MTHFR is a genetic test that aims to clarify who will respond to methylfolate in depression. But is it worth testing for?

Publication Date: 05/05/2025

Duration: 18 minutes, 52 seconds 

KELLIE NEWSOME: Many patients have already had it done, and many more are asking for it. But does testing the MTHFR gene do any good? Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.   

CHRIS AIKEN: I’m Chris Aiken, the editor-in-chief of the Carlat Report.   

KELLIE NEWSOME:  And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Welcome to part III of our folate series, where we are doing a deep dive into the gene that activates folate in the liver, MTHFR. There are two common variants of this gene - C677T and A1298C, and like most genetic tests, the promise with MTHFR is big, but what it delivers is more complex. Patients are already coming in with the test done – often through naturopathic clinics – and determined that MTHFR is the explanation for all of their psychiatric problems. That is unlikely – but MTHFR does play a role in depression. MTHFR mutations increase the risk of depression by about 40% (Gilbody S et al., Am J Epidemiol 2007;165(1):1–13), and they are more common in depression. In the general population, the rate of major MTHFR problems is 30%–40%, but patients with depression have a higher prevalence—around 60% (Mischoulon D et al., CNS Spectr 2012;17(2):76–86). These mutations are even more common in people of Hispanic or Mediterranean descent. But MTHFR is not a black-or-white issue, as hematologist and folate expert Victor Hoffbrand explains.  

VICTOR HOFFBRAND: It depends on dose. It's not an all-or-nothing. If you give enough folic acid, you'll certainly get plenty of methylfolate made, even in those people, they don't have a complete block, otherwise, they wouldn't be alive.   

CHRIS AIKEN: Last week, we explained that methylfolate has better data in depression than folic acid and that MTHFR problems may be the reason why. But if Dr. Hoffbrand’s theory is right, you could get the same result just by upping the dose of folic acid. So far though, that has not been studied. Back to our question – is it worth testing the MTHFR gene in depression? One company that offers this test is Genesight, and they only test for one of the variants, the C677T polymorphism, not the A1298C. That is still important information – C677T predicts a greater risk of depression. What is missing is whether it predicts a greater response to methylfolate. The methylfolate trials did not compare people with the gene or without, and there are many other factors that predict response to methylfolate and don’t cost anything to assess.  

KELLIE NEWSOME: Clinical trials have found that patients with obesity (a BMI over 30) or inflammation (measured by a high sensitivity CRP over 3) are more likely to respond to methylfolate. During inflammation, the body uses up more folate, and it also doesn’t absorb it well, so serum levels tend to be low. Obesity changes how folate is distributed throughout the body and also lowers serum level, besides, obesity is often an inflamed state. Other predictors of methylfolate response are risk factors for low serum folate, like renal failure, gastrointestinal disease, alcohol use disorders – especially liquor drinkers, smoking, eating disorders, and poor nutrition. Also, a host of medications that mess up folate levels and metabolism: lamotrigine, valproate, carbamazepine, phenytoin, fluoxetine, oral contraceptives, methotrexate, metformin, sulfasalazine, warfarin, and triamterene. We spoke last week about how folic acid can interfere with lamotrigine, but there is no evidence that methylfolate does, and in a small, randomized trial of bipolar depression, adding methylfolate 15 mg to lamotrigine improved mood without causing any mania. So, the MTHFR gene is just one of many factors that may point to a methylfolate trial, and since this vitamin is low-cost and very well tolerated, it’s often best to try it and see. Start with 15 mg a day. Get a depression rating before starting it, like with the PHQ-9, and again a month later. If there’s a difference, long-term supplementation might be in order.  

CHRIS AIKEN: Folate is a B vitamin, but what exactly is a vitamin? Vitamins are organic compounds that the body needs in small amounts but cannot produce on its own. There are 13 vitamins: A, C, D, E, K, and another eight that are grouped in the B family. Folate is part of this B family, which includes thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12). The B vitamins play important roles in enzyme functions (that is what they all have in common). Deficiencies of most B vitamins are associated with depression, although we only test routinely for thiamine (B12) and folate (B9) because these are the most common deficiencies out there. In cases of B12 deficiency, it is best to defer to the primary care physician for treatment as some patients are not able to absorb the B12 vitamin and are going to require injections.  

