Emily Deans, MD
Clinical Instructor, Harvard Medical School
Dr. Deans has disclosed that she has no relevant financial or other interests in any commercial companies pertaining to this educational activity.
With an ongoing desire for “natural” products, and disappointment with the cost and efficacy of current prescription medications, more patients have turned to supplements. As a psychiatrist, the more you know about these supplements, the better you can have a conversation about their known risks and benefits.
One relatively new group of supplements is called the “nootropics,” otherwise known as “smart drugs” or “neuroenhancers.” Young urban professional men, and students, in particular, try these in order to sharpen cognitive function. Up to 16% of young adult US students use herbal or prescription cognitive enhancers to help with school work (Wise J, BMJ 2012;345:e753). Cognitive performance in sleep-deprived physicians, for instance, is enhanced with modafinil (Nuvigil) (Sugden et al, Ann Surg 2012;255(2):222–227). Some bioethicists support the use of these cognitive enhancers in healthy people (Chinthapalli K, BMJ 2013;346:f1743).
One of the most popular non-prescription nootropics is “Alpha Brain” (www.onnit.com/alphabrain), a mix of vitamin B6 and many herbs, most notably huperzia serrata. This herb is a natural cholinesterase inhibitor, similar in action to donepezil (Aricept) and other dementia medicines. Extracts of this plant are in phase I and II clinical trials for dementia.
Not surprisingly, Alpha Brain itself has no efficacy data, and a perusal of the scientific articles linked on its website shows many papers about theoretical applications of its numerous active ingredients. It’s the sort of supplement I would generally advise against, especially in combination with other medications.
Other natural acetylcholinesterase inhibitors include Lycoris radiate (red spider lily, a natural source of galantamine), and I’d recommend the same precautions with this.
Another purported nootropic is cannabis. Perhaps your patients, like many of mine, have insisted that smoking pot is good for the brain! Truth be told, marijuana is a decidedly mixed bag. While the tetrahydrocannabinol (THC) component of marijuana is likely neurotoxic and can precipitate psychosis (Arsenault L et al, BMJ 2002;325(7374):1212–1213), particularly in the genetically vulnerable, another major component of the plant, cannabidiol, is almost certainly neuroprotective via antioxidant and acetylcholine-elevating mechanisms (Iuvone T, J Neurochem 2004;89(1):134–141).
Cannabidiol does not have the psychoactive effects of THC. In fact, companies are working to cultivate cannabidiol-heavy and THC-light strains of marijuana for medicinal purposes. Studies of those strains should give us more information about what to tell our patients about cannabis, particularly for psychiatrists who practice in states where marijuana is legal for medicinal purposes.
Most nootropics—like the prescription psychostimulants—have the potential side effects of anxiety and insomnia, and others—like modafinil and armodafinil (Nuvigil)—can cause headaches as well. The cholinesterase inhibitors may potentially cause bradycardia, diarrhea, and hypotension. Cannabis has its obvious downsides.
And then there’s the question of ethics. Helping someone burn the candle at both ends for an extended period of time can be problematic, but some prescribers may agree with the bioethicists and feel that limited (off-label) use for certain performance situations is appropriate. Certainly I have prescribed low-dose stimulants for adjunctive treatment of depression, but for final exams? I don’t know. The bioethicists don’t have to deal with that one.
Most supplements that we classically think of as antioxidants—such as vitamin E—don’t actually work at the mitochondrial level to clean up the oxidative products of cellular respiration; rather, exposure to appropriate amounts of these vitamins brings forth the body’s own antioxidant systems.
It’s not uncommon to see older, well-educated individuals taking these along with their multivitamin and fish oil from the local pharmacy. These supplements include N-acetyl cysteine (NAC), alpha-lipoic acid (ALA, also found in milk thistle), and L-glutamine, among others.
NAC (previously reviewed in TCPR, Sept 2009) is familiar to doctors as the savior of acetaminophen overdosers in the ED. NAC can replenish the essential antioxidant glutathione in the liver as it is gobbled up by the toxic acetaminophen metabolite NAPQI. In the central nervous system, NAC is one of the few agents that can decrease glutamate, thus decreasing excitotoxicity, via the mechanism of a cysteine-glutamate antiporter. Trials of most agents, like D-cycloserine, that purport to decrease excitotoxicity via glutamate have been a disappointment.
