S, Hall R, Yim K, Tonkovic M, Fitzgerald C, Anixiadis F, Vinh A, Dinh QN, Cronin RA, Hale MW, Wright BJ, Pane M, Tuck CJ, Biesiekierski JR. Evaluation of a probiotic blend on psychosocial health and biomarkers of inflammatory, immune and stress response in adults with subthreshold depression: A double-blind, randomised, placebo-controlled trial. Br J Nutr. 2026 Mar 14;135(5):481–495. doi: 10.1017/S0007114524001703. Epub 2024 Oct 29.
99. Noori M, Shateri Z, Babajafari S, Eskandari MH, Parastouei K, Ghasemi M, Afshari H, Samadi M. The effect of probiotic-fortified kefir on depression, appetite, oxidative stress, and inflammatory parameters in Iranian overweight and obese elderly: A randomized, double-blind, placebo-controlled clinical trial. J Health Popul Nutr. 2025 Feb 7;44(1):30. doi: 10.1186/s41043-025-00773-x.
100. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: A pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017 Aug;153(2):448–459.e8. doi: 10.1053/j.gastro.2017.05.003. Epub 2017 May 5.
101. Romijn AR, Rucklidge JJ, Kuijer RG, Frampton C. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017 Aug;51(8):810–821. doi: 10.1177/0004867416686694. Epub 2017 Jan 10.
102. Shafie M, Homayouni Rad A, Mohammad-Alizadeh-Charandabi S, Mirghafourvand M. The effect of probiotics on mood and sleep quality in postmenopausal women: A triple-blind randomized controlled trial. Clin Nutr ESPEN. 2022 Aug;50:15–23. doi: 10.1016/j.clnesp.2022.06.005. Epub 2022 Jun 9.
103. Smith-Ryan AE, Mock MG, Trexler ET, Hirsch KR, Blue MNM. Influence of a multistrain probiotic on body composition and mood in female occupational shift workers. Appl Physiol Nutr Metab. 2019 Jul;44(7):765–773. doi: 10.1139/apnm-2018-0645. Epub 2018 Dec 19.
104. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015 Aug;48:258–264. doi: 10.1016/j.bbi.2015.04.003. Epub 2015 Apr 7.
105. Tavares-Silva E, de Aquino Lemos V, de França E, Silvestre J, Dos Santos SA, Ravacci GR, Thomatieli-Santos RV. Protective effects of probiotics on runners' mood: Immunometabolic mechanisms post-exercise. Nutrients. 2024 Nov 1;16(21):3761. doi: 10.3390/nu16213761.
Sexual dysfunction
106. Azizi-Kutenaee M, Heidari S, Taghavi SA, Bazarganipour F. Probiotic effects on sexual function in women with polycystic ovary syndrome: A double blinded randomized controlled trial. BMC Womens Health. 2022 Sep 12;22(1):373. doi: 10.1186/s12905-022-01955-z.
107. Hashemi-Mohammadabad N, Taghavi SA, Lambert N, Moshtaghi R, Bazarganipour F, Sharifi M. Adjuvant administration of probiotic effects on sexual function in depressant women undergoing SSRIs treatment: A double-blinded randomized controlled trial. BMC Psychiatry. 2024 Jan 12;24(1):44. doi: 10.1186/s12888-023-05429-w.
108. Kazemi F, Abbasalizadeh M, Mehrpooya M, Najafi-Vosough R, Soltani F, Jenabi E. The effect of probiotic consumption on fatigue severity and sexual function among postmenopausal women: A double-blind randomized controlled trial in the west of Iran. Menopause. 2026 Mar 1;33(3):322–332. doi: 10.1097/GME.0000000000002655.
109. Taghavi SA, Sadri M, Hashemimohammadabad M, Hashemimohammadabad N, Hashemimohammadabad Z, Bazarganipour F. Adjuvant administration probiotic effects on sexual function in depressant men undergoing selective serotonin reuptake inhibitor treatment: A double-blinded randomized controlled trial. J Sex Med. 2026 Apr 9;23(5):qdag043. doi: 10.1093/jsxmed/qdag043.
110. Valizadeh R, Borhani F, Shabani F, Mirghafourvand M. The effect of probiotic supplementation on sexual function in premenopausal and menopausal women: A randomized controlled clinical trial. Sci Rep. 2025 Dec 2;16(1):1254. doi: 10.1038/s41598-025-30879-5.
Sleep quality
111. Aquino-Lemos V, Leite GSF, T Silva E, Batatinha HAP, Resende AS, Lancha-Junior AH, R Neto JC, Tufik S, Thomatieli-Santos RV. Probiotic supplementation can alter inflammation parameters and self-reported sleep after a marathon: A randomized, double-blind, placebo-controlled study. Nutrients. 2025 Nov 29;17(23):3762. doi: 10.3390/nu17233762.
113. Du Y, Wang L, Cui Y, Xu X, Zhang M, Li Y, Gao T, Gao D, Sheng Z, Wang S, Tuo H. Effect of probiotics supplementation on REM sleep behavior disorder and motor symptoms in Parkinson's disease: A pilot study. CNS Neurosci Ther. 2025 Jul;31(7):e70541. doi: 10.1111/cns.70541.
114. Freijy TM, Cribb L, Oliver G, Metri NJ, Opie RS, Jacka FN, Hawrelak JA, Rucklidge JJ, Ng CH, Sarris J. Effects of a high-prebiotic diet versus probiotic supplements versus synbiotics on adult mental health: The "Gut Feelings" randomised controlled trial. Front Neurosci. 2023 Feb 6;16:1097278. doi: 10.3389/fnins.2022.1097278.
115. Grant AD, Erfe MCB, Delebecque CJ, Keller D, Zimmerman NP, Kazaryan A, Oliver PL, Moos J, Luna V, Craft N. Lactiplantibacillus plantarum Lp815 improves sleep and increases urinary GABA in a randomized, double-blind, placebo-controlled study of sleep disturbance. Sci Rep. 2026 Jan 19;16(1):644. doi: 10.1038/s41598-025-27861-6.
116. Ho YT, Tsai YC, Kuo TBJ, Yang CCH. Effects of Lactobacillus plantarum PS128 on depressive symptoms and sleep quality in self-reported insomniacs: A randomized, double-blind, placebo-controlled pilot trial. Nutrients. 2021 Aug 17;13(8):2820. doi: 10.3390/nu13082820.
117. Horvath A, Haller R, Schmid-Zalaudek K, Goswami N, Wagner-Skacel J, Habisch H, Madl T, Stadlbauer V. The beneficial effect of a multispecies probiotic intervention on quality of sleep - a randomized, double-blinded, placebo-controlled study. J Psychiatr Res. 2026 Apr;195:244–256. doi: 10.1016/j.jpsychires.2026.01.040. Epub 2026 Jan 28.
118. Kerksick CM, Moon JM, Walden KE, Hagele AM, Allen LE, Gaige CJ, Krieger JM, Jäger R, Pane M, Mumford P. Multi-strain probiotic improves subjective sleep quality with no impact on body composition, hemodynamics, and physical activity. Benef Microbes. 2024 Jan 31;15(2):179–194. doi: 10.1163/18762891-bja00002.
119. Lee HJ, Hong JK, Kim JK, Kim DH, Jang SW, Han SW, Yoon IY. Effects of probiotic NVP-1704 on mental health and sleep in healthy adults: An 8-week randomized, double-blind, placebo-controlled trial. Nutrients. 2021 Jul 30;13(8):2660. doi: 10.3390/nu13082660.
120. Liu Y, Chen Y, Zhang Q, Zhang Y, Xu F. A double blinded randomized placebo trial of Bifidobacterium animalis subsp. lactis BLa80 on sleep quality and gut microbiota in healthy adults. Sci Rep. 2025 Apr 1;15(1):11095. doi: 10.1038/s41598-025-95208-2.
121. Marotta A, Sarno E, Del Casale A, Pane M, Mogna L, Amoruso A, Felis GE, Fiorio M. Effects of probiotics on cognitive reactivity, mood, and sleep quality. Front Psychiatry. 2019 Mar 27;10:164. doi: 10.3389/fpsyt.2019.00164.
122. Nishida K, Sawada D, Kawai T, Kuwano Y, Fujiwara S, Rokutan K. Para-psychobiotic Lactobacillus gasseri CP2305 ameliorates stress-related symptoms and sleep quality. J Appl Microbiol. 2017 Dec;123(6):1561–1570. doi: 10.1111/jam.13594. Epub 2017 Nov 7.
123. Patterson E, Tan HTT, Groeger D, Andrews M, Buckley M, Murphy EF, Groeger JA. Bifidobacterium longum 1714 improves sleep quality and aspects of well-being in healthy adults: A randomized, double-blind, placebo-controlled clinical trial. Sci Rep. 2024 Feb 14;14(1):3725. doi: 10.1038/s41598-024-53810-w.
124. Saleh-Ghadimi S, Dehghan P, Sarmadi B, Maleki P. Improvement of sleep by resistant dextrin prebiotic in type 2 diabetic women coincides with attenuation of metabolic endotoxemia: Involvement of gut-brain axis. J Sci Food Agric. 2022 Sep;102(12):5229–5237. doi: 10.1002/jsfa.11876. Epub 2022 Apr 15.
125. Shafie M, Homayouni Rad A, Mohammad-Alizadeh-Charandabi S, Mirghafourvand M. The effect of probiotics on mood and sleep quality in postmenopausal women: A triple-blind randomized controlled trial. Clin Nutr ESPEN. 2022 Aug;50:15–23. doi: 10.1016/j.clnesp.2022.06.005. Epub 2022 Jun 9.
126. Takada M, Nishida K, Gondo Y, Kikuchi-Hayakawa H, Ishikawa H, Suda K, Kawai M, Hoshi R, Kuwano Y, Miyazaki K, Rokutan K. Beneficial effects of Lactobacillus casei strain Shirota on academic stress-induced sleep disturbance in healthy adults: a double-blind, randomised, placebo-controlled trial. Benef Microbes. 2017 Apr 26;8(2):153–162. doi: 10.3920/BM2016.0150.
127. Tanihiro R, Yuki M, Sasai M, Haseda A, Kagami-Katsuyama H, Hirota T, Honma N, Nishihira J. Effects of prebiotic yeast mannan on gut health and sleep quality in healthy adults: A randomized, double-blind, placebo-controlled study. Nutrients. 2023 Dec 31;16(1):141. doi: 10.3390/nu16010141.
128. Zhu R, Fang Y, Li H, Liu Y, Wei J, Zhang S, Wang L, Fan R, Wang L, Li S, Chen T. Psychobiotic Lactobacillus plantarum JYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious college via modulating the gut microbiota and its metabolism. Front Immunol. 2023 Mar 23;14:1158137. doi: 10.3389/fimmu.2023.1158137.
Sleep quality / Methamphetamine use disorder
112. Badrfam R, Zandifar A, Hajialigol A, Rashidian M, Schmidt NB, Morabito D, Qorbani M, Shahrestanaki E, Mehrabani Natanzi M. Efficacy of probiotic supplements in improving the symptoms of psychosis, anxiety, insomnia, and anorexia due to amphetamine and methamphetamine use: A randomized clinical trial. Psychopharmacology (Berl). 2024 Jul;241(7):1463–1476. doi: 10.1007/s00213-024-06577-x. Epub 2024 Mar 21.
Binge eating after gastric bypass
129. Carlos LO, Ramos MRZ, Wagner NRF, Freitas LAC, Felicidade I, Campos ACL. Probiotic supplementation attenuates binge eating and food addiction 1 year after Roux-en-Y gastric bypass: A randomized, double-blind, placebo-controlled trial. Arq Bras Cir Dig. 2022 Jun 24;35:e1659. doi: 10.1590/0102-672020210002e1659.
Bipolar disorder
130. Borkent J, Ioannou M, Neijzen D, Haarman BCM, Sommer IEC. Probiotic formulation for patients with bipolar or schizophrenia spectrum disorder: A double-blind, randomized placebo-controlled trial. Schizophr Bull. 2025 Nov 10;51(6):1568–1580. doi: 10.1093/schbul/sbae188.
131. Dickerson F, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, Schweinfurth L, Stallings C, Sweeney K, Goga J, Yolken RH. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial. Bipolar Disord. 2018 Nov;20(7):614–621. doi: 10.1111/bdi.12652. Epub 2018 Apr 25.
Borderline personality disorder
132. Arteaga-Henríquez G, Ramos-Sayalero C, Ibañez-Jimenez P, Karina Rosales-Ortiz S, Kilencz T, Schiweck C, Schnorr I, Siegl A, Arias-Vasquez A, Bitter I, Fadeuilhe C, Ferrer M, Lavebratt C, Matura S, Reif A, Réthelyi JM, Richarte V, Rommelse N, Antoni Ramos-Quiroga J. Efficacy of a synbiotic in the management of adults with attention-deficit and hyperactivity disorder and/or borderline personality disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial. Brain Behav Immun. 2024 Aug;120:360–371. doi: 10.1016/j.bbi.2024.06.012. Epub 2024 Jun 15. Erratum in: Brain Behav Immun. 2024 Oct;121:404–405. doi: 10.1016/j.bbi.2024.08.019.
Long COVID
133. Thomas R, Williams M, Aldous J, Yanagisawa Y, Kumar R, Forsyth R, Chater A. A randomised, double-blind, placebo-controlled trial evaluating concentrated phytochemical-rich nutritional capsule in addition to a probiotic capsule on clinical outcomes among individuals with COVID-19—The UK Phyto-V study. COVID. 2022;2(4):433–449. doi: 10.3390/covid2040031.
Metabolic syndrome in schizophrenia
134. Basafa-Roodi P, Jazayeri S, Hadi F, Paghaleh SJ, Khosravi-Darani K, Malakouti SK. Effects of synbiotic supplementation on the components of metabolic syndrome in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. BMC Psychiatry. 2024 Oct 9;24(1):669. doi: 10.1186/s12888-024-06061-y.
135. Huang J, Kang D, Zhang F, Yang Y, Liu C, Xiao J, Long Y, Lang B, Peng X, Wang W, Wang X, Liu F, Davis JM, Zhao J, Wu R. Probiotics plus dietary fiber supplements attenuate olanzapine-induced weight gain in drug-naïve first-episode schizophrenia patients: Two randomized clinical trials. Schizophr Bull. 2022 Jun 21;48(4):850–859. doi: 10.1093/schbul/sbac044.
Methamphetamine use disorder
136. Badrfam R, Zandifar A, Hajialigol A, Rashidian M, Schmidt NB, Morabito D, Qorbani M, Shahrestanaki E, Mehrabani Natanzi M. Efficacy of probiotic supplements in improving the symptoms of psychosis, anxiety, insomnia, and anorexia due to amphetamine and methamphetamine use: a randomized clinical trial. Psychopharmacology (Berl). 2024 Jul;241(7):1463–1476. doi: 10.1007/s00213-024-06577-x. Epub 2024 Mar 21.
Schizophrenia
137. Borkent J, Ioannou M, Neijzen D, Haarman BCM, Sommer IEC. Probiotic formulation for patients with bipolar or schizophrenia spectrum disorder: A double-blind, randomized placebo-controlled trial. Schizophr Bull. 2025 Nov 10;51(6):1568–1580. doi: 10.1093/schbul/sbae188.
138. Kao AC, Safarikova J, Marquardt T, Mullins B, Lennox BR, Burnet PWJ. Pro-cognitive effect of a prebiotic in psychosis: A double blind placebo controlled cross-over study. Schizophr Res. 2019 Jun;208:460–461. doi: 10.1016/j.schres.2019.03.003. Epub 2019 Mar 12.
139. Mohammadi A, Sadighi G, Nazeri Astaneh A, Tajabadi-Ebrahimi M, Dejam T. Co-administration of probiotic and vitamin D significantly improves cognitive function in schizophrenic patients: A double-blinded randomized controlled trial. Neuropsychopharmacol Rep. 2024 Jun;44(2):389–398. doi: 10.1002/npr2.12431. Epub 2024 Apr 10.
Veisalgia (alcohol hangover)
140. Mo C, Bajgai J, Rahman MH, Abdul-Nasir S, Ma H, Pham TT, Zhang H, Cao B, Goh SH, Kim B, Kim H, Seol MK, Yu YG, Kim CS, Lee KJ, Lim ST. Efficacy of probiotic vita-pb2 from fermented foods on alcohol consumption and hangover symptoms: A randomized, double-blind, placebo-controlled trial. Nutrients. 2025 Jul 9;17(14):2276. doi: 10.3390/nu17142276.
Chamomile References
13 references
Sleep
1. Abbasinia H, Alizadeh Z, Vakilian K, Jafari Z, Poor PM, Ranjbaran M. Effect of chamomile extract on sleep disorder in menopausal women Iran J Obstet, Gynecol Infertil, 19 (20) (2016), pp. 1-7
2. Abdullahzadeh M, Matourypour P, Naji SA. Investigation effect of oral chamomilla on sleep quality in elderly people in Isfahan: A randomized control trial. J Educ Health Promot. 2017 Jun 5;6:53. doi: 10.4103/jehp.jehp_109_15. PMID: 28616420; PMCID: PMC5470311.
3. Adib-Hajbaghery M, Mousavi SN. The effects of chamomile extract on sleep quality among elderly people: a clinical trial. Complement Ther Med. 2017;35:109-114. PMID: 29154054
4. Chang SM, Chen CH. Effects of an intervention with drinking chamomile tea on sleep quality and depression in sleep disturbed postnatal women: a randomized controlled trial. J Adv Nurs. 2016;72(2):306-315. PMID: 26483209
5. Moeini ghamchini v, Hekmatpou D, Haghverdy F, Delavar M. Effect of Chamomile on sleep quality of hemodialysis patients: A clinical trial. CMJA. 2015;5(3):1224–1233.
6. Rashidi S, Shafie D, Mazaheri M, Babaei S. Effect of Matricaria Recutita drop on sleep quality in patients with chronic heart disease: a randomized controlled trial Arch Pharm Pract, 1 (2020), p. 162
7. Rasool A, Ishtiaq A, Rehman B. Outcome of use of high quality chamomile extract on sleep disorders occurring after menopause J Med Plants -Prod (2019), p. 52
8. Shariati A, Jahani S, Hooshmand M, Khalili N. The effect of exercise on the quality of sleep of hemodialysis patients [chamomile arm]. Iran J Nurs Midwifery Res. 2012. (Extracted from Cochrane CKD review)
9. Zick SM, Wright BD, Sen A, Arnedt JT. Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: a randomized placebo-controlled pilot study. BMC Complement Altern Med. 2011;11:78. PMID: 21939549
Generalized anxiety disorder
10. Amsterdam JD, Li QS, Xie SX, Mao JJ. Putative antidepressant effect of chamomile (Matricaria chamomilla L.) oral extract in subjects with comorbid generalized anxiety disorder and depression. J Altern Complement Med. 2020 Sep;26(9):813–819. doi: 10.1089/acm.2019.0252. Epub 2019 Dec 5.
11. Amsterdam JD, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol. 2009 Aug;29(4):378–382. doi: 10.1097/JCP.0b013e3181ac935c.
12. Mao JJ, Xie SX, Keefe JR, Soeller I, Li QS, Amsterdam JD. Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial. Phytomedicine. 2016 Dec 15;23(14):1735–1742. doi: 10.1016/j.phymed.2016.10.012. Epub 2016 Oct 24.
Sexual dysfunction in postmenopausal women
13. Bosak Z, Iravani M, Moghimipour E, Haghighizadeh MH, Jelodarian P. Effect of chamomile vaginal gel on the sexual function in postmenopausal women: A double-blind randomized controlled trial. J Sex Med. 2022 Jun;19(6):983–994. doi: 10.1016/j.jsxm.2022.03.536. Epub 2022 Apr 7.
Cocoa References
14 references
Cognition in older adults
1. Baker LD, Manson JE, Rapp SR, Sesso HD, Gaussoin SA, Shumaker SA, Espeland MA. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimers Dement. 2023 Apr;19(4):1308–1319. doi: 10.1002/alz.12767. Epub 2022 Sep 14.
2. Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, Small SA. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014 Dec;17(12):1798–1803. doi: 10.1038/nn.3850. Epub 2014 Oct 26.
3. Brickman AM, Yeung LK, Alschuler DM, Ottaviani JI, Kuhnle GGC, Sloan RP, Luttmann-Gibson H, Copeland T, Schroeter H, Sesso HD, Manson JE, Wall M, Small SA. Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2216932120. doi: 10.1073/pnas.2216932120. Epub 2023 May 30.
4. Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, Raffaele A, Ferri L, Bocale R, Lechiara MC, Marini C, Ferri C. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study. Hypertension. 2012 Sep;60(3):794–801. doi: 10.1161/HYPERTENSIONAHA.112.193060. Epub 2012 Aug 14.
5. Mastroiacovo D, Kwik-Uribe C, Grassi D, Necozione S, Raffaele A, Pistacchio L, Righetti R, Bocale R, Lechiara MC, Marini C, Ferri C, Desideri G. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: The Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial. Am J Clin Nutr. 2015 Mar;101(3):538–548. doi: 10.3945/ajcn.114.092189. Epub 2014 Dec 17.
6. Neshatdoust S, Saunders C, Castle SM, Vauzour D, Williams C, Butler L, Lovegrove JA, Spencer JP. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: Two randomised, controlled trials. Nutr Healthy Aging. 2016 Oct 27;4(1):81–93. doi: 10.3233/NHA-1615.
7. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology. 2013 Sep 3;81(10):904–909. doi: 10.1212/WNL.0b013e3182a351aa. Epub 2013 Aug 7.
8. Vyas CM, Manson JE, Sesso HD, Rist PM, Weinberg A, Kim E, Moorthy MV, Cook NR, Okereke OI. Effect of cocoa extract supplementation on cognitive function: Results from the clinic subcohort of the COSMOS trial. Am J Clin Nutr. 2024 Jan;119(1):39–48. doi: 10.1016/j.ajcnut.2023.10.031. Epub 2023 Dec 7.
Mood in healthy adults
9. Ibero-Baraibar I, Perez-Cornago A, Ramirez MJ, Martínez JA, Zulet MA. An increase in plasma homovanillic acid with cocoa extract consumption is associated with the alleviation of depressive symptoms in overweight or obese adults on an energy restricted diet in a randomized controlled trial. J Nutr. 2016;146(4):897S–904S. doi: 10.3945/jn.115.222828.
10. Massee LA, Ried K, Pase M, Travica N, Yoganathan J, Scholey A, Macpherson H, Kennedy G, Sali A, Pipingas A. The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: A randomized, controlled trial. Front Pharmacol. 2015 May 20;6:93. doi: 10.3389/fphar.2015.00093.