KELLIE NEWSOME: One B-complex vitamin we think is worth knowing about is Enlyte. This branded product is FDA-cleared as a prescription food supplement for depression. It contains a low dose of l-methylfolate (7 mg) and also includes folic acid, folinic acid, B1, B2, B3, B6, and B12, as well as other nutrients with potential benefits in depression (iron, magnesium, zinc, coenzyme Q10, and omega-3 fatty acids). Although the doses included are low, Enlyte attempts to deliver them in more potent, bioactive forms. And there’s a remarkable clinical trial that shows it works.  

CHRIS AIKEN: This two-month trial is remarkable because it tested Enlyte on its own, without an antidepressant. It was a large trial, and it achieved a large effect size of 0.9, enrolling a mix of untreated depressives and some who had failed antidepressants. So far, this sounds too good to be true, but there’s a catch that harkens back to that genetic test. All of these patients had depression and MTHFR abnormalities – either the A1298C polymorphism or the one that we more commonly tested for, C677T (Mech AW and Farah A, J Clin Psychiatry 2016, 77(5):668-71).   

KELLIE NEWSOME: We’re impressed with that because of the large effect size and because Enlyte contains many ingredients that are known to treat depression on their own. Enlyte costs around $90 a month and is available through the manufacturer's website at enlyte.com or through most ePrescribing platforms. Patients may be able to get a month trial free through the website, and if they are taking other supplements that are already in Enlyte, like omega-3 they may be able to save costs by stopping them. Enylte’s manufacturer, JayMac Pharmaceuticals, also makes a version for peripartum depression, EnBrace HR, which is identical to Enlyte except for its marketing. It’s a promising direction for women, but so far, EnBrace HR has only a small open-label trial in peripartum depression. Time for a preview of the CME quiz for this episode. Start earning CME for each episode through the link in the show notes.   

TRUE or FALSE: Methylfolate is converted into s-adenosylmethionine (SAMe).  

CHRIS AIKEN: We started this podcast series with the hope of finding simple causes of depression that are due to deficiencies. Folate simply meets the mark here, but when you get into the metabolic details it can get hard to follow, so thanks for sticking with us through the end. It’s a complex area that is always changing, and I need to offer up, an important update on that note. A few years ago, at The Carlat Report, we printed a piece suggesting SAMe (S-adenosylmethionine) is one of the most effective natural treatments for depression. That was true based on the studies we had at the time. SAMe is one of the chemicals in the folate cycle, L-Methylfolate converts into SAMe, so in many ways, SAMe functions just like methylfolate, increasing the monoamines serotonin, norepinephrine, and dopamine, and decreasing the depressogenic homocysteine. But since then, new studies have come out that were negative for old SAMe in depression, including a new meta-analysis that where it came up wanting. The problem here is that most of SAMe’s studies were not placebo-controlled. They used active drugs as controls, including tricyclic antidepressants and SSRIs. Now, when something goes head to head against a tricyclic antidepressant and works, that seems impressive, but remember that the placebo effect is bigger than any antidepressant effect. And if the placebo is particularly strong in that trial, it might wash over any med effect and make all treatments look equally positive, which might have been what it did with SAMe.   

KELLIE NEWSOME: I think of it as looking at wallpaper in a bright red light. The red light in this analogy is the placebo. It’s powerful. It overpowers two different colors in the wallpaper, making everything look more or less red. Likewise, even effective antidepressants can look about as good as a dud when the placebo effect pushes both treatments in the study.  

CHRIS AIKEN: What Kellie just said there is called a failed trial when the situations and scenarios of the trial make the placebo effect so powerful that you can't even tell if the drug worked. So, all this is one explanation for SAMe’s failures. The bottom line in this new analysis of the research is that SAMe did not work so great in studies where it went against an actual placebo, but it did work in head-to-head drug comparisons, which are not as good a point of data to rely on, and the bottom line is that it suggests SAMe, doesn't do much at all and is not one of our most powerful natural treatments. On the other hand, the studies are many – over two dozen- but most are small, so we don’t have any definitive answers, and SAMe is involved in the same pathway that methylfolate is, so there is a possible explanation for how it might work in depression, and maybe it does work, we just can't say for sure at this point, and the data is not as positive as it is for L-Methylfolate, so we are moving L-Methylfolate up and SAMe down.  

KELLIE NEWSOME: Let’s focus on the SAMe trials that did include a placebo arm. These are a mix of positive and negative, with more negative trials in recent years. When averaged together in a meta-analysis, SAMe looks no better than a placebo (Peng TR et al., Gen Hosp Psychiatry 2024, 86:118-126). One reason for this inconsistency may have to do with the molecule itself. SAMe is more temperamental than most supplements, requiring blister packaging to protect it from heat and moisture and enteric coating to prevent stomach acids from degrading it.   