NAC is inexpensive and available over the counter. It has a fairly remarkable track record of positive randomized placebo-controlled trials in trichotillomania, bipolar depression, and cocaine use, and is under investigation for treatment of OCD. In most of these studies (done in places like Yale, not the basement of the supplement company), NAC tends to have fewer side effects than placebo.
I’ve recommended NAC for trichotillomania (start with 600 mg bid and increase to up to a total of 3600 mg per day, if needed). Some formulations, like the prescription liquid from the emergency room, can have an awful rotten-egg smell and folks should buy a small amount before ordering it in bulk online.
Other indications will need to wait for better, larger, and replicated studies, but overall it seems to be a low-risk agent, at least for the short term. It appears to have no significant drug-drug interactions.
ALA is an antioxidant that has potential usages in neurodegenerative conditions, liver disease, and diabetes (Liu, Neurochem Res 2008;33:194–203). ALA can reduce insulin resistance and has some benefit in Parkinson’s disease, but as with NAC many of these investigations are preliminary. Side effects are few, and include a self-limited rash, possible hypoglycemia, and a drug-drug interaction with levothyroxine (Synthroid). Investigations of ALA are geared toward combination therapy with other mitochondrial boosters such as coenzyme Q10, or ubiquinone, which is a key player meeting our cellular energy requirements. ALA is generally safe, but it has questionable effectiveness in psychiatric disorders.
L-glutamine is used by bodybuilders and others trying to speed wound healing or to promote muscle growth. It is a peripheral-acting antioxidant that increases the availability of glutathione in the liver, much like NAC. Unfortunately, L-glutamine can be rapidly converted into glutamate in the brain, potentially worsening neuropsychiatric conditions associated with glutamate toxicity (such as psychosis, OCD, and dementia, among others). Given the availability of NAC, which is known to increase glutathione in the liver and actually decrease glutamate in the central nervous system, I advise my patients against taking L-glutamine as an antioxidant.
L-theanine is a derivative of green tea that readily crosses the blood-brain barrier. It has a similar structure to glutamate and can competitively inhibit glutamate at its receptors and transporters, reducing excitotoxicity. It potentiates and increases the levels of glycine in the CNS with similar neuroprotective effects and will also increase dopamine levels. L-theanine has been shown to increase the production of brain-derived neurotrophic factor (BDNF) in the hippocampus of rat brains (Wakabayashi C et al, Psychopharmacology 2012;219(4):1099–1109). In addition, like NAC, it increases intracellular glutathione and should have some antioxidant capabilities.
In a small Japanese study, L-theanine caused an increase in alpha waves and a subjective feeling of relaxation without sedation (Alt Med Rev 2005;10(2):136–138), somewhat similar to a “chemical yoga.” It’s been studied for anxiety and cognitive deficits in people with psychosis with positive effects (Ritsner MS et al, J Clin Psychiatry 2011;72:34–42). The typical recommended dose as a mild anxiolytic is 200 mg daily (some prefer a 100 mg divided dose). In the schizophrenia study, 400 mg daily was used to augment prescription antipsychotics and was well tolerated. My patients looking for a zoned-out, benzodiazepine-like feel are generally disappointed, but those who loathe the sedation of the benzos tend to be pleased.
Some supplements, like NAC, have exciting possibilities for otherwise difficult-to-treat conditions, such as trichotillomania. As a general rule, amino acid, oil, and vitamin supplements are relatively simple to distill and purify, compared to herbals such as St. Johns wort or huperzia serrata; these must be harvested at particular times of year and with care to isolate the active part of the plant and not toxic parts. This may be the problem causing hepatotoxicity in some preparations of the sleep aid, kava kava, for example (Fu S et al, World J Gastroenterol 2008;14(4):541–546). When patients insist on herbals, they can spend big bucks for pharmaceutical grade.
TCPR’s Verdict: A variety of complementary, low-risk interventions can supplement standard psychopharmacologic care. While they’re not studied nearly as rigorously as psychotropic medications—and their costs can be prohibitive—understanding the mechanisms of antioxidants, vitamins, minerals, and other supplements might help you to address novel biological pathways underlying mental illness, and to provide new alternatives for your patients.