11. Pase MP, Scholey AB, Pipingas A, Kras M, Nolidin K, Gibbs A, Wesnes K, Stough C. Cocoa polyphenols enhance positive mood states but not cognitive performance: – randomized, placebo-controlled trial. J Psychopharmacol. 2013 May;27(5):451–458. doi: 10.1177/0269881112473791. Epub 2013 Jan 29.
12. Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol. 2010 Oct;24(10):1505–1514. doi: 10.1177/0269881109106923. Epub 2009 Nov 26.
13. Shin JH, Kim CS, Cha J, Kim S, Lee S, Chae S, Chun WY, Shin DM. Consumption of 85% cocoa dark chocolate improves mood in association with gut microbial changes in healthy adults: A randomized controlled trial. J Nutr Biochem. 2022 Jan;99:108854. doi: 10.1016/j.jnutbio.2021.108854. Epub 2021 Sep 14.
Depression in postmenopausal women
14. Abdoli E, Rezaie E, Mirghafourvand M, Payahoo L, Naseri E, Ghanbari-Homaie S. A clinical trial of the effects of cocoa rich chocolate on depression and sleep quality in menopausal women. Sci Rep. 2024 Oct 14;14(1):23971. doi: 10.1038/s41598-024-74804-8.
Curcumin References
20 references
Major depressive disorder
1. Asadi S, Gholami MS, Siassi F, Qorbani M, Sotoudeh G. Beneficial effects of nano-curcumin supplement on depression and anxiety in diabetic patients with peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2020 Apr;34(4):896–903. doi: 10.1002/ptr.6571. Epub 2019 Dec 1.
2. Bergman J, Miodownik C, Bersudsky Y, Sokolik S, Lerner PP, Kreinin A, Polakiewicz J, Lerner V. Curcumin as an add-on to antidepressive treatment: A randomized, double-blind, placebo-controlled, pilot clinical study. Clin Neuropharmacol. 2013 May–Jun;36(3):73–77. doi: 10.1097/WNF.0b013e31828ef969.
3. Hamlbar EP, Mirghafourvand M, Shaseb E, Kamalifard M. The effect of curcumin on postpartum depression and anxiety in primiparous women: A double-blind randomized placebo-controlled clinical trial. BMC Complement Med Ther. 2025 Apr 25;25(1):157. doi: 10.1186/s12906-025-04798-x.
4. Kanchanatawan B, Tangwongchai S, Sughondhabhirom A, Suppapitiporn S, Hemrunrojn S, Carvalho AF, Maes M. Add-on treatment with curcumin has antidepressive effects in thai patients with major depression: Results of a randomized double-blind placebo-controlled study. Neurotox Res. 2018 Apr;33(3):621–633. doi: 10.1007/s12640-017-9860-4. Epub 2018 Jan 11.
5. Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368–375. doi: 10.1016/j.jad.2014.06.001. Epub 2014 Jun 11.
6. Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, Goel A, Tripathi CB. Efficacy and safety of curcumin in major depressive disorder: A randomized controlled trial. Phytother Res. 2014 Apr;28(4):579–585. doi: 10.1002/ptr.5025. Epub 2013 Jul 6.
7. Soltani M, Hosseinzadeh-Attar MJ, Rezaei M, Alipoor E, Vasheghani-Farahani A, Yaseri M, Rezayat SM. Effect of nano-curcumin supplementation on cardiometabolic risk factors, physical and psychological quality of life, and depression in patients with coronary slow flow phenomenon: A randomized double-blind clinical trial. Trials. 2024 Jul 31;25(1):515. doi: 10.1186/s13063-024-08354-9.
8. Yaikwawong M, Jansarikit L, Jirawatnotai S, Chuengsamarn S. Curcumin reduces depression in obese patients with type 2 diabetes: A randomized controlled trial. Nutrients. 2024 Jul 25;16(15):2414. doi: 10.3390/nu16152414.
9. Yu JJ, Pei LB, Zhang Y, Wen ZY, Yang JL. Chronic supplementation of curcumin enhances the efficacy of antidepressants in major depressive disorder: A randomized, double-blind, placebo-controlled pilot study. J Clin Psychopharmacol. 2015 Aug;35(4):406–410. doi: 10.1097/JCP.0000000000000352.
10. Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368–375. doi: 10.1016/j.jad.2014.06.001. Epub 2014 Jun 11.
Negative symptoms of schizophrenia
11. Kucukgoncu S, Guloksuz S, Tek C. Effects of curcumin on cognitive functioning and inflammatory state in schizophrenia: A double-blind, placebo-controlled pilot trial. J Clin Psychopharmacol. 2019 Mar/Apr;39(2):182–184. doi: 10.1097/JCP.0000000000001012.
12. Miodownik C, Lerner V, Kudkaeva N, Lerner PP, Pashinian A, Bersudsky Y, Eliyahu R, Kreinin A, Bergman J. Curcumin as add-on to antipsychotic treatment in patients with chronic schizophrenia: A randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2019 Jul/Aug;42(4):117–122. doi: 10.1097/WNF.0000000000000344.
13. Wynn JK, Green MF, Hellemann G, Karunaratne K, Davis MC, Marder SR. The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A randomized controlled study. Schizophr Res. 2018 May;195:572–573. doi: 10.1016/j.schres.2017.09.046. Epub 2017 Sep 29.
Cognition in older adults
14. Cox KH, Pipingas A, Scholey AB. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol. 2015 May;29(5):642-51. doi: 10.1177/0269881114552744. Epub 2014 Oct 2. PMID: 25277322.
15. Cox KHM, White DJ, Pipingas A, Poorun K, Scholey A. Further Evidence of Benefits to Mood and Working Memory from Lipidated Curcumin in Healthy Older People: A 12-Week, Double-Blind, Placebo-Controlled, Partial Replication Study. Nutrients. 2020 Jun 4;12(6):1678. doi: 10.3390/nu12061678. PMID: 32512782; PMCID: PMC7352411.
16. Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368-75. doi: 10.1016/j.jad.2014.06.001. Epub 2014 Jun 11. PMID: 25046624.
17. Rainey-Smith SR, Brown BM, Sohrabi HR, Shah T, Goozee KG, Gupta VB, Martins RN. Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. Br J Nutr. 2016 Jun;115(12):2106-13. doi: 10.1017/S0007114516001203. Epub 2016 Apr 22. PMID: 27102361.
18. Small GW, Siddarth P, Li Z, Miller KJ, Ercoli L, Emerson ND, Martinez J, Wong KP, Liu J, Merrill DA, Chen ST, Henning SM, Satyamurthy N, Huang SC, Heber D, Barrio JR. Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial. Am J Geriatr Psychiatry. 2018 Mar;26(3):266-277. doi: 10.1016/j.jagp.2017.10.010. Epub 2017 Oct 27. PMID: 29246725.
Non-specific anxiety
19. Pandaran Sudheeran S, Jacob D, Natinga Mulakal J, Gopinathan Nair G, Maliakel A, Maliakel B, Kuttan R, Im K. Safety, tolerance, and enhanced efficacy of a bioavailable formulation of curcumin with fenugreek dietary fiber on occupational stress: A randomized, double-blind, placebo-controlled pilot study. J Clin Psychopharmacol. 2016 Jun;36(3):236–243. doi: 10.1097/JCP.0000000000000508.
20. Esmaily H, Sahebkar A, Iranshahi M, Ganjali S, Mohammadi A, Ferns G, Ghayour-Mobarhan M. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial. Chin J Integr Med. 2015 May;21(5):332–338. doi: 10.1007/s11655-015-2160-z. Epub 2015 Mar 17.
Ginger References
31 references
Nausea
1. Apariman S, Ratchanon S, Wiriyasirivej B. Effectiveness of ginger for prevention of nausea and vomiting after gynecological laparoscopy. J Med Assoc Thai. 2006;89(12):2003–2009.
2. Arfeen Z, Owen H, Plummer JL, Ilsley AH, Sorby-Adams RA, Doecke CJ. A double-blind randomized controlled trial of ginger for the prevention of postoperative nausea and vomiting. Anaesth Intensive Care. 1995 Aug;23(4):449–452. doi: 10.1177/0310057X9502300406.
3. Basirat Z, Moghadamnia A, Kashifard M, Sarifi-Razavi A. The effect of ginger biscuit on nausea and vomiting in early pregnancy. Acta Med Iran. 1;47(1):51–56.
4. Beiranvand S, Alvani M, Sorori MM. The effect of ginger on postoperative nausea and vomiting among patients undergoing upper and lower limb surgery: A randomized controlled trial. J Perianesth Nurs. 2022 Jun;37(3):365–368. doi: 10.1016/j.jopan.2021.05.006. Epub 2022 Mar 15.
5. Bone ME, Wilkinson DJ, Young JR, McNeil J, Charlton S. Ginger root--a new antiemetic. The effect of ginger root on postoperative nausea and vomiting after major gynaecological surgery. Anaesthesia. 1990 Aug;45(8):669–671. doi: 10.1111/j.1365-2044.1990.tb14395.x.
6. Bossi P, Cortinovis D, Fatigoni S, Cossu Rocca M, Fabi A, Seminara P, Ripamonti C, Alfieri S, Granata R, Bergamini C, Agustoni F, Bidoli P, Nolè F, Pessi MA, Macchi F, Michellini L, Montanaro F, Roila F. A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin. Ann Oncol. 2017 Oct 1;28(10):2547–2551. doi: 10.1093/annonc/mdx315.
7. Choi J, Lee J, Kim K, Choi HK, Lee SA, Lee HJ. Effects of ginger intake on chemotherapy-induced nausea and vomiting: A systematic review of randomized clinical trials. Nutrients. 2022 Nov 23;14(23):4982. doi: 10.3390/nu14234982.
8. Crichton M, Marshall S, Isenring E, Lohning A, McCarthy AL, Molassiotis A, Bird R, Shannon C, Koh A, McPherson I, Marx W. Effect of a standardized ginger root powder regimen on chemotherapy-induced nausea and vomiting: A multicenter, double-blind, placebo-controlled randomized trial. J Acad Nutr Diet. 2024 Mar;124(3):313–330.e6. doi: 10.1016/j.jand.2023.09.003. Epub 2023 Sep 10.
9. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 1991;38(1):19–24. doi: 10.1016/0028-2243(91)90202-v.
10. Hu Y, Amoah AN, Zhang H, Fu R, Qiu Y, Cao Y, Sun Y, Chen H, Liu Y, Lyu Q. Effect of ginger in the treatment of nausea and vomiting compared with vitamin B6 and placebo during pregnancy: A meta-analysis. J Matern Fetal Neonatal Med. 2022 Jan;35(1):187–196. doi: 10.1080/14767058.2020.1712714. Epub 2020 Jan 14.
11. Kalava A, Darji SJ, Kalstein A, Yarmush JM, SchianodiCola J, Weinberg J. Efficacy of ginger on intraoperative and postoperative nausea and vomiting in elective cesarean section patients. Eur J Obstet Gynecol Reprod Biol. 2013;169(2):184–188. doi: 10.1016/j.ejogrb.2013.02.014. Epub 2013 Mar 17.
12. Keating A, Chez RA. Ginger syrup as an antiemetic in early pregnancy. Altern Ther Health Med. 2002 Sep–Oct;8(5):89–91.
13. Li X, Qin Y, Liu W, Zhou XY, Li YN, Wang LY. Efficacy of ginger in ameliorating acute and delayed chemotherapy-induced nausea and vomiting among patients with lung cancer receiving cisplatin-based regimens: A randomized controlled trial. Integr Cancer Ther. 2018 Sep;17(3):747–754. doi: 10.1177/1534735417753541. Epub 2018 Feb 8.
14. Mandal P, Das A, Majumdar S, Bhattacharyya T, Mitra T, Kundu R. The efficacy of ginger added to ondansetron for preventing postoperative nausea and vomiting in ambulatory surgery. Pharmacognosy Res. 2014;6(1):52–57. doi: 10.4103/0974-8490.122918.
15. Montazeri AS, Raei M, Ghanbari A, Dadgari A, Montazeri AS, Hamidzadeh A. Effect of herbal therapy to intensity chemotherapy-induced nausea and vomiting in cancer patients. Iran Red Crescent Med J. 2013 Feb;15(2):101–106. doi: 10.5812/ircmj.4392. Epub 2013 Feb 5.
16. Nanthakomon T, Pongrojpaw D. The efficacy of ginger in prevention of postoperative nausea and vomiting after major gynecologic surgery. J Med Assoc Thai. 2006;89(Suppl 4):S130–S136.
17. Ozgoli G, Goli M, Simbar M. Effects of ginger capsules on pregnancy, nausea, and vomiting. J Altern Complement Med. 2009;15(3):243–246. doi: 10.1089/acm.2008.0406.
18. Panahi Y, Saadat A, Sahebkar A, Hashemian F, Taghikhani M, Abolhasani E. Effect of ginger on acute and delayed chemotherapy-induced nausea and vomiting: A pilot, randomized, open-label clinical trial. Integr Cancer Ther. 2012 Sep;11(3):204–211. doi: 10.1177/1534735411433201. Epub 2012 Feb 7.
19. Phillips S, Ruggier R, Hutchinson SE. Zingiber officinale (ginger)--an antiemetic for day case surgery. Anaesthesia. 1993 Aug;48(8):715–717. doi: 10.1111/j.1365-2044.1993.tb07188.x.
20. Ryan JL, Heckler CE, Roscoe JA, Dakhil SR, Kirshner J, Flynn PJ, Hickok JT, Morrow GR. Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: A URCC CCOP study of 576 patients. Support Care Cancer. 2012 Jul;20(7):1479–1489. doi: 10.1007/s00520-011-1236-3. Epub 2011 Aug 5.
21. Saberi F, Sadat Z, Abedzadeh-Kalahroudi M, Taebi M. Effect of ginger on relieving nausea and vomiting in pregnancy: A randomized, placebo-controlled trial. Nurs Midwifery Stud. 2014 Apr;3(1):e11841. doi: 10.17795/nmsjournal11841. Epub 2014 Apr 17.
22. Sanaati F, Najafi S, Kashaninia Z, Sadeghi M. Effect of ginger and chamomile on nausea and vomiting caused by chemotherapy in Iranian women with breast cancer. Asian Pac J Cancer Prev. 2016;17(8):4125–4129.
23. Smith C, Crowther C, Willson K, Hotham N, McMillian V. A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy. Obstet Gynecol. 2004;103(4):639–645. doi: 10.1097/01.AOG.0000118307.19798.ec.
24. Thamlikitkul L, Srimuninnimit V, Akewanlop C, Ithimakin S, Techawathanawanna S, Korphaisarn K, Chantharasamee J, Danchaivijitr P, Soparattanapaisarn N. Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: A randomized, double-blind, placebo-controlled, crossover study. Support Care Cancer. 2017 Feb;25(2):459–464. doi: 10.1007/s00520-016-3423-8. Epub 2016 Oct 6.
25. Uthaipaisanwong A, Oranratanaphan S, Musigavong N. Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: A randomized controlled study. Support Care Cancer. 2020;28(8):3831–3838. doi: 10.1007/s00520-019-05201-5. Epub 2019 Dec 13.
26. Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: Randomized, double-masked, placebo-controlled trial. Obstet Gynecol. 2001;97(4):577–582. doi: 10.1016/s0029-7844(00)01228-x.
27. Willetts KE, Ekangaki A, Eden JA. Effect of a ginger extract on pregnancy-related nausea: A randomised controlled trial. Aust N Z J Obstet Gynaecol. 2003;43(2):139–144. doi: 10.1046/j.0004-8666.2003.00039.x.
28. Zhao C, Chen W, Wang D, Cong X, Zhu M, Zhu C, Xu J, Cai J. Ginger (Zingiber officinale Roscoe) preparations for prophylaxis of postoperative nausea and vomiting: A Bayesian network meta-analysis. J Ethnopharmacol. 2023 Dec 5;317:116791. doi: 10.1016/j.jep.2023.116791. Epub 2023 Jun 26.
29. Zick SM, Ruffin MT, Lee J, Normolle DP, Siden R, Alrawi S, Brenner DE. Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer. 2009 May;17(5):563–572. doi: 10.1007/s00520-008-0528-8. Epub 2008 Nov 13.
Age-related cognitive decline
30. Saenghong N, Wattanathorn J, Muchimapura S, Tongun T, Piyavhatkul N, Banchonglikitkul C, Kajsongkram T. Zingiber officinale improves cognitive function of the middle-aged healthy women. Evid Based Complement Alternat Med. 2012;2012:383062. doi: 10.1155/2012/383062. Epub 2011 Dec 22.
Premenstrual syndrome
31. Khayat S, Kheirkhah M, Behboodi Moghadam Z, Fanaei H, Kasaeian A, Javadimehr M. Effect of treatment with ginger on the severity of premenstrual syndrome symptoms. ISRN Obstet Gynecol. 2014 May 4;2014:792708. doi: 10.1155/2014/792708.
Ginkgo biloba References
77 references
Dementia
1. Haase J, Halama P, Hörr R. Effectiveness of brief infusions with Ginkgo biloba special extract EGb 761 in dementia of the vascular and Alzheimer type. Z Gerontol Geriatr. 1996;29(4):302–309.
2. Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012 Jun;46(6):716–723. doi: 10.1016/j.jpsychires.2012.03.003. Epub 2012 Mar 27.
3. Hofferberth B. Einfluss von Ginkgo biloba-Extrakt auf neurophysiologische und psychometrische Messergebnisse bei Patienten mit hirnorganischem Psychosyndrom. Eine Doppelblindstudie gegen Plazebo [The effect of Ginkgo biloba extract on neurophysiological and psychometric measurement results in patients with psychotic organic brain syndrome. A double-blind study against placebo]. Arzneimittelforschung. 1989;39(8):918-922.
4. Ihl R, Bachinskaya N, Korczyn AD, Vakhapova V, Tribanek M, Hoerr R, Napryeyenko O; GOTADAY Study Group. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: A randomized controlled trial. Int J Geriatr Psychiatry. 2011 Nov;26(11):1186–1194. doi: 10.1002/gps.2662. Epub 2010 Dec 7.
5. Kanowski S, Herrmann WM, Stephan K, Wierich W, Hörr R. Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry. 1996 Mar;29(2):47–56. doi: 10.1055/s-2007-979544.
6. Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997 Oct 22–29;278(16):1327–1332. doi: 10.1001/jama.278.16.1327.
7. Maurer K, Ihl R, Dierks T, Frölich L. Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J Psychiatr Res. 1997 Nov-Dec;31(6):645–655. doi: 10.1016/s0022-3956(97)00022-8.
8. Mazza M, Capuano A, Bria P, Mazza S. Ginkgo biloba and donepezil: A comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006 Sep;13(9):981–985. doi: 10.1111/j.1468-1331.2006.01409.x.
9. McCarney R, Fisher P, Iliffe S, van Haselen R, Griffin M, van der Meulen J, Warner J. Ginkgo biloba for mild to moderate dementia in a community setting: A pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2008 Dec;23(12):1222–1230. doi: 10.1002/gps.2055.
10. Napryeyenko O, Borzenko I; GINDEM-NP Study Group. Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4–11. doi: 10.1055/s-0031-1296579.
11. Nikolova G, Yancheva S, Raychev I, Hoerr R; PLAGIN Study Group. Ginkgo biloba extract in dementia: A 22-week randomised, placebo-controlled, double-blind trial. Bulg Neurol. 2013;14(3):139–143.
12. Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type. Curr Alzheimer Res. 2005 Dec;2(5):541–551. doi: 10.2174/156720505774932287.
13. van Dongen MCIJ, van Rossum E, Brouwers A, de Jong H, Knipschild P. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Geriatr Soc. 2000;48(10):1183–1194.
14. Wesnes K., Simmons D., Rook M., Simpson P. (1987). A double-blind placebo-controlled trial of tanakan in the treatment of idiopathic cognitive impairment in the elderly. Hum. Psychopharmacol. 3, 159–169. 10.1002/hup.470020305
15. Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R; GINDON Study Group. Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: A randomised, double-blind, exploratory trial. Aging Ment Health. 2009 Mar;13(2):183–190. doi: 10.1080/13607860902749057.
Post-stroke cognitive impairment
16. Cui M, You T, Zhao Y, Liu R, Guan Y, Liu J, Liu X, Wang X, Dong Q. Ginkgo biloba extract EGb 761® improves cognition and overall condition after ischemic stroke: Results from a pilot randomized trial. Front Pharmacol. 2023 Mar 29;14:1147860. doi: 10.3389/fphar.2023.1147860.
17. Demarin V, et al. EGb 761 in vascular cognitive impairment. 2017. (Conference/publication; cited in ref 64, Wieland LS et al, Cochrane Database Syst Rev 2026)
18. García-Alberca JM, Mendoza S, Gris E. Benefits of treatment with ginkgo biloba extract EGb 761 alone or combined with acetylcholinesterase inhibitors in vascular dementia. Clin Drug Investig. 2022 May;42(5):391–402. doi: 10.1007/s40261-022-01136-8. Epub 2022 Mar 28.
19. Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012 Jun;46(6):716–723. doi: 10.1016/j.jpsychires.2012.03.003. Epub 2012 Mar 27.
20. Ihl R, Bachinskaya N, Korczyn AD, Vakhapova V, Tribanek M, Hoerr R, Napryeyenko O; GOTADAY Study Group. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: A randomized controlled trial. Int J Geriatr Psychiatry. 2011 Nov;26(11):1186–1194. doi: 10.1002/gps.2662. Epub 2010 Dec 7. PMID: 21140383. [cerebral infarction subgroup (Feng 2025 meta-analysis)]
21. Jia J, Wei C, Chen S, Li F, Tang Y, Qin W, Shi L, Gong M, Xu H, Li F, He J, Song H, Yang S, Zhou A, Wang F, Zuo X, Chu C, Liang J, Jia L, Gauthier S. Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: A randomized clinical trial. Alzheimers Dement (N Y). 2018 Mar 22;4:108–117. doi: 10.1016/j.trci.2018.02.004.
22. Kanowski S, Herrmann WM, Stephan K, Wierich W, Hörr R. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Phytomedicine. 1997 Mar;4(1):3–13. doi: 10.1016/S0944-7113(97)80021-9. PMID: 23195239. [cerebral infarction subgroup (Feng 2025 meta-analysis)]
23. Napryeyenko O, Borzenko I; GINDEM-NP Study Group. Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4–11. doi: 10.1055/s-0031-1296579. PMID: 17341003. [cerebral infarction subgroup (Feng 2025 meta-analysis)]
24. Zhang Q, Wang A, Xu Q, Xia X, Tian X, Zhang Y, Li X, Yang X, Wang X, Peng J, Li Y, Liu L, Jin S, Meng X, Zhao X; GDLM group. Efficacy and safety of ginkgo diterpene lactone meglumine in acute ischemic stroke: A randomized clinical trial. JAMA Netw Open. 2023 Aug 1;6(8):e2328828. doi: 10.1001/jamanetworkopen.2023.28828.