CHRIS AIKEN: On balance, I’d say that SAMe probably works, but the data is not as firm as it is for methylfolate, and since both address the same pathway, I would go with methylfolate. SAMe does have a role for patients with depression medical comorbidities, it has good studies in osteoarthritis and fibromyalgia, and some studies in liver disease, Parkinson’s disease, dementia, and HIV. SAMe targets specific aspects of these diseases through its anti-inflammatory, antioxidant, and neuroprotective properties. Most convincing in these studies are the ones involving osteoarthritis and fibromyalgia, where SAMe relieved both depression and pain in large, randomized trials. The analgesic effects were comparable to those of NSAIDs. For the other medical comorbidities, the benefits are less clear, and what we know is drawn from preclinical studies and small clinical trials.  

KELLIE NEWSOME: SAMe can also reduce sexual side effects on antidepressants (Dording CM et al., Eur Psychiatry 2012;27(6):451-454). SAMe is very well tolerated and safe. It has been safely combined with most classes of antidepressants, including the MAOIs, although, in theory, the MAOI-SAMe combination could cause serotonin syndrome. If you use SAMe, start 400 mg QD, raise by 200-400 mg every 3-7 days to a target dose of 800-1600 mg QD. Take on an empty stomach for better absorption. Dr. Aiken has links to lab-tested products on his website at chrisaikenmd.com/supplements. They are just links to products on Amazon and the like – he doesn’t sell them directly or profit from them. SAMe costs around $40-80 per month, and a lot of brick-and-mortar stores have 2-for-one sales on them.  

CHRIS AIKEN: And so, we end our folate journey, the little vitamin that an underappreciated scientist discovered from a bowl of marmite in 1931. From there, it grew to industrial production as a spinach extract. Doctors started measuring it in the 1960s, and they found many were lacking, particularly those with depression, schizophrenia, and dementia. Supplementation helped, especially when people didn’t respond to antidepressants, and patients can now get the bioactive form at a pretty low cost – methylfolate 15 mg a day.  

KELLIE NEWSOME: Along the way, SAMe got involved sometime in the late 1970s, promising to boost levels of serotonin, dopamine, and norepinephrine, and it probably works but with its mixed trials and fragile composition we recommend starting with methylfolate.   

CHRIS AIKEN: Folate is one of the rare examples in psychiatry where you can treat depression by addressing a known deficit. When it was first discovered, we thought that was the whole story and used folate to augment antidepressants when the serum levels were low. But we’ve learned there are many reasons why people might respond to folate supplementation. The MTHFR gene is one of them, and there are probably other factors, as yet undiscovered. The bottom line? Well, the bottom line is this. Methylfolate treats depression with the same effect size as an augmenting antipsychotic like aripiprazole, around 0.3-0.4 (if you're into effect sizes). And if your patient has an MTHFR deficit, like about half of people with depression do, that effect size rises to the large range, 0.9. Methylfolate has well-designed, large trials, and unlike the antipsychotics, it addresses a known dysfunction in the pathophysiology of depression.  

KELLIE NEWSOME: And unlike antipsychotics, it doesn’t cause tardive dyskinesia, diabetes, weight gain, neuroleptic malignant syndrome, arrhythmias, akathisia, anticholinergic effects, sedation, or temperature imbalance.   

CHRIS AIKEN: Oops, we forgot to mention hypotension, falls, sexual dysfunction, and hyperprolactinemia.   

KELLIE NEWSOME: So, on balance, we think it ought to be moved up in the treatment algorithm, the problem is that patients may not believe it works in our pharmacogenetic culture. So, it's up to you to give it that placebo boost. And if that means matching the treatment up with a low serum level or a MTHFR test, good on you. Victor Hoffbrand is emeritus Professor of Haematology at University College, London. He has authored over 700 scientific articles and chapters, several textbooks on hematology, and the 2023 book, The Folate Story: A Vitamin Under the Microscope. Like the podcast? Share it with a friend. Use the arrow button in your podcast player or read us a review. We read every one of them. And if you have topics you’d like to hear about, let us know at asktheeditor@thecarlatreport.com. The Carlat Report is one of the few CME publications that depends entirely on subscribers. Thank you for helping us stay free of commercial support.