Cognition in healthy adults
25. Burns NR, Bryan J, Nettelbeck T. Ginkgo biloba: No robust effect on cognitive abilities or mood in healthy young or older adults. Hum Psychopharmacol. 2006;21(1):27–37. doi: 10.1002/hup.739.
26. Elsabagh S, Hartley DE, Ali O, Williamson EM, File SE. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl). 2005 May;179(2):437–446. doi: 10.1007/s00213-005-2206-6. Epub 2005 Mar 1.
27. Elsabagh S, Hartley DE, Ali O, Williamson EM, File SE. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl). 2005 May;179(2):437–446. doi: 10.1007/s00213-005-2206-6. Epub 2005 Mar 1.
28. Kaschel R. Specific memory effects of Ginkgo biloba extract EGb 761 in middle-aged healthy volunteers. Phytomedicine. 2011 Nov 15;18(14):1202–1207. doi: 10.1016/j.phymed.2011.06.021. Epub 2011 Jul 30.
29. Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology. 2000;151(4):416–423. doi: 10.1007/s002130000501.
30. Mix JA, Crews WD. An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med. 2000;6(3):219–229. doi: 10.1089/acm.2000.6.219.
31. Ong Lai Teik D, Lee XS, Lim CJ, Low CM, Muslima M, Aquili L. Ginseng and Ginkgo biloba effects on cognition as modulated by cardiovascular reactivity: A randomised trial. PLoS One. 2016;11(3):e0150447. doi: 10.1371/journal.pone.0150447.
32. Rigney U, Kimber S, Hindmarch I. The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytother Res. 1999;13(5):408–415. doi: 10.1002/(sici)1099-1573(199908/09)13:5<408::aid-ptr530>3.0.co;2-c.
33. Scholey AB, Kennedy DO. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: Differential interactions with cognitive demand. Hum Psychopharmacol. 2002 Jan;17(1):35–44. doi: 10.1002/hup.352.
34. Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4(2):131–134. doi: 10.1017/S1461145701002292.
Major depressive disorder in vascular disease
35. Zhang F, Yu K. Effect of ginkgo honey ring oral liquid on colonization resistance of gut microbiota and serum 5-HT in patients with depression after PCI of coronary heart disease. Zhongguo Zhongxiyi Jiehe Xinnaoxueguanbing Zazhi [J Integr Traditional Chin West Med Cardiovasc Cerebrovasc Dis]. 2021;19(12):2118-2120.
36. Chen B, Ruan Q, Su X. Contrast study of folium ginkgo preparation and citalopram combined treatment in vascular depression. Zhejiang Zhongyiyao Daxue Xuebao [J Zhejiang Univ Traditional Chin Med]. 2011;35(4):513-515.
37. Eckmann F. Cerebral insufficiency — treatment with Ginkgo biloba extract: Time of onset of effect in a double-blind study with 60 inpatients. Fortschr Med. 1990;108(29):557–560. [cited in ref 50, Birks J & Grimley Evans J, Cochrane Database Syst Rev 2009]
38. Fengqing Yu AW, Liu X. Clinical observation on ginkgo biloba leaf combined with prozac in the treatment of poststroke depression. Chin Tradit Pat Med. 2004;266(9):23–24.
39. Haixia Wu MG, Hao F. Evaluation of therapeutic effect of ginkgo biloba extract combined with fluoxetine on depression after acute cerebral infarction. J Int Psychiatry. 2016;43(3):474–476.
40. Hao Song JM, Chen Y. Analysis of the therapeutic effect of jieyu pill combined with ginkgo biloba capsule on post-stroke depression. Chin J Traditional Med Sci Technol. 2014;21(6):671–672.
41. He X, Liu D, Ni S, Li Z, Li S, Wu T, Dong X, Zhang X, Tang Y, Ling Y, Liao H, Kang J, Li Y, Wu H, Luo J, Wan X, Zhang D, Lu L, Long W, Yang Z. Efficacy and safety evaluation of Ginkgo biloba dropping pill (GBDP) on stable angina pectoris complicated with depression: A placebo-controlled, randomized, double-blind, multicenter study. Phytomedicine. 2024 Apr;126:155264. doi: 10.1016/j.phymed.2023.155264. Epub 2024 Jan 11.
42. He ZY. Observation on the therapeutic effect of psychological intervention mode combined with ginkgo biloba leaves on post-stroke depression. J Med Research. 2007;36(8):130.
43. Jia Yuan LZ, Gan L. (2011). Clinical study of Ginkgo biloba combined with interpersonal psychological intervention in the treatment of coronary heart disease with depression. Chin J New Drugs Clin Pract. 2011;30(12):920–924.
44. Liang ZH, Jia YB, Wang ML, Li ZR, Li M, Yun YL, Zhu RX. Efficacy of ginkgo biloba extract as augmentation of venlafaxine in treating post-stroke depression. Neuropsychiatr Dis Treat. 2019 Sep 3;15:2551–2557. doi: 10.2147/NDT.S215191.
45. Lin C. Effects of Ginkgo biloba extract on depression and neurological function after acute cerebral infarction. West China Med J. 2002;17(1).
46. Wei Chen MW. Clinical observation of fluoxetine hydrochloride combined with ginkgo biloba leaves in the treatment of post-stroke depression. Mod J Integr Traditional Chin West Med. 2006;15(2).
47. Xiangdong Luo JW, Zhou B. The efficacy of paroxetine combined with ginkgo biloba leaves in the treatment of vascular depression. Med J West China. 2011;23(9):1644–1646.
48. Zhang Y. Clinical study of ginkgo biloba and Eleutherococcus senticosus injection in the treatment of depression after cerebral infarction. Shanxi Med J. 2021;41(4):396–397.
49. Lin J, Sun X, Yang L. Effects and safety of Ginkgo biloba on depression: A systematic review and meta-analysis. Front Pharmacol. 2024 Mar 18;15:1364030. doi: 10.3389/fphar.2024.1364030.
Major depressive disorder (select populations)
50. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009;2009(1):CD003120. Published 2009 Jan 21. doi:10.1002/14651858.CD003120.pub3
51. He X, Liu D, Ni S, Li Z, Li S, Wu T, Dong X, Zhang X, Tang Y, Ling Y, Liao H, Kang J, Li Y, Wu H, Luo J, Wan X, Zhang D, Lu L, Long W, Yang Z. Efficacy and safety evaluation of Ginkgo biloba dropping pill (GBDP) on stable angina pectoris complicated with depression: A placebo-controlled, randomized, double-blind, multicenter study. Phytomedicine. 2024 Apr;126:155264. doi: 10.1016/j.phymed.2023.155264. Epub 2024 Jan 11.
52. Liang ZH, Jia YB, Wang ML, Li ZR, Li M, Yun YL, Zhu RX. Efficacy of ginkgo biloba extract as augmentation of venlafaxine in treating post-stroke depression. Neuropsychiatr Dis Treat. 2019 Sep 3;15:2551–2557. doi: 10.2147/NDT.S215191.
53. Lin J, Sun X, Yang L. Effects and safety of Ginkgo biloba on depression: A systematic review and meta-analysis. Front Pharmacol. 2024 Mar 18;15:1364030.
Schizophrenia
54. Doruk A, Uzun O, Ozşahin A. A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2008 Jul;23(4):223–227. doi: 10.1097/YIC.0b013e3282fcff2f.
55. Luo HC et al. Ginkgo biloba extract (EGb 761) plus antipsychotics for chronic schizophrenia. Chinese journal (CNKI). 1997.
56. Meng 1996. Ginkgo biloba extract (EGb 761) plus antipsychotics for chronic schizophrenia. Chinese journal (CNKI). 1996.
57. Zhang XY, Zhou DF, Su JM, Zhang PY. The effect of extract of Ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia. J Clin Psychopharmacol. 2001;21(1):85–88. doi: 10.1097/00004714-200102000-00015.
Schizophrenia / Extrapyramidal side effects
58. Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 2001 Nov;62(11):878–883. doi: 10.4088/jcp.v62n1107.
Generalized anxiety disorder
59. Woelk H, Arnoldt KH, Kieser M, Hoerr R. Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: A randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2007 Sep;41(6):472–480. doi: 10.1016/j.jpsychires.2006.05.004. Epub 2006 Jun 30.
Mild cognitive impairment
60. Brautigam MR, Blommaert FA, Verleye G, Castermans J, Jansen Steur EN, Kleijnen J. Treatment of age-related memory complaints with Ginkgo biloba extract: A randomized double blind placebo-controlled study. Phytomedicine. 1998 Dec;5(6):425–434. doi: 10.1016/S0944-7113(98)80038-X.
61. Demarin V, Bašić Kes V, Trkanjec Z, Budišić M, Bošnjak Pašić M, Črnac P, Budinčević H. Efficacy and safety of Ginkgo biloba standardized extract in the treatment of vascular cognitive impairment: A randomized, double-blind, placebo-controlled clinical trial. Neuropsychiatr Dis Treat. 2017 Feb 16;13:483–490. doi: 10.2147/NDT.S120790.
62. Dodge HH, Zitzelberger T, Oken BS, Howieson D, Kaye J. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology. 2008 May 6;70(19 Pt 2):1809–1817. doi: 10.1212/01.wnl.0000303814.13509.db. Epub 2008 Feb 27.
63. Wieland LS, Ludeman E, Chi Y, et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2026;2(2):CD013661. Published 2026 Feb 5. doi:10.1002/14651858.CD013661.pub2
64. Gavrilova SI, Preuss UW, Wong JW, Hoerr R, Kaschel R, Bachinskaya N; GIMCIPlus Study Group. Efficacy and safety of Ginkgo biloba extract EGb 761 in mild cognitive impairment with neuropsychiatric symptoms: A randomized, placebo-controlled, double-blind, multi-center trial. Int J Geriatr Psychiatry. 2014 Oct;29(10):1087–1095. doi: 10.1002/gps.4103. Epub 2014 Mar 16.
65. Grass-Kapanke B, Busmane A, Lasmanis A, Hoerr R, Kaschel R. Effects of Ginkgo biloba special extract EGb 761 in very mild cognitive impairment (vMCI). Neurosci Med. 2011;2(1):48–56. doi: 10.4236/nm.2011.21007. [cited in Cochrane 2026]
66. Gschwind YJ, Bridenbaugh SA, Reinhard S, Granacher U, Monsch AU, Kressig RW. Ginkgo biloba special extract LI 1370 improves dual-task walking in patients with MCI: a randomised, double-blind, placebo-controlled exploratory study. Aging Clin Exp Res. 2017;29(4):609-619. doi:10.1007/s40520-016-0699-y
67. Halama P, Bartsch G, Meng G. Hirnleistungsstörungen vaskulärer Genese. Randomisierte Doppelblindstudie zur Wirksamkeit von Gingko-biloba-Extrakt [Disorders of brain performance of vascular origin. Randomized double-blind study of the effectiveness of Gingko biloba extract]. Fortschr Med. 1988 Jun 30;106(19):408–412. German.
68. Mix JA, Crews WD Jr. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: Neuropsychological findings. Hum Psychopharmacol. 2002 Aug;17(6):267–277. doi: 10.1002/hup.412.
69. Snitz BE, O'Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, Saxton J, Lopez OL, Dunn LO, Sink KM, DeKosky ST; Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for preventing cognitive decline in older adults: A randomized trial. JAMA. 2009 Dec 23;302(24):2663–2670. doi: 10.1001/jama.2009.1913.
70. Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: A randomized controlled trial. JAMA. 2002 Aug 21;288(7):835–840. doi: 10.1001/jama.288.7.835.
71. Yu ZH, Zhang CY, Pu BH, Xiao SY, Dong ZH, Li YM. [Ginkgo leaves tablet improved the memory quotient of patients with mild cognitive impairment: A clinical observation]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Mar;34(3):287–291. Chinese.
72. Zhao MX, Dong ZH, Yu ZH, Xiao SY, Li YM. [Effects of Ginkgo biloba extract in improving episodic memory of patients with mild cognitive impairment: A randomized controlled trial]. Zhong Xi Yi Jie He Xue Bao. 2012 Jun;10(6):628–634. Chinese. doi: 10.3736/jcim20120605.
Premenstrual syndrome
73. Ozgoli G, Selselei EA, Mojab F, Majd HA. A randomized, placebo-controlled trial of Ginkgo biloba L. in treatment of premenstrual syndrome. J Altern Complement Med. 2009 Aug;15(8):845–851. doi: 10.1089/acm.2008.0493.
74. Tamborini A, Taurelle R. Intérêt de l’extrait standardisé de Ginkgo biloba (EGb 761) dans la prise en charge des symptômes congestifs du syndrome prémenstruel [Value of standardized Ginkgo biloba extract (EGb 761) in the management of congestive symptoms of premenstrual syndrome]. Rev Fr Gynecol Obstet. 1993 Jul–Sep;88(7–9):447–457. French.
Prevention of cognitive side effects from ECT
75. Nazarinasab M, Behrouzian F, Negahban S, Sadegh AM, Zeynali E. Investigating the efficacy of Ginkgo biloba on the cognitive function of patients undergoing treatment with electric shock: A double-blind clinical trial. J Med Life. 2022 Dec;15(12):1540–1547. doi: 10.25122/jml-2021-0262.
Tardive dyskinesia
76. Zhang WF, Tan YL, Zhang XY, Chan RC, Wu HR, Zhou DF. Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: A randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011 May;72(5):615–621. doi: 10.4088/JCP.09m05125yel. Epub 2010 Sep 21.
Dyslexia (child)
77. Donfrancesco R, Ferrante L. Ginkgo biloba in dyslexia: A pilot study. Phytomedicine. 2007 Jun;14(6):367–370. doi: 10.1016/j.phymed.2007.05.001. Epub 2007 May 22.
L-Theanine References
20 references
Cognition
1. Baba Y, Inagaki S, Nakagawa S, Kaneko T, Kobayashi M, Takihara T. Effects of L-theanine on cognitive function in middle-aged and older subjects: A randomized placebo-controlled study. J Med Food. 2021 Apr;24(4):333–341. doi: 10.1089/jmf.2020.4803. Epub 2021 Mar 22.
2. Dassanayake TL, Wijesundara D, Kahathuduwa CN, Weerasinghe VS. Dose-response effect of L-theanine on psychomotor speed, sustained attention, and inhibitory control: A double-blind, placebo-controlled, crossover study. Nutr Neurosci. 2023 Nov;26(11):1138–1146. doi: 10.1080/1028415X.2022.2136884. Epub 2022 Oct 20.
3. Furushima D, Sugiyama I, Nomura Y, Unno K, Yamada H. Effect of combined ingestion of L-theanine and L-arginine for short-term psychological stress in young adults: A randomized placebo-controlled study. J Nutr Sci Vitaminol. 2022;68(6):540–546. doi: 10.3177/jnsv.68.540.
4. Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008;77(2):113–122. doi: 10.1016/j.biopsycho.2007.09.008. Epub 2007 Sep 26.
5. Hidese S, Ogawa S, Ota M, Ishida I, Yasukawa Z, Ozeki M, Kunugi H. Effects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: A randomized controlled trial. Nutrients. 2019;11(10):2362. doi: 10.3390/nu11102362.
6. Kahathuduwa CN, Dassanayake TL, Amarakoon AMT, Weerasinghe VS. Acute effects of theanine, caffeine and theanine-caffeine combination on attention. Nutr Neurosci. 2017;20(6):369–377. doi: 10.1080/1028415X.2016.1144845. Epub 2016 Feb 12.
7. Karunaratne UW, Dassanayake TL. Effect of L-theanine on selective attention in a traffic-related reaction task in sleep-deprived young adults: A double-blind placebo-controlled, crossover study. Nutr Neurosci. 2025;28(4):471–480. doi: 10.1080/1028415X.2024.2383080.
8. McAllister MJ, Martaindale MH, Dillard CC, McCullough R. Impact of L-theanine and L-tyrosine on markers of stress and cognitive performance in response to a virtual reality based active shooter training drill. Stress. 2024;27(1):2375588. doi: 10.1080/10253890.2024.2375588.
9. Park SK, Jung IC, Lee WK, Lee YS, Park HK, Go HJ, Kim K, Lim NK, Hong JT, Ly SY, Rho SS. A combination of green tea extract and L-theanine improves memory and attention in subjects with mild cognitive impairment: A double-blind placebo-controlled study. J Med Food. 2011 Apr;14(4):334–343. doi: 10.1089/jmf.2009.1374. Epub 2011 Feb 8.
10. Yilmaz U, Buzdagli Y, Polat ML, Bakir Y, Ozhanci B, Alkazan S, Ucar H. Effect of single or combined caffeine and L-theanine supplementation on shooting and cognitive performance in elite curling athletes: A double-blind, placebo-controlled study. J Int Soc Sports Nutr. 2023 Dec;20(1):2267536. doi: 10.1080/15502783.2023.2267536. Epub 2023 Oct 10.
Anxiety
11. Kimura K, Ozeki M, Juneja LR, Ohira H. L-theanine reduces psychological and physiological stress responses. Biol Psychol. 2007;74(1):39–45. doi: 10.1016/j.biopsycho.2006.06.006. Epub 2006 Aug 22.
13. Unno K, Yamada H, Iguchi K, Ishida H, Iwao Y, Morita A, Nakamura Y. Anti-stress effect of green tea with lowered caffeine on humans: A pilot study. Biol Pharm Bull. 2017;40(6):902–909. doi: 10.1248/bpb.b17-00141.
Anxiety / Generalized anxiety disorder
12. Sarris J, Byrne GJ, Cribb L, Oliver G, Murphy J, Macdonald P, Nazareth S, Karamacoska D, Galea S, Short A, Ee C, Birling Y, Menon R, Ng CH. L-theanine in the adjunctive treatment of generalized anxiety disorder: A double-blind, randomised, placebo-controlled trial. J Psychiatr Res. 2019;110:31–37. doi: 10.1016/j.jpsychires.2018.12.014.
Insomnia
14. Hidese S, Ogawa S, Ota M, Ishida I, Yasukawa Z, Ozeki M, Kunugi H. Effects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: A randomized controlled trial. Nutrients. 2019 Oct 3;11(10):2362. doi: 10.3390/nu11102362.
15. Lyon MR, Kapoor MP, Juneja LR. The effects of L-theanine (Suntheanine®) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): A randomized, double-blind, placebo-controlled clinical trial. Altern Med Rev. 2011 Dec;16(4):348–354.
16. Sarris J, Byrne GJ, Cribb L, Oliver G, Murphy J, Macdonald P, Nazareth S, Karamacoska D, Galea S, Short A, Ee C, Birling Y, Menon R, Ng CH. L-theanine in the adjunctive treatment of generalized anxiety disorder: A double-blind, randomised, placebo-controlled trial. J Psychiatr Res. 2019 Mar;110:31–37. doi: 10.1016/j.jpsychires.2018.12.014. Epub 2018 Dec 8.
Major depressive disorder (augmentation)
17. Shamabadi A, Kafi F, Arab Bafrani M, Asadigandomani H, A Basti F, Akhondzadeh S. L-theanine adjunct to sertraline for major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial. J Affect Disord. 2023;333:38–43. doi: 10.1016/j.jad.2023.04.029.
OCD (augmentation)
18. Nematizadeh M, Ghorbanzadeh H, Moghaddam HS, Shalbafan M, Boroon M, Keshavarz-Akhlaghi AA, Akhondzadeh S. L-theanine combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci. 2023;77(9):478–485. doi: 10.1111/pcn.13565.
Schizophrenia
19. Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: An 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry. 2011;72(1):34–42. doi: 10.4088/JCP.09m05324gre.
20. Shamabadi A, Fattollahzadeh-Noor S, Fallahpour B, A Basti F, Khodaei Ardakani MR, Akhondzadeh S. L-theanine adjunct to risperidone in the treatment of chronic schizophrenia inpatients: A randomized, double-blind, placebo-controlled clinical trial. Psychopharmacology (Berl). 2023;240(12):2631–2640. doi: 10.1007/s00213-023-06458-9.
Lavender References
9 references
Generalized anxiety disorder
1. Kasper S, Anghelescu I, Dienel A. Efficacy of orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep--a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015 Nov;25(11):1960–1967. doi: 10.1016/j.euroneuro.2015.07.024. Epub 2015 Aug 7.
2. Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Dienel A, Schläfke S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of 'subsyndromal' anxiety disorder: A randomized, double-blind, placebo controlled trial. Int Clin Psychopharmacol. 2010;25(5):277–287. doi: 10.1097/YIC.0b013e32833b3242.
3. Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Schläfke S, Dienel A. Lavender oil preparation Silexan is effective in generalized anxiety disorder: A randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014;17(6):859–869. doi: 10.1017/S1461145714000017.
4. Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder. Phytomedicine. 2010;17(2):94–99. doi: 10.1016/j.phymed.2009.10.006.
Major depressive disorder
5. Akhondzadeh S, Kashani L, Fotouhi A, Jarvandi S, Mobaseri M, Moin M, Khani M, Jamshidi AH, Baghalian K, Taghizadeh M. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: A double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):123–127. doi: 10.1016/s0278-5846(02)00342-1.
6. Kasper S, Volz HP, Dienel A, Schläfke S. Efficacy of Silexan in mixed anxiety-depression: A randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2016;26(2):331–340. doi: 10.1016/j.euroneuro.2015.12.002.
7. Kasper S, Volz HP, Möller HJ, Schläfke S, Klement S, Anghelescu IG, Seifritz E. Lavender oil preparation Silexan is effective in mild-to-moderate major depression: A randomized, placebo- and reference-controlled trial. Eur Arch Psychiatry Clin Neurosci. 2025;275(6):1693–1703. doi: 10.1007/s00406-024-01783-2.
8. Firoozeei TS, Barekatain M, Karimi M, Zargaran A, Akhondzadeh S, Rezaeizadeh H. Lavender and dodder combined herbal syrup versus citalopram in major depressive disorder with anxious distress: A double-blind randomized trial. J Integr Med. 2020;18(5):409–415. doi: 10.1016/j.joim.2020.06.002.
Mood problems in women on oral contraceptives
9. Naghdi M, Farshbaf-Khalili A, Nahaee J, Hakimi P, Shahnazi M. The effect of lavender on mood disorders associated with the use of combined oral contraceptives (COCs): A triple-blinded randomized controlled trial. BMC Complement Med Ther. 2024;24(1):118. doi: 10.1186/s12906-024-04419-z.
Lemon Balm References
13 references
Mild depressive / anxiety symptoms
1. Alijaniha F, Naseri M, Afsharypuor S, Fallahi F, Noorbala A, Mosaddegh M, Faghihzadeh S, Sadrai S. Heart palpitation relief with Melissa officinalis leaf extract: Double blind, randomized, placebo controlled trial of efficacy and safety. J Ethnopharmacol. 2015 Apr 22;164:378–384. doi: 10.1016/j.jep.2015.02.007. Epub 2015 Feb 11.
2. Haybar H, Javid AZ, Haghighizadeh MH, Valizadeh E, Mohaghegh SM, Mohammadzadeh A. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN. 2018;26:47–52. doi: 10.1016/j.clnesp.2018.04.015.
3. Kennedy DO, Little W, Scholey AB. Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (lemon balm). Psychosom Med. 2004;66(4):607–613. doi: 10.1097/01.psy.0000132877.72833.71.
4. Kennedy DO, Scholey AB, Tildesley NTJ, Perry EK, Wesnes KA. Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm). Pharmacol Biochem Behav. 2002;72(4):953–964. doi: 10.1016/s0091-3057(02)00777-3.
5. Kennedy DO, Wake G, Savelev S, Tildesley NT, Perry EK, Wesnes KA, Scholey AB. Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties. Neuropsychopharmacology. 2003;28(10):1871–1881. doi: 10.1038/sj.npp.1300230.
6. Safari M, Asadi A, Aryaeian N, Huseini HF, Shidfar F, Jazayeri S, Malek M, Hosseini AF, Hamidi Z. The effects of melissa officinalis on depression and anxiety in type 2 diabetes patients with depression: A randomized double-blinded placebo-controlled clinical trial. BMC Complement Med Ther. 2023;23(1):140. doi: 10.1186/s12906-023-03978-x.
7. Scholey A, Gibbs A, Neale C, Perry N, Ossoukhova A, Bilog V, Kras M, Scholz C, Sass M, Buchwald-Werner S. Anti-stress effects of lemon balm-containing foods. Nutrients. 2014 Oct 30;6(11):4805-21. doi: 10.3390/nu6114805.
8. Soltanpour A, Alijaniha F, Naseri M, Kazemnejad A, Heidari MR. Effects of Melissa officinalis on anxiety and sleep quality in patients undergoing coronary artery bypass surgery: A double-blind randomized placebo-controlled trial. Eur J Integr Med. 2019;28(11):27–32. doi: 10.1016/j.eujim.2019.01.010.
Sleep quality
9. Di Pierro F, Sisti D, Rocchi M, Belli A, Bertuccioli A, Cazzaniga M, Palazzi CM, Tanda ML, Zerbinati N. Effects of Melissa officinalis phytosome on sleep quality: Results of a prospective, double-blind, placebo-controlled, and cross-over study. Nutrients. 2024;16(23):4199. doi: 10.3390/nu16234199.
10. Haybar H, Javid AZ, Haghighizadeh MH, Valizadeh E, Mohaghegh SM, Mohammadzadeh A. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN. 2018;26:47–52. doi: 10.1016/j.clnesp.2018.04.015
11. Safari M, Asadi A, Aryaeian N, Huseini HF, Shidfar F, Jazayeri S, Malek M, Hosseini AF, Hamidi Z. The effects of melissa officinalis on depression and anxiety in type 2 diabetes patients with depression: A randomized double-blinded placebo-controlled clinical trial. BMC Complement Med Ther. 2023 May 2;23(1):140. doi: 10.1186/s12906-023-03978-x.
12. Shirazi M, Jalalian MN, Abed M, Ghaemi M. The Effectiveness of Melissa officinalis L. versus citalopram on quality of life of menopausal women with sleep disorder: A randomized double-blind clinical trial. Rev Bras Ginecol Obstet. 2021;43(2):126–130. doi: 10.1055/s-0040-1721857.
13. Soltanpour A, Alijaniha F, Naseri M, Kazemnejad A, Heidari MR. Effects of Melissa officinalis on anxiety and sleep quality in patients undergoing coronary artery bypass surgery: A double-blind randomized placebo-controlled trial. Eur J Integr Med. 2019;28(11):27–32. doi: 10.1016/j.eujim.2019.01.010.
Lion’s Mane References
6 references
Cognition
1. Docherty S, Doughty FL, Smith EF. The acute and chronic effects of lion's mane mushroom supplementation on cognitive function, stress and mood in young adults: A double-blind, parallel groups, pilot study. Nutrients. 2023;15(22):4842. doi: 10.3390/nu15224842.
2. La Monica MB, Raub B, Ziegenfuss EJ, Hartshorn S, Grdic J, Gustat A, Sandrock J, Ziegenfuss TN. Acute effects of naturally occurring guayusa tea and nordic lion's mane extracts on cognitive performance. Nutrients. 2023;15(24):5018. doi: 10.3390/nu15245018.
3. Li IC, Chang HH, Lin CH, Chen WP, Lu TH, Lee LY, Chen YW, Chen YP, Chen CC, Lin DP. Prevention of early Alzheimer's disease by erinacine A-enriched Hericium erinaceus mycelia pilot double-blind placebo-controlled study. Front Aging Neurosci. 2020 Jun 3;12:155. doi: 10.3389/fnagi.2020.00155.
4. Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebo-controlled clinical trial. Phytother Res. 2009;23(3):367–372. doi: 10.1002/ptr.2634.
5. Nagano M, Shimizu K, Kondo R, Hayashi C, Sato D, Kitagawa K, Ohnuki K. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010 Aug;31(4):231–237. doi: 10.2220/biomedres.31.231.
6. Saitsu Y, Nishide A, Kikushima K, Shimizu K, Ohnuki K. Improvement of cognitive functions by oral intake of Hericium erinaceus. Biomed Res. 2019;40(4):125–131. doi: 10.2220/biomedres.40.125.
Maca Root References
8 references
Erectile dysfunction in men (incl. men on SSRIs)
1. Gonzales GF, Córdova A, Vega K, Chung A, Villena A, Góñez C, Castillo S. Effect of Lepidium meyenii (MACA) on sexual desire and its absent relationship with serum testosterone levels in adult healthy men. Andrologia. 2002 Dec;34(6):367–372. doi: 10.1046/j.1439-0272.2002.00519.x.
2. Stone M, Ibarra A, Roller M, Zangara A, Stevenson E. A pilot investigation into the effect of maca supplementation on physical activity and sexual desire in sportsmen. J Ethnopharmacol. 2009;126(3):574–576. doi: 10.1016/j.jep.2009.09.012. Epub 2009 Sep 23.
3. Zenico T, Cicero AF, Valmorri L, Mercuriali M, Bercovich E. Subjective effects of Lepidium meyenii (Maca) extract on well-being and sexual performances in patients with mild erectile dysfunction: a randomised, double-blind clinical trial. Andrologia. 2009;41(2):95–99. doi: 10.1111/j.1439-0272.2008.00892.x.
Sexual dysfunction in postmenopausal women / women on SSRIs
4. Brooks NA, Wilcox G, Walker KZ, Ashton JF, Cox MB, Stojanovska L. Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content. Menopause. 2008 Nov–Dec;15(6):1157–1162. doi: 10.1097/gme.0b013e3181732953.
5. Dording CM, Schettler PJ, Dalton ED, Parkin SR, Walker RS, Fehling KB, Fava M, Mischoulon D. A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women. Evid Based Complement Alternat Med. 2015;2015:949036. doi: 10.1155/2015/949036. Epub 2015 Apr 14.
6. Gonzales-Arimborgo C, Yupanqui I, Montero E, Alarcón-Yaquetto DE, Zevallos-Concha A, Caballero L, Gasco M, Zhao J, Khan IA, Gonzales GF. Acceptability, safety, and efficacy of oral administration of extracts of black or red maca (Lepidium meyenii) in adult human subjects: A randomized, double-blind, placebo-controlled study. Pharmaceuticals (Basel). 2016 Aug 18;9(3):49. doi: 10.3390/ph9030049.
7. Stojanovska L, Law C, Lai B, Chung T, Nelson K, Day S, Apostolopoulos V, Haines C. Maca reduces blood pressure and depression, in a pilot study in postmenopausal women. Climacteric. 2015 Feb;18(1):69–78. doi: 10.3109/13697137.2014.929649. Epub 2014 Aug 7.
Subsyndromal anxiety and depression in postmenopausal women
8. Stojanovska L, Law C, Lai B, Chung T, Nelson K, Day S, Apostolopoulos V, Haines C. Maca reduces blood pressure and depression, in a pilot study in postmenopausal women. Climacteric. 2015 Feb;18(1):69–78. doi: 10.3109/13697137.2014.929649. Epub 2014 Aug 7.
Maritime Pine Bark References
12 references
Perimenopause / Sexual dysfunction
1. Bottari A, Belcaro G, Ledda A, Luzzi R, Cesarone MR, Dugall M. Lady Prelox® improves sexual function in generally healthy women of reproductive age. Minerva Ginecol. 2013 Aug;65(4):435–444. PMID: 24051943. [cited in Cochrane review, Robertson 2020]
Perimenopause
2. Errichi S, Bottari A, Belcaro G, Cesarone MR, Hosoi M, Cornelli U, Dugall M, Ledda A, Feragalli B. Supplementation with Pycnogenol® improves signs and symptoms of menopausal transition. Panminerva Med. 2011 Sep;53(3 Suppl 1):65–70.
3. Kohama T, Negami M. Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: A randomized, double-blind, placebo-controlled trial. J Reprod Med. 2013;58(1-2):39–46.
4. Yang HM, Liao MF, Zhu SY, Liao MN, Rohdewald P. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol Scand. 2007;86(8):978–985. doi: 10.1080/00016340701446108.
Memory in older adults
5. Hosoi M, Belcaro G, Saggino A, Luzzi R, Dugall M, Feragalli B. Pycnogenol® supplementation in minimal cognitive dysfunction. J Neurosurg Sci. 2018 Jun;62(3):279–284. doi: 10.23736/S0390-5616.18.04382-5.
6. Pipingas A, Silberstein RB, Vitetta L, Rooy CV, Harris EV, Young JM, Frampton CM, Sali A, Nastasi J. Improved cognitive performance after dietary supplementation with a Pinus radiata bark extract formulation. Phytother Res. 2008 Sep;22(9):1168–1174. doi: 10.1002/ptr.2388.
7. Ryan J, Croft K, Mori T, Wesnes K, Spong J, Downey L, Kure C, Lloyd J, Stough C. An examination of the effects of the antioxidant Pycnogenol on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population. J Psychopharmacol. 2008 Jul;22(5):553–562. doi: 10.1177/0269881108091584.
Sexual dysfunction in men and women (incl. SSRIs)
8. Bottari A, Belcaro G, Ledda A, Luzzi R, Cesarone MR, Dugall M. Lady Prelox® improves sexual function in generally healthy women of reproductive age. Minerva Ginecol. 2013 Aug;65(4):435–444. PMID: 24051943. [cited in Cochrane review, Robertson 2020]
9. Cai T, Morgia G, Carrieri G, Terrone C, Imbimbo C, Verze P, Mirone V; IDIProst® Gold Study Group. An improvement in sexual function is related to better quality of life, regardless of urinary function improvement: Results from the IDIProst® Gold Study. Arch Ital Urol Androl. 2013 Dec 31;85(4):184–189. doi: 10.4081/aiua.2013.4.184.
10. D̆uračková Z, Trebatický B, Novotný V, Žitňanová I, Breza J. Lipid metabolism and erectile function improvement by Pycnogenol®, extract from the bark of Pinus pinaster in patients suffering from erectile dysfunction-a pilot study. Nutr Res. 2003;23:1189–1198. doi: 10.1016/S0271-5317(03)00126-X.
11. Ledda A, Belcaro G, Cesarone MR, Dugall M, Schönlau F. Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double-blind, placebo-controlled, parallel-arm study. BJU Int. 2010 Oct;106(7):1030–1033. doi: 10.1111/j.1464-410X.2010.09213.x. Epub 2010 Feb 22.
12. Stanislavov R, Nikolova V, Rohdewald P. Improvement of erectile function with Prelox: A randomized, double-blind, placebo-controlled, crossover trial. Int J Impot Res. 2008;20(2):173–180. doi: 10.1038/sj.ijir.3901597. Epub 2007 Aug 16.
Resveratrol References
8 references
Cognition in older adults
1. Anton SD, Ebner N, Dzierzewski JM, Zlatar ZZ, Gurka MJ, Dotson VM, Kirton J, Mankowski RT, Marsiske M, Manini TM. Effects of 90 days of resveratrol supplementation on cognitive function in elders: A pilot study. J Altern Complement Med. 2018 Jul;24(7):725–732. doi: 10.1089/acm.2017.0398. Epub 2018 Mar 27.
2. Evans HM, Howe PR, Wong RH. Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial. Nutrients. 2017 Jan 3;9(1):27. doi: 10.3390/nu9010027.
3. Huhn S, Beyer F, Zhang R, Lampe L, Grothe J, Kratzsch J, Willenberg A, Breitfeld J, Kovacs P, Stumvoll M, Trampel R, Bazin PL, Villringer A, Witte AV. Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults - a randomized controlled trial. Neuroimage. 2018 Jul 1;174:177–190. doi: 10.1016/j.neuroimage.2018.03.023. Epub 2018 Mar 13.
4. Myhal V, Kazakov Y, Shut S, Tribrat T, Petrov Y, Ivanytska T, Chekalina N. Resveratrol improves cognitive function and quality of life in postmenopausal women. Pol Merkur Lekarski. 2026;54(1):17–23. doi: 10.36740/Merkur202601103.
5. Thaung Zaw JJ, Howe PR, Wong RH. Long-term effects of resveratrol on cognition, cerebrovascular function and cardio-metabolic markers in postmenopausal women: A 24-month randomised, double-blind, placebo-controlled, crossover study. Clin Nutr. 2021 Mar;40(3):820–829. doi: 10.1016/j.clnu.2020.08.025. Epub 2020 Aug 27.
6. Witte AV, Kerti L, Margulies DS, Flöel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. 2014 Jun 4;34(23):7862–7870. doi: 10.1523/JNEUROSCI.0385-14.2014.
ADHD
7. Rafeiy-Torghabeh M, Ashraf-Ganjouei A, Moradi K, Bagheri S, Mohammadi MR, Akhondzadeh S. Resveratrol adjunct to methylphenidate improves symptoms of attention-deficit/hyperactivity disorder: A randomized, double-blinded, placebo-controlled clinical trial. Eur Child Adolesc Psychiatry. 2021 May;30(5):799–807. doi: 10.1007/s00787-020-01562-z. Epub 2020 May 24.
Schizophrenia
8. Samaei A, Moradi K, Bagheri S, Ashraf-Ganjouei A, Alikhani R, Mousavi SB, Rezaei F, Akhondzadeh S. Resveratrol adjunct therapy for negative symptoms in patients with stable schizophrenia: A double-blind, randomized placebo-controlled trial. Int J Neuropsychopharmacol. 2020 Dec 29;23(12):775–782. doi: 10.1093/ijnp/pyaa006.
Saffron References
52 references
Insomnia
1. Lang L, Ditton A, Stanescu A, Jainani V, McArthur S, Pourtau L, Gaudout D, Pontifex MG, Tsigarides J, Steward T, Sami S, Muller M, Hornberger M, Vauzour D, Lazar AS. A standardised saffron extract improves subjective and objective sleep quality in healthy older adults with sleep complaints: Results from the gut-sleep-brain axis randomised, double-blind, placebo-controlled pilot study. Food Funct. 2025 Aug 26;16(17):6817–6832. doi: 10.1039/d5fo00917k.
2. Lopresti AL, Smith SJ, Drummond PD. An investigation into an evening intake of a saffron extract (Affron®) on sleep quality, cortisol, and melatonin concentrations in adults with poor sleep: A randomised, double-blind, placebo-controlled, multi-dose study. Sleep Med. 2021 Oct;86:7–18. doi: 10.1016/j.sleep.2021.08.001. Epub 2021 Aug 11.
3. Lopresti AL, Smith SJ, Metse AP, Drummond PD. Effects of saffron on sleep quality in healthy adults with self-reported poor sleep: A randomized, double-blind, placebo-controlled trial. J Clin Sleep Med. 2020 Jun 15;16(6):937–947. doi: 10.5664/jcsm.8376.
4. Pachikian BD, Copine S, Suchareau M, Deldicque L. Effects of saffron extract on sleep quality: A randomized double-blind controlled clinical trial. Nutrients. 2021 Apr 27;13(5):1473. doi: 10.3390/nu13051473.
6. Umigai N, Takeda R, Mori A. Effect of crocetin on quality of sleep: A randomized, double-blind, placebo-controlled, crossover study. Complement Ther Med. 2018;41:47–51. doi: 10.1016/j.ctim.2018.09.003. Epub 2018 Sep 8.
Insomnia / Mild depression
5. Tajaddini A, Roshanravan N, Mobasseri M, Aeinehchi A, Sefid-Mooye Azar P, Hadi A, Ostadrahimi A. Saffron improves life and sleep quality, glycaemic status, lipid profile and liver function in diabetic patients: A double-blind, placebo-controlled, randomised clinical trial. Int J Clin Pract. 2021 Aug;75(8):e14334. doi: 10.1111/ijcp.14334. Epub 2021 May 26.
Major depressive disorder
7. Ahmadpanah M, Ramezanshams F, Ghaleiha A, Akhondzadeh S, Sadeghi Bahmani D, Brand S. Crocus Sativus L. (saffron) versus sertraline on symptoms of depression among older people with major depressive disorders-a double-blind, randomized intervention study. Psychiatry Res. 2019 Dec;282:112613. doi: 10.1016/j.psychres.2019.112613. Epub 2019 Oct 12.
8. Akhondzadeh Basti A, Moshiri E, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: A pilot double-blind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):439–442. doi: 10.1016/j.pnpbp.2006.11.010. Epub 2006 Dec 15.
9. Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med. 2004 Sep 2;4:12. doi: 10.1186/1472-6882-4-12.
10. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, Amini H, Fallah-Pour H, Jamshidi AH, Khani M. Crocus sativus L. in the treatment of mild to moderate depression: A double-blind, randomized and placebo-controlled trial. Phytother Res. 2005 Feb;19(2):148–151. doi: 10.1002/ptr.1647.
11. Bahrami F, Pour FJ, Hassanpour M, Saki M, Ebrahimzadeh F, Jafaripour L. The effect of saffron and corrective exercises on depression and quality of life in women with multiple sclerosis: A randomized controlled clinical trial. Mult Scler Relat Disord. 2023 Nov;79:105038. doi: 10.1016/j.msard.2023.105038. Epub 2023 Sep 26.
12. Dormal V, Suchareau M, Copine S, Simar L, Deldicque L. The effects of combined scutellaria and saffron supplementation on mood regulation in participants with mild-to-moderate depressive symptoms: A randomized, double-blind, placebo-controlled study. Nutrients. 2025 Feb 26;17(5):809. doi: 10.3390/nu17050809.
13. Ghajar A, Neishabouri SM, Velayati N, Jahangard L, Matinnia N, Haghighi M, Ghaleiha A, Afarideh M, Salimi S, Meysamie A, Akhondzadeh S. Crocus sativus L. versus citalopram in the treatment of major depressive disorder with anxious distress: A double-blind, controlled clinical trial. Pharmacopsychiatry. 2017 Jul;50(4):152–160. doi: 10.1055/s-0042-116159. Epub 2016 Oct 4.
14. Jalali F, Hashemi SF. The effect of saffron on depression among recovered consumers of methamphetamine living with HIV/AIDS. Subst Use Misuse. 2018 Oct 15;53(12):1951–1957. doi: 10.1080/10826084.2018.1447583. Epub 2018 Mar 15.
15. Kashani L, Esalatmanesh S, Eftekhari F, Salimi S, Foroughifar T, Etesam F, Safiaghdam H, Moazen-Zadeh E, Akhondzadeh S. Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: A double-blind, randomized, placebo-controlled trial. Arch Gynecol Obstet. 2018 Mar;297(3):717–724. doi: 10.1007/s00404-018-4655-2. Epub 2018 Jan 13.
16. Kashani L, Eslatmanesh S, Saedi N, Niroomand N, Ebrahimi M, Hosseinian M, Foroughifar T, Salimi S, Akhondzadeh S. Comparison of saffron versus fluoxetine in treatment of mild to moderate postpartum depression: A double-blind, randomized clinical trial. Pharmacopsychiatry. 2017 Mar;50(2):64–68. doi: 10.1055/s-0042-115306. Epub 2016 Sep 5.
17. Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depressive disorder: A randomised, double-blind, placebo-controlled study. J Affect Disord. 2017;207:188–196. doi: 10.1016/j.jad.2016.09.047. Epub 2016 Oct 1.
18. Lopresti AL, Smith SJ, Hood SD, Drummond PD. Efficacy of a standardised saffron extract (Affron®) as an add-on to antidepressant medication for the treatment of persistent depressive symptoms in adults: A randomised, double-blind, placebo-controlled study. J Psychopharmacol. 2019 Nov;33(11):1415–1427. doi: 10.1177/0269881119867703. Epub 2019 Sep 2.
19. Mazidi M, Shemshian M, Mousavi SH, Norouzy A, Kermani T, Moghiman T, Sadeghi A, Mokhber N, Ghayour-Mobarhan M, Ferns GA. A double-blind, randomized and placebo-controlled trial of saffron (Crocus sativus L.) in the treatment of anxiety and depression. J Complement Integr Med. 2016 Jun 1;13(2):195–199. doi: 10.1515/jcim-2015-0043.
20. Moshiri E, Basti AA, Noorbala AA, Jamshidi AH, Hesameddin Abbasi S, Akhondzadeh S. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine. 2006 Nov;13(9–10):607–611. doi: 10.1016/j.phymed.2006.08.006. Epub 2006 Sep 18.
21. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: A double-blind, randomized pilot trial. J Ethnopharmacol. 2005 Feb 28;97(2):281–284. doi: 10.1016/j.jep.2004.11.004. Epub 2005 Jan 6.
22. Sahraian A, Jelodar S, Javid Z, Mowla A, Ahmadzadeh L. Study the effects of saffron on depression and lipid profiles: A double blind comparative study. Asian J Psychiatr. 2016 Aug;22:174–176. doi: 10.1016/j.ajp.2015.10.012. Epub 2015 Nov 10.
23. Shahmansouri N, Farokhnia M, Abbasi SH, Kassaian SE, Noorbala Tafti AA, Gougol A, Yekehtaz H, Forghani S, Mahmoodian M, Saroukhani S, Arjmandi-Beglar A, Akhondzadeh S. A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord. 2014 Feb;155:216–222. doi: 10.1016/j.jad.2013.11.003. Epub 2013 Nov 16.
24. Tabeshpour J, Sobhani F, Sadjadi SA, Hosseinzadeh H, Mohajeri SA, Rajabi O, Taherzadeh Z, Eslami S. A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. Phytomedicine. 2017 Dec 1;36:145–152. doi: 10.1016/j.phymed.2017.10.005. Epub 2017 Oct 7.
25. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: A randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015 Mar 15;174:51–56. doi: 10.1016/j.jad.2014.11.035. Epub 2014 Nov 26.
Mild depressive symptoms
26. Shah S, Shah N, Shah J, S D, S J, Sudha Rani P. Standardized Saffron Extract Formulation for Low Mood and Subclinical Depressive Symptoms: A Randomized, Double-Blind, Placebo-Controlled Trial. Cureus. 2026;18(6):e110935. Published 2026 Jun 15. doi:10.7759/cureus.110935
27. Lopresti AL, Smith SJ. The effects of a saffron extract (Affron®) on mood, sleep, self-esteem, and exploratory measures of physical appearance in women aged 50 to 70 years experiencing low mood and poor sleep: a randomised, double-blind, placebo-controlled trial. Front Nutr. 2026 Jun 17;13:1838513. doi: 10.3389/fnut.2026.1838513.
Mild depressive / anxiety symptoms
28. Akhondzadeh S, Mostafavi SA, Keshavarz SA, Mohammadi MR, Hosseini S, Eshraghian MR. A placebo controlled randomized clinical trial of Crocus sativus L. (saffron) on depression and food craving among overweight women with mild to moderate depression. J Clin Pharm Ther. 2020 Feb;45(1):134–143. doi: 10.1111/jcpt.13040. Epub 2019 Oct 10.
29. Amadieu C, Leyrolle Q, Farneti M, Anesi A, Bruchet E, Montet J, Dexpert S, Gaudout D, Mattivi F, Pourtau L, Castanon N, Capuron L. Effect of saffron extract supplementation on mood in healthy adults with subclinical symptoms of depression: A randomized, double-blind placebo-controlled study. Am J Clin Nutr. 2025 Dec;122(6):1625–1635. doi: 10.1016/j.ajcnut.2025.09.050. Epub 2025 Oct 3.
30. Ebrahimi N, Javadinia SA, Salek R, Fanipakdel A, Sepahi S, Dehghani M, Valizadeh N, Mohajeri SA. Randomized, double-blind, placebo-controlled clinical trial of concurrent use of crocin during chemoradiation for esophageal squamous cell carcinoma. Cancer Invest. 2024 Feb;42(2):155–164. doi: 10.1080/07357907.2024.2319754. Epub 2024 Feb 22.
31. Jam IN, Sahebkar AH, Eslami S, Mokhber N, Nosrati M, Khademi M, Foroutan-Tanha M, Ghayour-Mobarhan M, Hadizadeh F, Ferns G, Abbasi M. The effects of crocin on the symptoms of depression in subjects with metabolic syndrome. Adv Clin Exp Med. 2017 Sep;26(6):925–930. doi: 10.17219/acem/62891.
32. Kell G, Rao A, Beccaria G, Clayton P, Inarejos-García AM, Prodanov M. Affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med. 2017 Aug;33:58–64. doi: 10.1016/j.ctim.2017.06.001. Epub 2017 Jun 13.
33. Lopresti AL, Drummond PD, Inarejos-García AM, Prodanov M. Affron®, a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: A randomised, double-blind, placebo-controlled study. J Affect Disord. 2018 May;232:349–357. doi: 10.1016/j.jad.2018.02.070. Epub 2018 Feb 26.
34. Lopresti AL, Smith SJ, Marx W, Díez-Municio M, Morán-Valero MI. An examination into the effects of a saffron extract (Affron) on mood and general wellbeing in adults experiencing low mood: A randomized, double-blind, placebo-controlled trial. J Nutr. 2025 Jul;155(7):2300–2311. doi: 10.1016/j.tjnut.2025.05.024. Epub 2025 May 23.
35. Milajerdi A, Jazayeri S, Shirzadi E, Hashemzadeh N, Azizgol A, Djazayery A, Esmaillzadeh A, Akhondzadeh S. The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial. Complement Ther Med. 2018 Dec;41:196–202. doi: 10.1016/j.ctim.2018.09.023. Epub 2018 Sep 26.
36. Moazen-Zadeh E, Abbasi SH, Safi-Aghdam H, Shahmansouri N, Arjmandi-Beglar A, Hajhosseinn Talasaz A, Salehiomran A, Forghani S, Akhondzadeh S. Effects of saffron on cognition, anxiety, and depression in patients undergoing coronary artery bypass grafting: A randomized double-blind placebo-controlled trial. J Altern Complement Med. 2018 Apr;24(4):361–368. doi: 10.1089/acm.2017.0173. Epub 2017 Nov 29.
37. Tajaddini A, Roshanravan N, Mobasseri M, Aeinehchi A, Sefid-Mooye Azar P, Hadi A, Ostadrahimi A. Saffron improves life and sleep quality, glycaemic status, lipid profile and liver function in diabetic patients: A double-blind, placebo-controlled, randomised clinical trial. Int J Clin Pract. 2021 Aug;75(8):e14334. doi: 10.1111/ijcp.14334. Epub 2021 May 26.
38. Tajaddini A, Roshanravan N, Mobasseri M, Aeinehchi A, Sefid-Mooye Azar P, Hadi A, Ostadrahimi A. Saffron improves life and sleep quality, glycaemic status, lipid profile and liver function in diabetic patients: A double-blind, placebo-controlled, randomised clinical trial. Int J Clin Pract. 2021 Aug;75(8):e14334. doi: 10.1111/ijcp.14334. Epub 2021 May 26.
ADHD
39. Baziar S, Aqamolaei A, Khadem E, Mortazavi SH, Naderi S, Sahebolzamani E, Mortezaei A, Jalilevand S, Mohammadi MR, Shahmirzadi M, Akhondzadeh S. Crocus sativus L. versus methylphenidate in treatment of children with attention-deficit/hyperactivity disorder: A randomized, double-blind pilot study. J Child Adolesc Psychopharmacol. 2019 Apr;29(3):205–212. doi: 10.1089/cap.2018.0146. Epub 2019 Feb 11.
40. Blasco-Fontecilla H, Moyano-Ramírez E, Méndez-González O, Rodrigo-Yanguas M, Martin-Moratinos M, Bella-Fernández M. Effectivity of saffron extract (Saffr’Activ) on treatment for children and adolescents with attention deficit/hyperactivity disorder (ADHD): A clinical effectivity study. Nutrients. 2022 Sep 28;14(19):4046. doi: 10.3390/nu14194046.
Mild cognitive impairment
41. Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SSh, Yousefi MH, Alimardani R, Jamshidi A, Zare F, Moradi A. Saffron in the treatment of patients with mild to moderate Alzheimer's disease: A 16-week, randomized and placebo-controlled trial. J Clin Pharm Ther. 2010 Oct;35(5):581–588. doi: 10.1111/j.1365-2710.2009.01133.x.
42. Farokhnia M, Shafiee Sabet M, Iranpour N, Gougol A, Yekehtaz H, Alimardani R, Farsad F, Kamalipour M, Akhondzadeh S. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: A double-blind randomized clinical trial. Hum Psychopharmacol. 2014 Jul;29(4):351–359. doi: 10.1002/hup.2412.
43. Tsolaki M, Karathanasi E, Lazarou I, Dovas K, Verykouki E, Karacostas A, Georgiadis K, Tsolaki A, Adam K, Kompatsiaris I, Sinakos Z. Efficacy and safety of Crocus sativus L. in patients with mild cognitive impairment: One year single-blind randomized, with parallel groups, clinical trial. J Alzheimers Dis. 2016 Jul 27;54(1):129–133. doi: 10.3233/JAD-160304.
Metabolic syndrome on antipsychotics
44. Fadai F, Mousavi B, Ashtari Z, Ali beigi N, Farhang S, Hashempour S, Shahhamzei N, Bathaie SZ. Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: A randomized triple blind placebo controlled study. Pharmacopsychiatry. 2014 Jul;47(4–5):156–161. doi: 10.1055/s-0034-1382001. Epub 2014 Jun 23.
OCD
45. Esalatmanesh S, Biuseh M, Noorbala AA, Mostafavi SA, Rezaei F, Mesgarpour B, Mohammadinejad P, Akhondzadeh S. Comparison of saffron and fluvoxamine in the treatment of mild to moderate obsessive-compulsive disorder: A double blind randomized clinical trial. Iran J Psychiatry. 2017 Jul;12(3):154–162.
46. Kazemi F, Vosough I, Sepahi S, Mohajeri SA. Effect of crocin versus fluoxetine in treatment of mild to moderate obsessive-compulsive disorder: A double blind randomized clinical trial. Hum Psychopharmacol. 2021 Jul;36(4):e2780. doi: 10.1002/hup.2780. Epub 2021 Feb 18.
Opioid use disorder
47. Abbaszadeh-Mashkani S, Hoque SS, Banafshe HR, Ghaderi A. The effect of crocin (the main active saffron constituent) on the cognitive functions, craving, and withdrawal syndrome in opioid patients under methadone maintenance treatment. Phytother Res. 2021 Mar;35(3):1486–1494. doi: 10.1002/ptr.6913. Epub 2020 Oct 19.
Premenstrual syndrome
48. Agha-Hosseini M, Kashani L, Aleyaseen A, Ghoreishi A, Rahmanpour H, Zarrinara AR, Akhondzadeh S. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: A double-blind, randomised and placebo-controlled trial. BJOG. 2008 Mar;115(4):515–519. doi: 10.1111/j.1471-0528.2007.01652.x.
49. Nahid K, Fariborz M, Ataolah G, Solokian S. The effect of an Iranian herbal drug on primary dysmenorrhea: A clinical controlled trial. J Midwifery Womens Health. 2009;54(5):401–404. doi: 10.1016/j.jmwh.2008.12.006.
Sexual dysfunction
50. Izadi S, Mohammad-Alizadeh-Charandabi S, Yadollahi P, Mirghafourvand M. Effect of vitamin E with and without saffron on the sexual function in women of reproductive age with sexual dysfunction: A randomized controlled trial. BMC Womens Health. 2024 Feb 26;24(1):143. doi: 10.1186/s12905-024-02980-w.
51. Kashani L, Raisi F, Saroukhani S, Sohrabi H, Modabbernia A, Nasehi AA, Jamshidi A, Ashrafi M, Mansouri P, Ghaeli P, Akhondzadeh S. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol. 2013 Jan;28(1):54–60. doi: 10.1002/hup.2282. Epub 2012 Dec 20.
52. Modabbernia A, Sohrabi H, Nasehi AA, Raisi F, Saroukhani S, Jamshidi A, Tabrizi M, Ashrafi M, Akhondzadeh S. Effect of saffron on fluoxetine-induced sexual impairment in men: Randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). 2012 Oct;223(4):381–388. doi: 10.1007/s00213-012-2729-6. Epub 2012 May 3.
Sulforaphane References
12 references
ADHD
1. Ghannadi F, Shamabadi A, Talebinejad MS, Naseh E, Heidari E, Paknezhad S, Mohammadi M, Akhondzadeh S. Sulforaphane adjunct to methylphenidate for attention-deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2025 Nov–Dec 01;48(6):181–187. doi: 10.1097/WNF.0000000000000658. Epub 2025 Oct 30.
Autism
2. Magner M, Thorová K, Žúpová V, Houška M, Švandová I, Novotná P, Tříska J, Vrchotová N, Soural I, Jílek L. Sulforaphane treatment in children with autism: A prospective randomized double-blind study. Nutrients. 2023 Jan 31;15(3):718. doi: 10.3390/nu15030718.
3. Momtazmanesh S, Amirimoghaddam-Yazdi Z, Moghaddam HS, Mohammadi MR, Akhondzadeh S. Sulforaphane as an adjunctive treatment for irritability in children with autism spectrum disorder: A randomized, double-blind, placebo-controlled clinical trial. Psychiatry Clin Neurosci. 2020 Jul;74(7):398–405. doi: 10.1111/pcn.13016. Epub 2020 May 26.
4. Ou J, Smith RC, Tobe RH, Lin J, Arriaza J, Fahey JW, Liu R, Zeng Y, Liu Y, Huang L, Shen Y, Li Y, Cheng D, Cornblatt B, Davis JM, Zhao J, Wu R, Jin H. Efficacy of sulforaphane in treatment of children with autism spectrum disorder: A randomized double-blind placebo-controlled multi-center trial. J Autism Dev Disord. 2024 Feb;54(2):628–641. doi: 10.1007/s10803-022-05784-9. Epub 2022 Nov 24.
5. Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550–15555. doi: 10.1073/pnas.1416940111. Epub 2014 Oct 13.
6. Zimmerman AW, Singh K, Connors SL, Liu H, Panjwani AA, Lee LC, Diggins E, Foley A, Melnyk S, Singh IN, James SJ, Frye RE, Fahey JW. Randomized controlled trial of sulforaphane and metabolite discovery in children with autism spectrum disorder. Mol Autism. 2021 May 25;12(1):38. doi: 10.1186/s13229-021-00447-5.
Schizophrenia
7. Chen H, Lu J, Zou T, Teng Z, Qin Y, Wu R, Yan Y, Fu K, Jiang W, Ju Y, Zhu R, Mo J, Lu J, Huang J. Effects of sulforaphane on negative symptoms and cognitive impairments in chronic schizophrenia patients: A randomized double-blind trial. J Psychiatr Res. 2025 Apr;184:464–472. doi: 10.1016/j.jpsychires.2025.03.023. Epub 2025 Mar 13.
8. Dickerson F, Origoni A, Katsafanas E, Squire A, Newman T, Fahey J, Xiao JC, Stallings C, Goga J, Khushalani S, Yolken R. Randomized controlled trial of an adjunctive sulforaphane nutraceutical in schizophrenia. Schizophr Res. 2021 May;231:142–144. doi: 10.1016/j.schres.2021.03.018. Epub 2021 Apr 8.
9. Hei G, Smith RC, Li R, Ou J, Song X, Zheng Y, He Y, Arriaza J, Fahey JW, Cornblatt B, Kang D, Yang Y, Huang J, Wang X, Cadenhead K, Zhang M, Davis JM, Zhao J, Jin H, Wu R. Sulforaphane effects on cognition and symptoms in first and early episode schizophrenia: A randomized double-blind trial. Schizophr Bull Open. 2022 Mar 7;3(1):sgac024. doi: 10.1093/schizbullopen/sgac024.
10. Huang J, Chen A, Jin H, Liu F, Hei G, Teng Z, Xiao J, Wu R, Zhao J, Davis JM, Shao P, Smith RC. Efficacy and safety of sulforaphane added to antipsychotics for the treatment of negative symptoms of schizophrenia: A randomized controlled trial. J Clin Psychiatry. 2025 Jan 20;86(1):24m15272. doi: 10.4088/JCP.24m15272.
Mood and cognition
11. Ghazizadeh-Hashemi F, Bagheri S, Ashraf-Ganjouei A, Moradi K, Shahmansouri N, Mehrpooya M, Noorbala AA, Akhondzadeh S. Efficacy and safety of sulforaphane for treatment of mild to moderate depression in patients with history of cardiac interventions: A randomized, double-blind, placebo-controlled clinical trial. Psychiatry Clin Neurosci. 2021 Aug;75(8):250–255. doi: 10.1111/pcn.13276. Epub 2021 Jun 30.
12. Nouchi R, Hu Q, Ushida Y, Suganuma H, Kawashima R. Effects of sulforaphane intake on processing speed and negative moods in healthy older adults: Evidence from a randomized controlled trial. Front Aging Neurosci. 2022;14:929628. doi: 10.3389/fnagi.2022.929628.
13. Nouchi R, Hu Q, Saito T, Kawata NYDS, Nouchi H, Kawashima R. Brain Training and Sulforaphane Intake Interventions Separately Improve Cognitive Performance in Healthy Older Adults, Whereas a Combination of These Interventions Does Not Have More Beneficial Effects: Evidence from a Randomized Controlled Trial. Nutrients. 2021;13(2):352.
Valerian References
21 references
Insomnia
1. Ahmadi M, Khalili H, Abbasian L, Ghaeli P. Effect of valerian in preventing neuropsychiatric adverse effects of efavirenz in HIV-positive patients. Ann Pharmacother. 2017;51(6):457–464. doi: 10.1177/1060028017696105. Epub 2017 Feb 1.
2. Balderer G, Borbély AA. Effect of valerian on human sleep. Psychopharmacology. 1985;87(4):406–409. doi: 10.1007/BF00432503.
3. Chandra Shekhar H, Joshua L, Thomas JV. Standardized extract of Valeriana officinalis improves overall sleep quality in human subjects with sleep complaints: A randomized, double-blind, placebo-controlled, clinical study. Adv Ther. 2024 Jan;41(1):246–261. doi: 10.1007/s12325-023-02708-6. Epub 2023 Oct 30.
4. Coxeter PD, Schluter PJ, Eastwood HL, Nikles CJ, Glasziou PP. Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials. Complement Ther Med. 2003 Dec;11(4):215–222. doi: 10.1016/s0965-2299(03)00122-5.
5. Diaper A, Hindmarch I. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res. 2004;18(10):831–836. doi: 10.1002/ptr.1574.
6. Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000 Mar;33(2):47–53. doi: 10.1055/s-2000-7972.
7. Gutiérrez-Romero SA, Torres-Narváez ES, Zamora-Gómez AC, Castillo-Castillo S, Latorre-Velásquez AL, Betancourt-Villamizar C, Mendivil CO. Effect of a nutraceutical combination on sleep quality among people with impaired sleep: A randomised, placebo-controlled trial. Sci Rep. 2024 Apr 5;14(1):8062. doi: 10.1038/s41598-024-58661-z.
8. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav. 1982 Jul;17(1):65–71. doi: 10.1016/0091-3057(82)90264-7.
9. Morin CM, Koetter U, Bastien C, Ware JC, Wooten V. Valerian-hops combination and diphenhydramine for treating insomnia. Sleep. 2005;28(11):1465–1471. doi: 10.1093/sleep/28.11.1465.
10. Oxman AD, Flottorp S, Håvelsrud K, Fretheim A, Odgaard-Jensen J, Austvoll-Dahlgren A, Carling C, Pallesen S, Bjorvatn B. A televised, web-based randomised trial of an herbal remedy (valerian) for insomnia. PLoS One. 2007 Oct 17;2(10):e1040. doi: 10.1371/journal.pone.0001040.
11. Taavoni S, Ekbatani N, Kashaniyan M, Haghani H. Effect of valerian on sleep quality in postmenopausal women. Menopause. 2011;18(9):951–955. doi: 10.1097/gme.0b013e31820e9acf.
12. Taibi DM, Vitiello MV, Barsness S, Elmer GW, Anderson GD, Landis CA. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med. 2009;10(3):319–328. doi: 10.1016/j.sleep.2008.02.001. Epub 2008 May 14.
13. Vorbach EU, Görtelmeyer R, Brüning J. Therapie von Insomnien: Wirksamkeit und Verträglichkeit eines Baldrian-Präparates [Treatment of insomnia: Effectiveness and tolerance of a valerian extract]. Psychopharmakotherapie. 1996;3:109–115. German.
14. Ziegler G, Ploch M, Miettinen-Baumann A, Collet W. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia. Eur J Med Res. 2002;7(11):480–486.
Anxiety in healthy adults
15. Cropley M, Cave Z, Ellis J, Middleton RW. Effect of kava and valerian on human physiological and psychological responses to mental stress assessed under laboratory conditions. Phytother Res. 2002;16(1):23–27. doi: 10.1002/ptr.1002.
16. Dodd F, Kennedy D, Wightman E, Khan J, Patan M, Elcoate R, Jackson P. The chronic effects of a combination of herbal extracts (Euphytose®) on psychological mood state and response to a laboratory stressor: A randomised, placebo-controlled, double blind study in healthy humans. J Psychopharmacol. 2022 Nov;36(11):1243–1256. doi: 10.1177/02698811221112933. Epub 2022 Jul 23.
17. Jacobs BP, Bent S, Tice JA, Blackwell T, Cummings SR. An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine. 2005;84(4):197–207. doi: 10.1097/01.md.0000172299.72364.95.
18. Kennedy DO, Little W, Haskell CF, Scholey AB. Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress. Phytother Res. 2006;20(2):96–102. doi: 10.1002/ptr.1787.
19. Meier S, Haschke M, Zahner C, Kruttschnitt E, Drewe J, Liakoni E, Hammann F, Gaab J. Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men - an explorative randomized placebo-controlled double-blind study. Phytomedicine. 2018 Jan 15;39:85–92. doi: 10.1016/j.phymed.2017.12.005. Epub 2017 Dec 12.
Generalized anxiety disorder
20. Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in generalized anxiety disorder: A randomized placebo-controlled pilot study. Phytother Res. 2002;16(7):650–654. doi: 10.1002/ptr.1027.
OCD
21. Pakseresht S, Boostani H, Sayyah M. Extract of valerian root (Valeriana officinalis L.) vs. placebo in treatment of obsessive-compulsive disorder: A randomized double-blind study. J Complement Integr Med. 2011 Oct 11;8. doi: 10.2202/1553-3840.1465.
Ashwagandha References
39 references
Insomnia
1. Deshpande A, Irani N, Balkrishnan R, Benny IR. A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults. Sleep Med. 2020 Aug;72:28–36. doi: 10.1016/j.sleep.2020.03.012. Epub 2020 Mar 21.
2. Fatima K, Malik J, Muskan F, Raza G, Waseem A, Shahid H, Jaffery SF, Khan U, Zaheer MK, Shaikh Y, Rashid AM. Safety and efficacy of Withania somnifera for anxiety and insomnia: Systematic review and meta-analysis. Hum Psychopharmacol. 2024 Nov;39(6):e2911. doi: 10.1002/hup.2911. Epub 2024 Jul 31.
3. Kelgane SB, Salve J, Sampara P, Debnath K. Efficacy and tolerability of ashwagandha root extract in the elderly for improvement of general well-being and sleep: A prospective, randomized, double-blind, placebo-controlled study. Cureus. 2020;12(2):e7083. doi: 10.7759/cureus.7083.
4. Langade D, Kanchi S, Salve J, Debnath K, Ambegaokar D. Efficacy and safety of ashwagandha (Withania somnifera) root extract in insomnia and anxiety: A double-blind, randomized, placebo-controlled study. Cureus. 2019;11(9):e5797. doi: 10.7759/cureus.5797.
5. Langade D, Thakare V, Kanchi S, Kelgane S. Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallel-group, placebo-controlled study. J Ethnopharmacol. 2021 Jan 10;264:113276. doi: 10.1016/j.jep.2020.113276. Epub 2020 Aug 17.
8. Manjunath NK, Telles S. Influence of yoga and Ayurveda on self-rated sleep in a geriatric population. Indian J Med Res. 2005;121(5):683–690.
10. Movva N, Salve J, Wankhede K, Thakare V, Langade D. Comparative evaluation of ashwagandha (Withania somnifera) root extract and melatonin for improving sleep quality in adults. Clocks Sleep. 2026 Mar 27;8(2):15. doi: 10.3390/clockssleep8020015.
Insomnia / Stress
6. Mahadevan M, Gopukumar K, Gupta R, Morde A, Patni P, Srinivas SS, Bhuvanendran A, Phanindra A. A new ashwagandha formulation (Zenroot™) alleviates stress and anxiety symptoms while improving mood and sleep quality: A randomized, double-blind, placebo-controlled clinical study. Adv Ther. 2025 Oct;42(10):5238–5254. doi: 10.1007/s12325-025-03327-z. Epub 2025 Aug 28.
7. Majeed M, Nagabhushanam K, Murali A, Vishwanathan DT, Mamidala RV, Mundkur L. A standardized Withania somnifera (Linn.) root extract with piperine alleviates the symptoms of anxiety and depression by increasing serotonin levels: A double-blind, randomized, placebo-controlled study. J Integr Complement Med. 2024 May;30(5):459–468. doi: 10.1089/jicm.2023.0279. Epub 2023 Oct 25.
9. McKinney E, Stewart J, Kewalramani R, Singh S. Effects of multi-herb and ashwagandha root formulas on stress modulation: A randomized, double-blind, placebo-controlled clinical study. Trials. 2026;27(1):205. doi: 10.1186/s13063-026-09495-9.
11. Salve J, Pate S, Debnath K, Langade D. Adaptogenic and anxiolytic effects of ashwagandha root extract in healthy adults: A double-blind, randomized, placebo-controlled clinical study. Cureus. 2019;11(12):e6466. doi: 10.7759/cureus.6466.
12. Thanawala S, Shah R, Alluri KV, Bhupathiraju K, Desomayanandanam P, Bhuvenendran A. Efficacy and safety of ashwagandha root extract sustained-release (AshwaSR) capsules in healthy adult, stressed subjects: A randomized, double-blind, placebo-controlled, parallel-group, 3-arm clinical trial. Medicine (Baltimore). 2026 Mar 13;105(11):e47990. doi: 10.1097/MD.0000000000047990.
Stress
13. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S. A standardized Withania somnifera extract significantly reduces stress-related parameters in chronically stressed humans: a double-blind, randomized, placebo-controlled study. JANA. 2008;11(1):50–56.
14. Baker C, Kirby JB, O’Connor J, Lindsay KG, Hutchins A, Harris M. The perceived impact of ashwagandha on stress, sleep quality, energy, and mental clarity for college students: Qualitative analysis of a double-blind randomized control trial. J Med Food. 2022 Dec;25(12):1095–1101. doi: 10.1089/jmf.2022.0042. Epub 2022 Aug 18.
15. Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 2012;34(3):255–262. doi: 10.4103/0253-7176.106022.
16. Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with ashwagandha root extract: A double-blind, randomized, placebo-controlled trial. J Evid Based Complementary Altern Med. 2017 Jan;22(1):96–106. doi: 10.1177/2156587216641830. Epub 2016 Apr 6.
17. Cooley K, Szczurko O, Perri D, Mills EJ, Bernhardt B, Zhou Q, Seely D. Naturopathic care for anxiety: A randomized controlled trial ISRCTN78958974. PLoS One. 2009 Aug 31;4(8):e6628. doi: 10.1371/journal.pone.0006628.
19. Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine (Baltimore). 2019 Sep;98(37):e17186. doi: 10.1097/MD.0000000000017186.
20. Majeed M, Nagabhushanam K, Mundkur L. A standardized ashwagandha root extract alleviates stress, anxiety, and improves quality of life in healthy adults. Medicine (Baltimore). 2023 Oct 13;102(41):e35521. doi: 10.1097/MD.0000000000035521.
21. O’Connor J, Lindsay K, Baker C, Kirby J, Hutchins A, Harris M. The impact of ashwagandha on stress, sleep quality, and food cravings in college students: Quantitative analysis of a double-blind randomized control trial. J Med Food. 2022 Dec;25(12):1086–1094. doi: 10.1089/jmf.2022.0040. Epub 2022 Aug 18. Erratum in: J Med Food. 2023 Apr;26(4):275. doi: 10.1089/jmf.2022.0040.correx.
22. Pakhale K, Salve J, Ademola J, Parraca J, Langade D. Safety of 8-week administration with ashwagandha (Withania somnifera) root extract in adults with stress and anxiety: Findings from a prospective, randomized, multi-center, double-blinded, placebo-controlled study. Phytother Res. 2026 Apr 6. doi: 10.1002/ptr.70315. Epub ahead of print.
23. Smith SJ, Lopresti AL, Fairchild TJ. Exploring the efficacy and safety of a novel standardized ashwagandha (Withania somnifera) root extract (Witholytin®) in adults experiencing high stress and fatigue in a randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2023 Nov;37(11):1091–1104. doi: 10.1177/02698811231200023. Epub 2023 Sep 23.
Stress / Mild cognitive impairment
18. Gopukumar K, Thanawala S, Somepalli V, Rao TSS, Thamatam VB, Chauhan S. Efficacy and safety of ashwagandha root extract on cognitive functions in healthy, stressed adults: A randomized, double-blind, placebo-controlled study. Evid Based Complement Alternat Med. 2021 Nov 30;2021:8254344. doi: 10.1155/2021/8254344.
Mild cognitive impairment
24. Choudhary D, Bhattacharyya S, Bose S. Efficacy and safety of ashwagandha (Withania somnifera (L.) Dunal) root extract in improving memory and cognitive functions. J Diet Suppl. 2017;14(6):599–612. doi: 10.1080/19390211.2017.1284970. Epub 2017 Feb 21.
25. Kale S, Lopresti A, Suri R, Garg N, Langade D. Safety and efficacy of ashwagandha root extract on cognition, energy and mood problems in adults: Prospective, randomized, placebo-controlled study. J Psychoactive Drugs. 2026 Jan–Mar;58(1):45–57. doi: 10.1080/02791072.2024.2424279. Epub 2024 Nov 5.
26. Leonard M, Dickerson B, Estes L, Gonzalez DE, Jenkins V, Johnson S, Xing D, Yoo C, Ko J, Purpura M, Jäger R, Faries M, Kephart W, Sowinski R, Rasmussen CJ, Kreider RB. Acute and repeated ashwagandha supplementation improves markers of cognitive function and mood. Nutrients. 2024 Jun 8;16(12):1813. doi: 10.3390/nu16121813.
27. Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res. 2014;6(1):12–18. doi: 10.4103/0974-8490.122912.
28. Rai HP, Mishra DN. Effect of ashwagandha (Withania somnifera) extract with Sominone (Somin-On™) to improve memory in adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study. J Psychopharmacol. 2025 Apr;39(4):350–363. doi: 10.1177/02698811251324377. Epub 2025 Mar 18.
29. Xing D, Yoo C, Gonzalez D, Jenkins V, Nottingham K, Dickerson B, Leonard M, Ko J, Faries M, Kephart W, Purpura M, Jäger R, Sowinski R, Rasmussen CJ, Kreider RB. Effects of acute ashwagandha ingestion on cognitive function. Int J Environ Res Public Health. 2022 Sep 20;19(19):11852. doi: 10.3390/ijerph191911852.
Generalized anxiety disorder
30. Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R. A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of withania somnifera. Indian J Psychiatry. 2000 Jul;42(3):295–301.
31. Fuladi S, Emami SA, Mohammadpour AH, Karimani A, Manteghi AA, Sahebkar A. Assessment of the efficacy of Withania somnifera root extract in patients with generalized anxiety disorder: A randomized double-blind placebo-controlled trial. Curr Rev Clin Exp Pharmacol. 2021;16(2):191–196. doi: 10.2174/1574884715666200413120413.
32. Khyati S, Anup B. A randomized double blind placebo controlled study of ashwagandha on generalized anxiety disorder. Int Ayurvedic Med J. 2013 Sept–Oct;1(5):1–7.
OCD
33. Jahanbakhsh SP, Manteghi AA, Emami SA, Mahyari S, Gholampour B, Mohammadpour AH, Sahebkar A. Evaluation of the efficacy of Withania somnifera (ashwagandha) root extract in patients with obsessive-compulsive disorder: A randomized double-blind placebo-controlled trial. Complement Ther Med. 2016 Aug;27:25–29. doi: 10.1016/j.ctim.2016.03.018. Epub 2016 Apr 9.
Schizophrenia
34. Chengappa KNR, Brar JS, Gannon JM, Schlicht PJ. Adjunctive use of a standardized extract of Withania somnifera (ashwagandha) to treat symptom exacerbation in schizophrenia: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2018 Jul 10;79(5):17m11826. doi: 10.4088/JCP.17m11826.
Metabolic profile in schizophrenia
35. Agnihotri AP, Sontakke SD, Thawani VR, Saoji A, Goswami VS. Effects of Withania somnifera in patients of schizophrenia: A randomized, double blind, placebo controlled pilot trial study. Indian J Pharmacol. 2013 Jul–Aug;45(4):417–418. doi: 10.4103/0253-7613.115012.
Sexual dysfunction
36. Chauhan S, Srivastava MK, Pathak AK. Effect of standardized root extract of ashwagandha (Withania somnifera) on well-being and sexual performance in adult males: A randomized controlled trial. Health Sci Rep. 2022;5(4):e741. doi: 10.1002/hsr2.741.
37. Dongre S, Langade D, Bhattacharyya S. Efficacy and safety of ashwagandha (Withania somnifera) root extract in improving sexual function in women: a pilot study. Biomed Res Int. 2015;2015:284154. doi: 10.1155/2015/284154. Epub 2015 Oct 4.
38. Lopresti AL, Drummond PD, Smith SJ. A randomized, double-blind, placebo-controlled, crossover study examining the hormonal and vitality effects of ashwagandha (Withania somnifera) in aging, overweight males. Am J Mens Health. 2019;13(2):1557988319835985. doi: 10.1177/1557988319835985.
Cognition in bipolar disorder
39. Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013 Nov;74(11):1076–1083. doi: 10.4088/JCP.13m08413.
Bacopa monnieri References
12 references
Cognition in healthy adults
1. Benson S, Downey LA, Stough C, Wetherell M, Zangara A, Scholey A. An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood. Phytother Res. 2014 Apr;28(4):551–559. doi: 10.1002/ptr.5029. Epub 2013 Jun 21.
2. Best T, Miller J, Teo WP. Neurocognitive effects of a combined polyphenolic-rich herbal extract in healthy middle-aged adults — a randomised, double-blind, placebo-controlled study. Nutr Neurosci. 2024;27(11):1293–1305. doi: 10.1080/1028415X.2024.2325227. Epub 2024 Mar 21.
3. Calabrese C, Gregory WL, Leo M, Kraemer D, Bone K, Oken B. Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: A randomized, double-blind, placebo-controlled trial. J Altern Complement Med. 2008 Jul;14(6):707–713. doi: 10.1089/acm.2008.0018.
4. Downey LA, Kean J, Nemeh F, Lau A, Poll A, Gregory R, Murray M, Rourke J, Patak B, Pase MP, Zangara A, Lomas J, Scholey A, Stough C. An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance. Phytother Res. 2013 Sep;27(9):1407–1413. doi: 10.1002/ptr.4864. Epub 2012 Dec 19.
5. Kumar N, Abichandani LG, Thawani V, Gharpure KJ, Naidu MU, Venkat Ramana G. Efficacy of standardized extract of Bacopa monnieri (Bacognize®) on cognitive functions of medical students: A six-week, randomized placebo-controlled trial. Evid Based Complement Alternat Med. 2016;2016:4103423. doi: 10.1155/2016/4103423. Epub 2016 Oct 10.
6. Lopresti AL, Smith SJ. The effects of a Bacopa monnieri extract (Bacumen®) on cognition, stress, and fatigue in healthy adults. Clin Drug Investig. 2025. doi: 10.1007/s40261-025-01492-1. Epub 2025 Oct 15.
7. Morgan A, Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. J Altern Complement Med. 2010;16(7):753–759. doi: 10.1089/acm.2009.0342.
8. Peth-Nui T, Wattanathorn J, Muchimapura S, Tong-Un T, Piyavhatkul N, Rangseekajee P, Ingkaninan K, Vittaya-Areekul S. Effects of 12-week Bacopa monnieri consumption on attention, cognitive processing, working memory, and functions of both cholinergic and monoaminergic systems in healthy elderly volunteers. Evid Based Complement Alternat Med. 2012;2012:606424. doi: 10.1155/2012/606424. Epub 2012 Dec 18.
9. Roodenrys S, Booth D, Bulzomi S, Phipps A, Micallef C, Smoker J. Chronic effects of Brahmi (Bacopa monnieri) on human memory. Neuropsychopharmacology. 2002 Aug;27(2):279–281. doi: 10.1016/S0893-133X(01)00419-5.
10. Sathyanarayanan V, Thomas T, Einöther SJ, Dobriyal R, Joshi MK, Krishnamachari S. Brahmi for the better? New findings challenging cognition and anti-anxiety effects of Brahmi (Bacopa monniera) in healthy adults. Psychopharmacology (Berl). 2013 May;227(2):299–306. doi: 10.1007/s00213-013-2978-z. Epub 2013 Jan 26.
11. Stough C, Downey LA, Lloyd J, Silber B, Redman S, Hutchison C, Wesnes K, Nathan PJ. Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial. Phytother Res. 2008 Dec;22(12):1629–1634. doi: 10.1002/ptr.2537.
12. Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl). 2001 Aug;156(4):481–484. doi: 10.1007/s002130100815. Erratum in: Psychopharmacology (Berl). 2015 Jul;232(13):2427. Dosage error in article text.
Ginseng References
53 references
Cognition in healthy adults
1. Baek HI, Ha KC, Park YK, Kim TY, Park SJ. Efficacy and safety of panax ginseng sprout extract in subjective memory impairment: A randomized, double-blind, placebo-controlled clinical trial. Nutrients. 2024;16(12):1952. doi: 10.3390/nu16121952.
2. Bell L, Whyte A, Duysburgh C, Marzorati M, Van den Abbeele P, Le Cozannet R, Fança-Berthon P, Fromentin E, Williams C. A randomized, placebo-controlled trial investigating the acute and chronic benefits of American Ginseng (Cereboost®) on mood and cognition in healthy young adults, including in vitro investigation of gut microbiota changes as a possible mechanism of action. Eur J Nutr. 2022 Feb;61(1):413–428. doi: 10.1007/s00394-021-02654-5. Epub 2021 Aug 15.
3. D'Angelo L, Grimaldi R, Caravaggi M, Marcoli M, Perucca E, Lecchini S, Frigo GM, Crema A. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol. 1986 Apr–May;16(1):15–22. doi: 10.1016/0378-8741(86)90063-2.
4. Dormal V, Jonniaux L, Buchet M, Simar L, Copine S, Deldicque L. Effect of hydroponically grown red panax ginseng on perceived stress level, emotional processing, and cognitive functions in moderately stressed adults: A randomized, double-blind, placebo-controlled study. Nutrients. 2025;17(6):955. doi: 10.3390/nu17060955.
5. Kennedy DO, Scholey AB, Wesnes KA. Dose dependent changes in cognitive performance and mood following acute administration of ginseng to healthy young volunteers. Nutr Neurosci. 2001;4(4):295–310. doi: 10.1080/1028415x.2001.11747370.
6. Kennedy DO, Scholey AB, Wesnes KA. Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a Ginkgo/ginseng combination to healthy young adults. Physiol Behav. 2002;75(5):739–751. doi: 10.1016/s0031-9384(02)00665-0.
7. Kennedy DO, Scholey AB, Wesnes KA. Modulation of cognition and mood following administration of single doses of Korean Panax ginseng extract for 8 weeks. Hum Psychopharmacol. 2007;22(4):199–210.
8. Kim J, Chung SY, Park S, Park JH, Byun S, Hwang M, Oh DS, Choi H, Kim MY, Bu YC, Doré S, Whang WW, Kim H. Enhancing effect of HT008-1 on cognitive function and quality of life in cognitively declined healthy adults: A randomized, double-blind, placebo-controlled, trial. Pharmacol Biochem Behav. 2008 Oct;90(4):517–524. doi: 10.1016/j.pbb.2008.03.033.
9. Mariage PA, Hovhannisyan A, Panossian AG. Efficacy of Panax ginseng Meyer herbal preparation HRG80 in preventing and mitigating stress-induced failure of cognitive functions in healthy subjects: A pilot, randomized, double-blind, placebo-controlled crossover trial. Pharmaceuticals (Basel). 2020 Mar 29;13(4):57. doi: 10.3390/ph13040057.
10. Namgung E, Kim J, Jeong H, Hong G, Kim M, Kim RY, Kim S, Lyoo IK. Effects of Korean red ginseng on human gray matter volume and cognitive function: A voxel-based morphometry study. Hum Psychopharmacol. 2021;36(2):e2767. doi: 10.1002/hup.2767.
11. Ong Lai Teik D, Lee XS, Lim CJ, Low CM, Muslima M, Aquili L. Ginseng and Ginkgo biloba effects on cognition as modulated by cardiovascular reactivity: A randomised trial. PLoS One. 2016 Mar 3;11(3):e0150447. doi: 10.1371/journal.pone.0150447.
12. Ossoukhova A, Owen L, Savage K, Meyer M, Ibarra A, Roller M, Pipingas A, Wesnes K, Scholey A. Improved working memory performance following administration of a single dose of American ginseng (Panax quinquefolius L.) to healthy middle-age adults. Hum Psychopharmacol. 2015;30(2):108–122. doi: 10.1002/hup.2463.
13. Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained 'mentally demanding' tasks. J Psychopharmacol. 2006;20(6):771–781. doi: 10.1177/0269881106061516. Epub 2006 Jan 9.
14. Reay JL, Kennedy DO, Scholey AB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol. 2005;19(4):357–365. doi: 10.1177/0269881105053286.
15. Reay JL, Scholey AB, Kennedy DO. Panax ginseng (G115) improves aspects of working memory performance and subjective ratings of calmness in healthy young adults. Hum Psychopharmacol. 2010;25(6):462–471. doi: 10.1002/hup.1138.
16. Scholey A, Ossoukhova A, Owen L, Ibarra A, Pipingas A, He K, Roller M, Stough C. Effects of American ginseng (Panax quinquefolius) on neurocognitive function: An acute, randomised, double-blind, placebo-controlled, crossover study. Psychopharmacology (Berl). 2010 Oct;212(3):345–356. doi: 10.1007/s00213-010-1964-y. Epub 2010 Jul 31.
17. Sørensen H, Sonne J. A double-masked study of the effects of ginseng on cognitive functions. Curr Ther Res. 1996;57(12):959–968. doi: 10.1016/S0011-393X(96)80114-7.
18. Sünram-Lea SI, Birchall RJ, Wesnes KA, Petrini O. The effect of acute administration of 400 mg of Panax ginseng on cognitive performance and mood in healthy young volunteers. Curr Top Nutraceutical Res. 2005;3(1):65–74.
19. Wesnes KA, Ward T, McGinty A, Petrini O. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology (Berl). 2000 Nov;152(4):353–361. doi: 10.1007/s002130000533.
20. White DJ, Camfield DA, Ossoukhova A, Savage K, Le Cozannet R, Fanca-Berthon P, Scholey A. Effects of Panax quinquefolius (American ginseng) on the steady state visually evoked potential during cognitive performance. Hum Psychopharmacol. 2020;35(6):1–6. doi: 10.1002/hup.2756.
Male erectile dysfunction
21. Choi HK, Choi YD, Adaikan PG, Yu J. Effectiveness of Korea red ginseng in erectile dysfunction - multi-national approach. Journal of Ginseng Research. 1999;23(4):247–256.
22. Choi HK, Choi YJ, Kim JH. Penile blood change after oral medication of Korean red ginseng in erectile dysfunction patients. Journal of Ginseng Research. 2003;27(4):165–170.
23. Choi HK, Choi YJ. Evaluation of clinical efficacy of Korea red ginseng for erectile dysfunction by International Index of Erectile Function (IIEF). Journal of Ginseng Research. 2001;25(3):112–117.
24. Choi HK, Seong DH, Rha KH. Clinical efficacy of Korean red ginseng for erectile dysfunction. Int J Impot Res. 1995;7(3):181–186.
25. Choi YD, Park CW, Jang J, Kim SH, Jeon HY, Kim WG, Lee SJ, Chung WS. Effects of Korean ginseng berry extract on sexual function in men with erectile dysfunction: A multicenter, placebo-controlled, double-blind clinical study. Int J Impot Res. 2013;25(2):45–50. doi: 10.1038/ijir.2012.45.
26. de Andrade E, de Mesquita AA, Claro Jde A, de Andrade PM, Ortiz V, Paranhos M, Srougi M. Study of the efficacy of Korean red ginseng in the treatment of erectile dysfunction. Asian J Androl. 2007 Mar;9(2):241–244. doi: 10.1111/j.1745-7262.2007.00210.x. Epub 2006 Jul 11.
27. Farnia V, Alikhani M, Ebrahimi A, Golshani S, Sadeghi Bahmani D, Brand S. Ginseng treatment improves the sexual side effects of methadone maintenance treatment. Psychiatry Res. 2019;276:142–150. doi: 10.1016/j.psychres.2019.05.004.
28. Hong B, Ji YH, Hong JH, Nam KY, Ahn TY. A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: A preliminary report. J Urol. 2002;168(5):2070–2073. doi: 10.1016/S0022-5347(05)64298-X.
29. Kim TH, Jeon SH, Hahn EJ, Paek KY, Park JK, Youn NY, Lee HL. Effects of tissue-cultured mountain ginseng (Panax ginseng CA Meyer) extract on male patients with erectile dysfunction. Asian J Androl. 2009;11(3):356–361. doi: 10.1038/aja.2008.32. Epub 2009 Feb 23.
30. Kim YC, Hong YK, Shin JS, Kang MS, Sung DH, Choi HK. Effect of Korean red ginseng on sexual dysfunction and serum lipid level in old aged men. Journal of Ginseng Research. 1996;20(2):125–132.
Alzheimer's dementia
31. Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. Eur J Neurol. 2008 Aug;15(8):865–868. doi: 10.1111/j.1468-1331.2008.02157.x.
32. Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutr Neurosci. 2012 Nov;15(6):278–282. doi: 10.1179/1476830512Y.0000000027.
33. Jia J, Wei C, Chen S, Li F, Tang Y, Qin W, Shi L, Gong M, Xu H, Li F, He J, Song H, Yang S, Zhou A, Wang F, Zuo X, Chu C, Liang J, Jia L, Gauthier S. Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: A randomized clinical trial. Alzheimers Dement (N Y). 2018;4:108–117. doi: 10.1016/j.trci.2018.02.004.
34. Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):222–226. doi: 10.1097/WAD.0b013e31816c92e6.
35. Neri M, Andermarcher E, Pradelli JM, Salvioli G. Influence of a double blind pharmacological trial on two domains of well-being in subjects with age associated memory impairment. Arch Gerontol Geriatr. 1995;21(3):241–252. doi: 10.1016/0167-4943(95)00659-9.
ADHD
36. Ko HJ, Kim I, Kim JB, Moon Y, Whang MC, Lee KM, Jung SP. Effects of Korean red ginseng extract on behavior in children with symptoms of inattention and hyperactivity/impulsivity: A double-blind randomized placebo-controlled trial. J Child Adolesc Psychopharmacol. 2014 Nov;24(9):501–508. doi: 10.1089/cap.2014.0013. Epub 2014 Nov 4.
37. Lee J, Lee SI. Efficacy of omega-3 and Korean red ginseng in children with subthreshold ADHD: A double-blind, randomized, placebo-controlled trial. J Atten Disord. 2021;25(14):1977–1987. doi: 10.1177/1087054720951868.
Fatigue
38. Barton DL, Liu H, Dakhil SR, Linquist B, Sloan JA, Nichols CR, McGinn TW, Stella PJ, Seeger GR, Sood A, Loprinzi CL. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: A randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013 Aug 21;105(16):1230–1238. doi: 10.1093/jnci/djt181. Epub 2013 Jul 13.
39. Etemadifar M, Sayahi F, Abtahi SH, Shemshaki H, Dorooshi GA, Goodarzi M, Akbari M, Fereidan-Esfahani M. Ginseng in the treatment of fatigue in multiple sclerosis: A randomized, placebo-controlled, double-blind pilot study. Int J Neurosci. 2013 Jul;123(7):480–486. doi: 10.3109/00207454.2013.764499. Epub 2013 Feb 11.
40. Kim JW, Han SW, Cho JY, Chung IJ, Kim JG, Lee KH, Park KU, Baek SK, Oh SC, Lee MA, Oh D, Shim B, Ahn JB, Shin D, Lee JW, Kim YH. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial. Eur J Cancer. 2020 May;130:51–62. doi: 10.1016/j.ejca.2020.02.018. Epub 2020 Mar 13.
41. Jiang SL, Liu HJ, Liu ZC, et al: Adjuvant effects of fermented red ginseng extract on advanced non-small cell lung cancer patients treated with chemotherapy. Chin J Integr Med 23:331-337, 2017
42. Rahmani A, Sanaat Z, H HN, Shamsi A, Ghaderi M. The effect of ginseng extract on fatigue in cancer survivors: A randomized double-blind clinical trial. Support Care Cancer. 2026 Mar 16;34(4):327. doi: 10.1007/s00520-026-10398-3.
43. Yennurajalingam S, Tannir NM, Williams JL, Lu Z, Hess KR, Frisbee-Hume S, House HL, Lim ZD, Lim KH, Lopez G, Reddy A, Azhar A, Wong A, Patel SM, Kuban DA, Kaseb AO, Cohen L, Bruera E. A double-blind, randomized, placebo-controlled trial of Panax ginseng for cancer-related fatigue in patients with advanced cancer. J Natl Compr Canc Netw. 2017 Sep;15(9):1111–1120. doi: 10.6004/jnccn.2017.0149.
Sexual dysfunction in women
44. Chung HS, Hwang I, Oh KJ, Lee MN, Park K. The effect of Korean red ginseng on sexual function in premenopausal women: Placebo-controlled, double-blind, crossover clinical trial. Evid Based Complement Alternat Med. 2015;2015:913158. doi: 10.1155/2015/913158. Epub 2015 Dec 22.
45. Chung YS, Lee IO, Lee JY, Nam EJ, Kim SW, Kim YT, Kim S. Effects of Korean red ginseng (Panax ginseng C.A. Meyer) on menopausal symptoms in premenopausal women after gynecologic cancer surgery: A double-blind, randomized controlled trial. J Altern Complement Med. 2021 Jan;27(1):66-72. doi: 10.1089/acm.2019.0429. Epub 2020 Nov 20.
46. Ghamari K, Kashani L, Jafarinia M, Tadayon Najafabadi B, Shokraee K, Esalatmanesh S, Akhondzadeh S. Vitamin E and ginseng supplementation to enhance female sexual function: A randomized, double-blind, placebo-controlled, clinical trial. Women Health. 2020 Nov–Dec;60(10):1164–1173. doi: 10.1080/03630242.2020.1803465. Epub 2020 Sep 6.
47. Ghorbani Z, Mirghafourvand M, Charandabi SM, Javadzadeh Y. The effect of ginseng on sexual dysfunction in menopausal women: A double-blind, randomized, controlled trial. Complement Ther Med. 2019;45:57–64. doi: 10.1016/j.ctim.2019.05.015. Epub 2019 May 22.
48. Oh KJ, Chae MJ, Lee HS, Hong HD, Park K. Effects of Korean red ginseng on sexual arousal in menopausal women: Placebo-controlled, double-blind crossover clinical study. J Sex Med. 2010;7(4 Pt 1):1469–1477. doi: 10.1111/j.1743-6109.2009.01700.x. Epub 2010 Feb 5.
Schizophrenia
49. Chen EY, Hui CL. HT1001, a proprietary North American ginseng extract, improves working memory in schizophrenia: A double-blind, placebo-controlled study. Phytother Res. 2012;26(8):1166–72. doi: 10.1002/ptr.3700.
Rhodiola rosea References
11 references
Major depressive disorder
1. Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry. 2007;61(5):343–348. doi: 10.1080/08039480701643290. Erratum in: Nord J Psychiatry. 2007;61(6):503.
2. Gao L, Wu C, Liao Y, Wang J. Antidepressants effects of Rhodiola capsule combined with sertraline for major depressive disorder: A randomized double-blind placebo-controlled clinical trial. J Affect Disord. 2020 Mar 15;265:99–103. doi: 10.1016/j.jad.2020.01.065. Epub 2020 Jan 15.
3. Mao JJ, Xie SX, Zee J, Soeller I, Li QS, Rockwell K, Amsterdam JD. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine. 2015 Mar 15;22(3):394–399. doi: 10.1016/j.phymed.2015.01.010. Epub 2015 Feb 23.
Stress
4. Boyle NB, Billington J, Lawton C, Quadt F, Dye L. A combination of green tea, rhodiola, magnesium and B vitamins modulates brain activity and protects against the effects of induced social stress in healthy volunteers. Nutr Neurosci. 2022;25(9):1845–1859.
5. Cropley M, Banks AP, Boyle J. The effects of Rhodiola rosea L. extract on anxiety, stress, cognition and other mood symptoms. Phytother Res. 2015 Dec;29(12):1934–1939. doi: 10.1002/ptr.5486. Epub 2015 Oct 27.
6. Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H. Rhodiola rosea in stress induced fatigue--a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine. 2000 Oct;7(5):365–371. doi: 10.1016/S0944-7113(00)80055-0.
7. McKinney E, Stewart J, Kewalramani R, Singh S. Effects of multi-herb and ashwagandha root formulas on stress modulation: A randomized, double-blind, placebo-controlled clinical study. Trials. 2026;27(1):205.
8. Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009 Feb;75(2):105–112. doi: 10.1055/s-0028-1088346. Epub 2008 Nov 18.
9. Punja S, Shamseer L, Olson K, Vohra S. Rhodiola rosea for mental and physical fatigue in nursing students: A randomized controlled trial. PLoS One. 2014;9(9):e108416.
10. Spasov AA, Wikman GK, Mandrikov VB, Mironova IA, Neumoin VV. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine. 2000 Apr;7(2):85–89. doi: 10.1016/S0944-7113(00)80078-1.
Generalized anxiety disorder
11. Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD). J Altern Complement Med. 2008 Mar;14(2):175–180. doi: 10.1089/acm.2007.7117.
Cannabidiol References
23 references
Anxiety disorders
1. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011 May;36(6):1219–1226. doi: 10.1038/npp.2011.6. Epub 2011 Feb 9.
2. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, Hallak JE. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: A preliminary report. J Psychopharmacol. 2011 Jan;25(1):121–130. doi: 10.1177/0269881110379283. Epub 2010 Sep 9.
3. Gundugurti PR, Banda N, Yadlapalli SSR, Narala A, Thatikonda R, Kocherlakota C, Kothapalli KS. Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial. Asian J Psychiatr. 2024 Jul;97:104073. doi: 10.1016/j.ajp.2024.104073. Epub 2024 May 18.
4. Kwee CM, Baas JM, van der Flier FE, Groenink L, Duits P, Eikelenboom M, van der Veen DC, Moerbeek M, Batelaan NM, van Balkom AJ, Cath DC. Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial. Eur Neuropsychopharmacol. 2022 Jun;59:58–67. doi: 10.1016/j.euroneuro.2022.04.003. Epub 2022 May 10.
5. Masataka N. Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front Psychol. 2019;10:2466. doi: 10.3389/fpsyg.2019.02466.
Non-specific anxiety
6. Arndt DL, de Wit H. Cannabidiol does not dampen responses to emotional stimuli in healthy adults. Cannabis Cannabinoid Res. 2017;2(1):105–113. doi: 10.1089/can.2017.0014.
7. de Faria SM, de Morais Fabrício D, Tumas V, Castro PC, Ponti MA, Hallak JE, Zuardi AW, Crippa JAS, Chagas MHN. Effects of acute cannabidiol administration on anxiety and tremors induced by a simulated public speaking test in patients with Parkinson's disease. J Psychopharmacol. 2020 Feb;34(2):189–196. doi: 10.1177/0269881119895536. Epub 2020 Jan 7.
8. Gournay LR, Ferretti ML, Bilsky S, Vance E, Nguyen AM, Mann E, Williams P, Leen-Feldner EW. The effects of cannabidiol on worry and anxiety among high trait worriers: A double-blind, randomized placebo controlled trial. Psychopharmacology (Berl). 2023 Oct;240(10):2147–2161. doi: 10.1007/s00213-023-06437-0. Epub 2023 Aug 8.
9. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7(1 Suppl):82-88. doi: 10.1177/026988119300700112.
10. Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, Crippa JAS. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol. 2017 May 11;8:259. doi: 10.3389/fphar.2017.00259.
Insomnia
11. Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981;21(S1):417S–427S. doi: 10.1002/j.1552-4604.1981.tb02622.x. PMID: 7028792.
12. Narayan AJ, Downey LA, Rose S, Di Natale L, Hayley AC. Cannabidiol for moderate-severe insomnia: A randomized controlled pilot trial of 150 mg of nightly dosing. J Clin Sleep Med. 2024;20(5):753–763. doi: 10.5664/jcsm.10998.
13. Ried K, Tamanna T, Matthews S, Sali A. Medicinal cannabis improves sleep in adults with insomnia: A randomised double-blind placebo-controlled crossover study. J Sleep Res. 2023;32(3):e13793. doi: 10.1111/jsr.13793. Epub 2022 Dec 20.
14. Suraev A, McGregor IS, McCartney D, Marshall NS, Kao CH, Wassing R, D'Rozario AL, Wong KKH, Yee BJ, Sivam S, Kevin RC, Vandrey R, Irwin C, Gordon CJ, Bartlett D, Arnold JC, Grunstein RR, Hoyos CM. Acute effects of oral cannabinoids on sleep and high-density EEG in insomnia: A pilot randomised controlled trial. J Sleep Res. 2026 Feb;35(1):e70124. doi: 10.1111/jsr.70124. Epub 2025 Jul 9.
15. Walsh JH, Maddison KJ, Rankin T, Murray K, McArdle N, Ree MJ, Hillman DR, Eastwood PR. Treating insomnia symptoms with medicinal cannabis: A randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo. Sleep. 2021 Nov 12;44(11):zsab149. doi: 10.1093/sleep/zsab149.
16. Wang M, Faust M, Abbott S, Patel V, Chang E, Clark JI, Stella N, Muchowski PJ. Effects of a cannabidiol/terpene formulation on sleep in individuals with insomnia: A double-blind, placebo-controlled, randomized, crossover study. J Clin Sleep Med. 2025 Jan 1;21(1):69–80. doi: 10.5664/jcsm.11324.
Anorexia nervosa
17. Sahota N, Grelotti DJ, Nguyen T, Kaye WH, Swindle S, Suhandynata R, Seely S, Shott ME, Frank GKW. Cannabidiol in anorexia nervosa: A double-blind randomized placebo controlled pilot study to test safety, pharmacokinetics, and symptom change. Int J Eat Disord. 2026 Mar 29. doi: 10.1002/eat.70034. Epub ahead of print.
Cannabis use disorder
18. Freeman TP, Hindocha C, Baio G, Shaban NDC, Thomas EM, Astbury D, Freeman AM, Lees R, Craft S, Morrison PD, Bloomfield MAP, O'Ryan D, Kinghorn J, Morgan CJA, Mofeez A, Curran HV. Cannabidiol for the treatment of cannabis use disorder: A phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry. 2020 Oct;7(10):865–874. doi: 10.1016/S2215-0366(20)30290-X. Epub 2020 Jul 28.
19. Spiga F, Parkhouse T, Tang VM, Savović J, Le Foll B, Nielsen S. Pharmacotherapies for cannabis use disorder. Cochrane Database Syst Rev. 2025;9(9):CD008940. Published 2025 Sep 30. doi:10.1002/14651858.CD008940.pub4
Psychotic symptoms in schizophrenia
20. Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, Schnakenberg Martin AM, Thurnauer H, Davies A, D'Souza DC, Ranganathan M. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl). 2018 Jul;235(7):1923–1932. doi: 10.1007/s00213-018-4885-9. Epub 2018 Apr 5.
21. Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2(3):e94. doi: 10.1038/tp.2012.15.
22. McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Taylor A, Wright S. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am J Psychiatry. 2018 Mar 1;175(3):225–231. doi: 10.1176/appi.ajp.2017.17030325. Epub 2017 Dec 15.
Treatment-resistant anxiety disorders
23. Berger M, Li E, Rice S, Davey CG, Ratheesh A, Adams S, Jackson H, Hetrick S, Parker A, Spelman T, Kevin R, McGregor IS, McGorry P, Amminger GP. Cannabidiol for treatment-resistant anxiety disorders in young people: An open-label trial. J Clin Psychiatry. 2022 Aug 3;83(5):21m14130. doi: 10.4088/JCP.21m14130.
Chasteberry References
15 references
Premenstrual syndrome
1. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2003;18(3):191–195. doi: 10.1002/hup.470.
2. Berger D, Schaffner W, Schrader E, Meier B, Brattström A. Efficacy of Vitex agnus castus L. extract Ze 440 in patients with pre-menstrual syndrome (PMS). Arch Gynecol Obstet. 2000 Nov;264(3):150–153. doi: 10.1007/s004040000123.
3. Canning S, Waterman M, Orsi N, Ayres J, Simpson N, Dye L. The efficacy of Hypericum perforatum (St John's wort) for the treatment of premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. CNS Drugs. 2010;24(3):207–225. doi: 10.2165/11530120-000000000-00000.
4. Halaska M, Beles P, Gorkow C, Sieder C. Treatment of cyclical mastalgia with a solution containing a Vitex agnus castus extract: Results of a placebo-controlled double-blind study. Breast. 1999;8(4):175–181. doi: 10.1054/brst.1999.0039.
5. He Z, Chen R, Zhou Y, Geng L, Zhang Z, Chen S, Yao Y, Lu J, Lin S. Treatment for premenstrual syndrome with Vitex agnus castus: A prospective, randomized, multi-center placebo controlled study in China. Maturitas. 2009 May 20;63(1):99–103. doi: 10.1016/j.maturitas.2009.01.006. Epub 2009 Mar 9.
6. Ibrahim NA, Shalaby AS, Farag RS, Elbaroty GS, Nofal SM, Hassan EM. Gynecological efficacy and chemical investigation of Vitex agnus-castus L. fruits growing in Egypt. Nat Prod Res. 2008 Apr 15;22(6):537–546. doi: 10.1080/14786410701592612.
7. Kilicdag EB, Tarim E, Bagis T, Erkanli S, Aslan E, Ozsahin K, Kuscu E. Fructus agni casti and bromocriptine for treatment of hyperprolactinemia and mastalgia. Int J Gynaecol Obstet. 2004 Jun;85(3):292–293. doi: 10.1016/j.ijgo.2004.01.001.
8. Lauritzen C, Reuter HD, Repges R, Böhnert KJ, Schmidt U. Treatment of premenstrual tension syndrome with Vitex agnus castus: Controlled, double-blind study versus pyridoxine. Phytomedicine. 1997;4(3):183–189. doi: 10.1016/S0944-7113(97)80066-9.
9. Ma L, Lin S, Chen R, Wang X. Treatment of moderate to severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women. Gynecol Endocrinol. 2010 Aug;26(8):612–616. doi: 10.3109/09513591003632126.
10. Momoeda M, Sasaki H, Tagashira E, Ogishima M, Takano Y, Hashimoto K. Efficacy and safety of Vitex agnus-castus extract for treatment of premenstrual syndrome in Japanese patients: A prospective, randomized, double-blind, placebo-controlled study. Adv Ther. 2014;31(3):362–373. doi: 10.1007/s12325-014-0106-z. Epub 2014 Mar 7.
11. Pakgohar M, Moradi M, Jamshidi A, Mehran A. Assessment of Vitex agnus- castus L. Extract Effect on Treatment of Premenstrual Syndrome. J. Med. Plants 2009; 8 (32) :98-107URL: http://jmp.ir/article-1-353-en.html
12. Schellenberg R, Zimmermann C, Drewe J, Hoexter G, Zahner C. Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome. Phytomedicine. 2012;19(14):1325–1331. doi: 10.1016/j.phymed.2012.08.006. Epub 2012 Sep 28.
13. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: Prospective, randomised, placebo controlled study. BMJ. 2001;322(7279):134–137. doi: 10.1136/bmj.322.7279.134.
14. Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstrual syndrome: A case study. Complement Ther Med. 1993;1(2):73-77. doi: 10.1016/0965-2299(93)90096-V.
15. Zamani M, Neghab N, Torabian S. Therapeutic effect of Vitex agnus castus in patients with premenstrual syndrome. Acta Med Iran. 2012;50(2):101–106.
Cytisinicline References
9 references
Nicotine cessation
1. Dogar O, Keding A, Gabe R, Marshall AM, Huque R, Barua D, Fatima R, Khan A, Zahid R, Mansoor S, Kotz D, Boeckmann M, Elsey H, Kralikova E, Parrott S, Li J, Readshaw A, Sheikh A, Siddiqi K; TB and Tobacco Consortium. Cytisine for smoking cessation in patients with tuberculosis: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Glob Health. 2020 Nov;8(11):e1408–e1417. doi: 10.1016/S2214-109X(20)30312-0.
2. Nides M, Rigotti NA, Benowitz N, Clarke A, Jacobs C. A multicenter, double-blind, randomized, placebo-controlled phase 2b trial of cytisinicline in adult smokers (the ORCA-1 trial). Nicotine Tob Res. 2021;23(10):1656–1663. doi: 10.1093/ntr/ntab073.
3. Phusahat P, Dilokthornsakul P, Boonsawat W, Zaeoue U, Hansuri N, Tawinkan N, Theeranut A, Lertsinudom S. Efficacy and safety of cytisine in combination with a community pharmacists' counselling for smoking cessation in Thailand: A randomized double-blinded placebo-controlled trial. Int J Environ Res Public Health. 2022 Oct 16;19(20):13358. doi: 10.3390/ijerph192013358.
4. Rigotti NA, Benowitz NL, Prochaska J, Leischow S, Nides M, Blumenstein B, Clarke A, Cain D, Jacobs C. Cytisinicline for smoking cessation: A randomized clinical trial. JAMA. 2023 Jul 11;330(2):152–160. doi: 10.1001/jama.2023.10042.
5. Rigotti NA, Benowitz NL, Prochaska JJ, Rubinstein M, Clarke A, Blumenstein B, Cain DF, Jacobs C. Cytisinicline for Smoking Cessation: The ORCA phase 3 replication randomized clinical trial. JAMA Intern Med. 2025 Jun 1;185(6):648–655. doi: 10.1001/jamainternmed.2025.0628.
6. Rigotti NA, Benowitz NL, Prochaska JJ, Cain DF, Ball J, Clarke A, Blumenstein BA, Jacobs C. Cytisinicline for vaping cessation in adults using nicotine e-cigarettes: The ORCA-V1 randomized clinical trial. JAMA Intern Med. 2024 Aug 1;184(8):922–930. doi: 10.1001/jamainternmed.2024.1313.
7. Vinnikov D, Brimkulov N, Burjubaeva J. A double-blind, randomised, placebo-controlled trial of cytisine for smoking cessation in medium-dependent workers. J Smoking Cessation. 2008;3(1):57–62. doi: 10.1375/jsc.3.1.57.
8. West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, Stapleton J. Placebo-controlled trial of cytisine for smoking cessation. N Engl J Med. 2011 Sep 29;365(13):1193–1200. doi: 10.1056/NEJMoa1102035.
9. Zatonski W, Cedzynska M, Tutka P, West R. An uncontrolled trial of cytisine (Tabex) for smoking cessation. Tob Control. 2006 Dec;15(6):481–484. doi: 10.1136/tc.2006.016097.
Galphimia glauca References
4 references
Generalized anxiety disorder
1. Herrera-Arellano A, Jiménez-Ferrer E, Zamilpa A, Morales-Valdéz M, García-Valencia CE, Tortoriello J. Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam. Planta Med. 2007 Jul;73(8):713–717. doi: 10.1055/s-2007-981539. Epub 2007 Jun 11.
2. Herrera-Arellano A, Jiménez-Ferrer JE, Zamilpa A, García-Alonso G, Herrera-Alvarez S, Tortoriello J. Therapeutic effectiveness of Galphimia glauca vs. lorazepam in generalized anxiety disorder. A controlled 15-week clinical trial. Planta Med. 2012 Sep;78(14):1529–1535. doi: 10.1055/s-0032-1315110. Epub 2012 Jul 24.
3. Romero-Cerecero O, Islas-Garduño AL, Zamilpa A, Herrera-Arellano A, Jiménez-Ferrer E, Tortoriello J. Galphimine-B standardized extract versus alprazolam in patients with generalized anxiety disorder: A ten-week, double-blind, randomized clinical trial. Biomed Res Int. 2019 Jan 30;2019:1037036. doi: 10.1155/2019/1037036.
Social anxiety disorder
4. Romero-Cerecero O, Islas-Garduño AL, Zamilpa A, Pérez-García MD, Tortoriello J. Therapeutic effectiveness of Galphimia glauca in young people with social anxiety disorder: A pilot study. Evid Based Complement Alternat Med. 2018;2018:1716939. doi: 10.1155/2018/1716939.
Kudzu References
6 references
Alcohol use disorder
1. Lukas SE, Penetar D, Berko J, Vicens L, Palmer C, Mallya G, Macklin EA, Lee DY. An extract of the Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers in a naturalistic setting. Alcohol Clin Exp Res. 2005;29(5):756–762.
2. Lukas SE, Penetar D, Su Z, Geaghan T, Maywalt M, Tracy M, Rodolico J, Palmer C, Ma Z, Lee DY. A standardized kudzu extract (NPI-031) reduces alcohol consumption in nontreatment-seeking male heavy drinkers. Psychopharmacology (Berl). 2013;226(1):65–73. doi: 10.1007/s00213-012-2884-9.
3. Penetar DM, Maclean RR, McNeil JF, Lukas SE. Kudzu extract treatment does not increase the intoxicating effects of acute alcohol in human volunteers. Alcohol Clin Exp Res. 2011;35(4):726–734. doi: 10.1111/j.1530-0277.2010.01390.x. Epub 2011 Jan 18.
4. Penetar DM, Toto LH, Farmer SL, Lee DY, Ma Z, Liu Y, Lukas SE. The isoflavone puerarin reduces alcohol intake in heavy drinkers: A pilot study. Drug Alcohol Depend. 2012 Nov 1;126(1–2):251–256. doi: 10.1016/j.drugalcdep.2012.04.012. Epub 2012 May 10.
5. Penetar DM, Toto LH, Lee DY, Lukas SE. A single dose of kudzu extract reduces alcohol consumption in a binge drinking paradigm. Drug Alcohol Depend. 2015;153:194–200. doi: 10.1016/j.drugalcdep.2015.05.025.
6. Shebek J, Rindone JP. A pilot study exploring the effect of kudzu root on the drinking habits of patients with chronic alcoholism. J Altern Complement Med. 2000;6(1):45–48. doi: 10.1089/acm.2000.6.45.
St. John’s Wort References
26 references
Major depressive disorder
1. Brenner R, Azbel V, Madhusoodanan S, Pawlowska M. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: A double-blind, randomized pilot study. Clin Ther. 2000;22(4):411–419. doi: 10.1016/S0149-2918(00)89010-4.
2. Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, Murck H, Rosenbaum JF. A double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. 2005 Oct;25(5):441–447. doi: 10.1097/01.jcp.0000178416.60426.29.
3. Gastpar M, Singer A, Zeller K. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: A double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry. 2006;39(2):66–75. doi: 10.1055/s-2006-931544.
4. Gastpar M, Singer A, Zeller K. Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry. 2005;38(2):78–86. doi: 10.1055/s-2005-837807.
5. Hänsgen KD, Vesper J, Ploch M. Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160. J Geriatr Psychiatry Neurol. 1994;7(Suppl 1):S15–S18. doi: 10.1177/089198879400700106.
6. Hypericum Depression Trial Study Group; Davidson JR, Gadde KM, Fairbank JA, Krishnan KRR, Califf RM, Binanay C, Parker CB, Pugh N, Hartwell TD, Vitiello B, Ritz L, Severe J, Cole JO, de Battista C, Doraiswamy PM, Feighner JP, Keck P, Kelsey J, Lin KM, Londborg PD, Nemeroff CB, Schatzberg AF, Sheehan DV, Srivastava RK, Taylor L, Trivedi MH, Weisler RH. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: A randomized controlled trial. JAMA. 2002 Apr 10;287(14):1807–1814. doi: 10.1001/jama.287.14.1807.
7. Kasper S, Anghelescu IG, Szegedi A, Dienel A, Kieser M. Superior efficacy of St John’s wort extract WS 5570 compared to placebo in patients with major depression: A randomized, double-blind, placebo-controlled, multi-center trial. BMC Med. 2006;4:14. doi: 10.1186/1741-7015-4-14.
8. Laakmann G, Schüle C, Baghai T, Kieser M. St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(Suppl 1):54–59. doi: 10.1055/s-2007-979346.
9. Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John’s wort extract WS 5570 in major depression: A double-blind, placebo-controlled trial. Am J Psychiatry. 2002;159(8):1361–1366. doi: 10.1176/appi.ajp.159.8.1361.
10. Montgomery SA, Hübner WD, Grigoleit HG. Efficacy and tolerability of St. John’s wort extract compared with placebo in patients with a mild to moderate depressive disorder. Phytomedicine. 2000;7(Suppl 2):107.
11. Philipp B, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ. 1999;319(7224):1534–1538. doi: 10.1136/bmj.319.7224.1534. Erratum in: BMJ. 2000;320(7231):361.
12. Schrader E, Meier B, Brattström A. Hypericum treatment of mild-moderate depression in a placebo-controlled study: A prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol. 1998;13(3):163–169. doi: 10.1002/(SICI)1099-1077(199804)13:3%3C163::AID-HUP5%3E3.0.CO;2-I.
13. Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: A randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15(2):61–68. doi: 10.1097/00004850-200015020-00001.
14. Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U. Effectiveness of St John's wort in major depression: A randomized controlled trial. JAMA. 2001 Apr 18;285(15):1978–1986. doi: 10.1001/jama.285.15.1978.
15. Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John’s wort): Randomised controlled double blind non-inferiority trial versus paroxetine. BMJ. 2005;330(7490):503. doi: 10.1136/bmj.38356.655266.82. Epub 2005 Feb 11. Erratum in: BMJ. 2005;330(7494):759. Dosage error in article text.
16. Uebelhack R, Gruenwald J, Graubaum HJ, Busch R. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: A double-blind, randomized, placebo-controlled clinical trial. Adv Ther. 2004 Jul–Aug;21(4):265–275. doi: 10.1007/BF02850158.
17. van Gurp G, Meterissian GB, Haiek LN, McCusker J, Bellavance F. St John's wort or sertraline? Randomized controlled trial in primary care. Can Fam Physician. 2002 May;48:905–912.
18. Vorbach EU, Hübner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: Randomized double-blind study with 135 outpatients. J Geriatr Psychiatry Neurol. 1994;7(Suppl 1):S19–S23. doi: 10.1177/089198879400700107.
19. Witte B, Harrer G, Kaptan T, Podzuweit H, Schmidt U. Behandlung depressiver Verstimmungen mit einem hochkonzentrierten Hypericumpräparat [Treatment of depressive symptoms with a high concentration hypericum preparation. A multicenter placebo-controlled double-blind study]. Fortschr Med. 1995 Oct 10;113(28):404–408. German.
20. Woelk H. Comparison of St John’s wort and imipramine for treating depression: Randomised controlled trial. BMJ. 2000;321(7260):536–539. doi: 10.1136/bmj.321.7260.536.
Perimenopausal symptoms
21. Abdali K, Khajehei M, Tabatabaee HR. Effect of St John’s wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: A randomized, double-blind, placebo-controlled study. Menopause. 2010;17(2):326–331. doi: 10.1097/gme.0b013e3181b8e02d.
22. Al-Akoum M, Maunsell E, Verreault R, Provencher L, Otis H, Dodin S. Effects of Hypericum perforatum (St. John's wort) on hot flashes and quality of life in perimenopausal women: A randomized pilot trial. Menopause. 2009 Mar–Apr;16(2):307–314. doi: 10.1097/gme.0b013e31818572a0.
23. Chung DJ, Kim HY, Park KH, Jeong KA, Lee SK, Lee YI, Hur SE, Cho MS, Lee BS, Bai SW, Kim CM, Cho SH, Hwang JY, Park JH. Black cohosh and St. John's wort (GYNO-Plus) for climacteric symptoms. Yonsei Med J. 2007 Apr 30;48(2):289–294. doi: 10.3349/ymj.2007.48.2.289.
24. Eatemadnia A, Ansari S, Abedi P, Najar S. The effect of Hypericum perforatum on postmenopausal symptoms and depression: A randomized controlled trial. Complement Ther Med. 2019;45:109–113. doi: 10.1016/j.ctim.2019.05.028. Epub 2019 May 31.
25. Uebelhack R, Blohmer JU, Graubaum HJ, Busch R, Gruenwald J, Wernecke KD. Black cohosh and St. John's wort for climacteric complaints: A randomized trial. Obstet Gynecol. 2006 Feb;107(2 Pt 1):247–255. doi: 10.1097/01.AOG.0000196504.49378.83.
26. van Die MD, Burger HG, Bone KM, Cohen MM, Teede HJ. Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: A randomized, controlled trial. Menopause. 2009;16(1):156–163. doi: 10.1097/gme.0b013e31817fa9e0.
Racetams References
16 references
Dyslexia
1. Ackerman PT, Dykman RA, Holloway C, Paal NP, Gocio MY. A trial of piracetam in two subgroups of students with dyslexia enrolled in summer tutoring. J Learn Disabil. 1991 Nov;24(9):542–549. doi: 10.1177/002221949102400906.
2. Di Ianni M, Wilsher CR, Blank MS, Conners CK, Chase CH, Funkenstein HH, Helfgott E, Holmes JM, Lougee L, Maletta GJ, Milewski J, Pirozzolo FJ, Rudel RG, Tallal P. The effects of piracetam in children with dyslexia. J Clin Psychopharmacol. 1985 Oct;5(5):272–278. doi: 10.1097/00004714-198510000-00004.
3. Helfgott E, Rudel RG, Krieger J. Effect of piracetam on the single word and prose reading of dyslexic children. Psychopharmacol Bull. 1984 Fall;20(4):688–690.
4. Wilsher C, Atkins G, Manfield P. Piracetam as an aid to learning in dyslexia. Preliminary report. Psychopharmacology (Berl). 1979 Sep;65(1):107–109. doi: 10.1007/BF00491989.
5. Wilsher CR, Bennett D, Chase CH, Conners CK, DiIanni M, Feagans L, Hanvik LJ, Helfgott E, Koplewicz H, Overby P, Reader MJ, Rudel RG, Tallal P. Piracetam and dyslexia: Effects on reading tests. J Clin Psychopharmacol. 1987 Aug;7(4):230–237. doi: 10.1097/00004714-198708000-00004.
ADHD in children
6. Zavadenko NN, Suvorinova NIu. [Atomoxetine and piracetam in the treatment of attention deficit hyperactivity disorder in children]. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(7):43–47. Russian.
Autism in children
7. Akhondzadeh S, Tajdar H, Mohammadi MR, Mohammadi M, Nouroozinejad GH, Shabstari OL, Ghelichnia HA. A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder. Child Psychiatry Hum Dev. 2008 Sep;39(3):237–245. doi: 10.1007/s10578-007-0084-3. Epub 2007 Oct 11.
Cognition
8. Barnas C, Miller C, Ehrmann H, Schett P, Günther V, Fleischhacker WW. High versus low-dose piracetam in alcohol organic mental disorder: A placebo controlled study. Psychopharmacology (Berl). 1990;100(3):361–365. doi: 10.1007/BF02244607.
9. Fesenko UA. Piracetam improves children’s memory after general anaesthesia. Anestezjol Intens Ter. 2009 Jan–Mar;41(1):16–21.
10. Fleischhacker WW, Günther V, Barnas C, Lieder F, Miller C. Piracetam in alcoholic organic mental disorder: A placebo controlled study comparing two dosages. Int Clin Psychopharmacol. 1986 Jul;1(3):210–215. doi: 10.1097/00004850-198607000-00003.
11. Szalma I, Kiss A, Kardos L, Horváth G, Nyitrai E, Tordai Z, Csiba L. Piracetam prevents cognitive decline in coronary artery bypass: A randomized trial versus placebo. Ann Thorac Surg. 2006 Oct;82(4):1430–1435. doi: 10.1016/j.athoracsur.2006.05.005.
12. Tang WK, Ungvari GS, Leung HC. Effect of piracetam on ECT-induced cognitive disturbances: A randomized, placebo-controlled, double-blind study. J ECT. 2002 Sep;18(3):130–137. doi: 10.1097/00124509-200209000-00004.
13. Uebelhack R, Vohs K, Zytowski M, Schewe HJ, Koch C, Konertz W. Effect of piracetam on cognitive performance in patients undergoing bypass surgery. Pharmacopsychiatry. 2003 May;36(3):89–93. doi: 10.1055/s-2003-39981.
Schizophrenia
14. Dimond SJ, Scammell RE, Pryce IG, Huws D, Gray C. Some effects of piracetam (UCB 6215, Nootropyl) on chronic schizophrenia. Psychopharmacology (Berl). 1979 Sep;64(3):341–348. doi: 10.1007/BF00427522.
15. Noorbala AA, Akhondzadeh S, Davari-Ashtiani R, Amini-Nooshabadi H. Piracetam in the treatment of schizophrenia: Implications for the glutamate hypothesis of schizophrenia. J Clin Pharm Ther. 1999 Oct;24(5):369–374. doi: 10.1046/j.1365-2710.1999.00238.x.
Tardive dyskinesia
16. Libov I, Miodownik C, Bersudsky Y, Dwolatzky T, Lerner V. Efficacy of piracetam in the treatment of tardive dyskinesia in schizophrenic patients: A randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2007 Jul;68(7):1031–1037. doi: 10.4088/jcp.v68n0709.
Enlyte References
3 references
Major depressive disorder
1. Mech AW, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2016 May;77(5):668–671. doi: 10.4088/JCP.15m10166.
Prevention of depression
2. Freeman MP, Savella GM, Church TR, Góez-Mogollón L, Sosinsky AZ, Noe OB, Kaimal A, Cohen LS. A prenatal supplement with methylfolate for the treatment and prevention of depression in women trying to conceive and during pregnancy. Ann Clin Psychiatry. 2019 Feb;31(1):4–16.
ADHD
3. Arroyo J, Miller J, Sangrey K, Nadeau Z, Olson M, Bargatze E, Muñoz L, Kay E, Farah A. Nutrigenomic-based coenzyme and cofactor monotherapy for children with ADHD. Journal of Childhood & Developmental Disorders. 2026;12(2):163.
Micronutrients References
16 references
ADHD
1. Johnstone JM, Hatsu I, Tost G, Srikanth P, Eiterman LP, Bruton AM, Ast HK, Robinette LM, Stern MM, Millington EG, Gracious BL, Hughes AJ, Leung BMY, Arnold LE. Micronutrients for attention-deficit/hyperactivity disorder in youths: A placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2022 May;61(5):647–661. doi: 10.1016/j.jaac.2021.07.005. Epub 2021 Jul 22. Erratum in: J Am Acad Child Adolesc Psychiatry. 2022 Aug;61(8):1066. doi: 10.1016/j.jaac.2022.04.021. Erratum in: J Am Acad Child Adolesc Psychiatry. 2023 May;62(5):607. doi: 10.1016/j.jaac.2022.12.009. Erratum in: J Am Acad Child Adolesc Psychiatry. 2023 Nov;62(11):1276. doi: 10.1016/j.jaac.2023.07.995.
2. Rucklidge JJ, Eggleston MJF, Johnstone JM, Darling K, Frampton CM. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: A fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry. 2018 Mar;59(3):232–246. doi: 10.1111/jcpp.12817. Epub 2017 Oct 2.
3. Rucklidge JJ, Frampton CM, Gorman B, Boggis A. Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: Double-blind randomised placebo-controlled trial. Br J Psychiatry. 2014;204:306–315. doi: 10.1192/bjp.bp.113.132126. Epub 2014 Jan 30.
Autism
4. Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr. 2011 Dec 12;11:111. doi: 10.1186/1471-2431-11-111.
Dementia
5. Cummings J, Passmore P, McGuinness B, Mok V, Chen C, Engelborghs S, Woodward M, Manzano S, Garcia-Ribas G, Cappa S, Bertolucci P, Chu LW. Souvenaid in the management of mild cognitive impairment: An expert consensus opinion. Alzheimers Res Ther. 2019 Aug 17;11(1):73. doi: 10.1186/s13195-019-0528-6.
6. Pardini M, Serrati C, Guida S, Mattei C, Abate L, Massucco D, Sassos D, Amore M, Krueger F, Cocito L, Emberti Gialloreti L. Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: A proof-of-concept study. Neurodegener Dis. 2015;15(1):58–62. doi: 10.1159/000369811. Epub 2015 Jan 15.
7. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, Harrison J, Swinkels SH, Stam CJ, de Waal H, Wurtman RJ, Wieggers RL, Vellas B, Kamphuis PJ. Efficacy of Souvenaid in mild Alzheimer's disease: Results from a randomized, controlled trial. J Alzheimers Dis. 2012;31(1):225–236. doi: 10.3233/JAD-2012-121189.
8. Shah RC, Kamphuis PJ, Leurgans S, Swinkels SH, Sadowsky CH, Bongers A, Rappaport SA, Quinn JF, Wieggers RL, Scheltens P, Bennett DA. The S-Connect study: Results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer's disease. Alzheimers Res Ther. 2013 Nov 26;5(6):59. doi: 10.1186/alzrt224.
Psychological functioning after trauma
9. Rucklidge JJ, Andridge R, Gorman B, Blampied N, Gordon H, Boggis A. Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Hum Psychopharmacol. 2012 Sep;27(5):440–454. doi: 10.1002/hup.2246. Epub 2012 Jul 11.
10. Rucklidge JJ, Blampied N, Gorman B, Gordon HA, Sole E. Psychological functioning 1 year after a brief intervention using micronutrients to treat stress and anxiety related to the 2011 Christchurch earthquakes: A naturalistic follow-up. Hum Psychopharmacol. 2014 May;29(3):230–243. doi: 10.1002/hup.2392. Epub 2014 Feb 19.
Stress management in healthy adults
11. Armborst D, Metzner C, Alteheld B, Bitterlich N, Rösler D, Siener R. Impact of a specific amino acid composition with micronutrients on well-being in subjects with chronic psychological stress and exhaustion conditions: A pilot study. Nutrients. 2018 Apr 29;10(5):551. doi: 10.3390/nu10050551.
Prevention of depression in pregnant women
12. El-Heis S, Barton SJ, Chang HF, Nield H, Cox V, Galani S, Cutfield W, Chan SY, Godfrey KM; NiPPeR Study Group. Maternal mood, anxiety and mental health functioning after combined myo-inositol, probiotics, micronutrient supplementation from preconception: Findings from the NiPPeR RCT. Psychiatry Res. 2024 Apr;334:115813. doi: 10.1016/j.psychres.2024.115813. Epub 2024 Feb 23.
13. Mitchell M, Bradley H, Blampied NM, Mulder RT, Rucklidge JJ. Protective effect of micronutrients used to treat antenatal depression on rates of postnatal depression at six months: A secondary analysis of NUTRIMUM. J Affect Disord. 2025 Nov 1;388:119560. doi: 10.1016/j.jad.2025.119560. Epub 2025 May 31.
14. Nguyen PH, DiGirolamo AM, Gonzalez-Casanova I, Pham H, Hao W, Nguyen H, Truong TV, Nguyen S, Harding KB, Reinhart GA, Martorell R, Ramakrishnan U. Impact of preconceptional micronutrient supplementation on maternal mental health during pregnancy and postpartum: Results from a randomized controlled trial in Vietnam. BMC Womens Health. 2017 Jun 17;17(1):44. doi: 10.1186/s12905-017-0401-3.
Premenstrual syndrome
15. Retallick-Brown H, Blampied N, Rucklidge JJ. A pilot randomized treatment-controlled trial comparing vitamin B6 with broad-spectrum micronutrients for premenstrual syndrome. J Altern Complement Med. 2020 Feb;26(2):88–97. doi: 10.1089/acm.2019.0305. Epub 2020 Jan 10.
Bipolar disorder
16. Frazier EA, Gracious B, Arnold LE, Failla M, Chitchumroonchokchai C, Habash D, Fristad MA. Nutritional and safety outcomes from an open-label micronutrient intervention for pediatric bipolar spectrum disorders. J Child Adolesc Psychopharmacol. 2013 Oct;23(8):558–567. doi: 10.1089/cap.2012.0098.
Xiao Yao San References
6 references
Generalized anxiety disorder
1. Hu J, Teng J, Wang W, Yang N, Tian H, Zhang W, Peng X, Zhang J. Clinical efficacy and safety of traditional Chinese medicine Xiao Yao San in insomnia combined with anxiety. Medicine (Baltimore). 2021 Oct 29;100(43):e27608. doi: 10.1097/MD.0000000000027608.
2. Wang Y, Chen X, Wei W, Ding Y, Guo R, Xing J, Wang J. Efficacy and safety of the Chinese herbal medicine Xiao Yao San for treating anxiety: A systematic review with meta-analysis and trial sequential analysis. Front Pharmacol. 2023 Oct 12;14:1169292. doi: 10.3389/fphar.2023.1169292.
Major depressive disorder
3. Qin F, Wu XA, Tang Y, Huang Q, Zhang ZJ, Yuan JH. Meta-analysis of randomized controlled trials to assess the effectiveness and safety of free and easy wanderer plus, a polyherbal preparation for depressive disorders. J Psychiatr Res. 2011 Nov;45(11):1518–1524. doi: 10.1016/j.jpsychires.2011.06.018. Epub 2011 Aug 5.
Post-stroke depression
4. Li LT, Wang SH, Ge HY, Chen J, Yue SW, Yu M. The beneficial effects of the herbal medicine free and easy wanderer plus (FEWP) and fluoxetine on post-stroke depression. J Altern Complement Med. 2008 Sep;14(7):841–846. doi: 10.1089/acm.2008.0010.
5. Bak J, Jin H, Yun JM, Leem J. Effects of modified Soyo-san (Xiao-yao-san, Shoyo-san) combined with antidepressants on post-stroke depression and functional recovery: A systematic review and meta-analysis. Front Pharmacol. 2026 Jan 2;16:1651831. doi: 10.3389/fphar.2025.1651831.
Bipolar depression
6. Zhang ZJ, Kang WH, Li Q, Tan QR. The beneficial effects of the herbal medicine free and easy wanderer plus (FEWP) for mood disorders: Double-blind, placebo-controlled studies. J Psychiatr Res. 2007 Nov;41(10):828–836. doi: 10.1016/j.jpsychires.2006.08.002. Epub 2006 Sep 29.
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