- L-methylfolate is the form of folate that circulates in the blood. In the US it is sold as Deplin, a "medical food". Medical foods do not go through FDA premarket approval (FDA), so Deplin has never been approved as a treatment for depression.
- The main positive evidence is two linked US trials in people whose depression had not responded to an SSRI. At 7.5 mg a day (148 people) there was no benefit. At 15 mg a day (75 people) number needed to treat about 6 (Papakostas 2012).
- Plain folic acid has the strongest negative trial. In FolATED, a publicly funded UK trial of 475 people, adding 5 mg folic acid to an antidepressant for 12 weeks did not improve any outcome (Bedson 2014).
- Independent reviews find a small signal at best. A 2018 NIHR-supported meta-analysis rated all the evidence "low or very low" quality (Roberts 2018).
- MTHFR gene testing is widely marketed alongside methylfolate. The American College of Medical Genetics and Genomics (ACMG) says the evidence does not support routine MTHFR testing (ACMG 2013; 2020 addendum). The CDC says people with MTHFR variants can process folic acid (CDC).
- Money trail: ClinicalTrials.gov lists Pamlab, L.L.C., Deplin's original maker, as a collaborator on both Papakostas trials (NCT00321152; NCT00955955). An independent 2012 review says many methylfolate articles were underwritten by Pamlab. Pamlab was bought by Nestlé Health Science in 2013 (Nestlé) and by Italy's Alfasigma in 2017 (Alfasigma).
- Evidence grade: Weak for L-methylfolate 15 mg added to an SSRI. Moderate (against) for folic acid added to antidepressants in people who are not deficient. Insufficient for MTHFR-guided treatment and for methylfolate on its own. Risk of missing a vitamin B12 deficiency.
Independent evidence review · Supplement
L-methylfolate at 15 mg a day may add a small benefit when an SSRI antidepressant has not worked well enough, but the case rests largely on one 75-person trial whose trials list the maker as a registry collaborator, and a sister trial at a lower dose was negative. High-dose folic acid failed in a large, publicly funded UK trial. Independent reviewers grade the whole evidence base as low or very low quality, and no regulator has approved any folate product for depression. MTHFR gene tests, often used to justify methylfolate, are not recommended by medical geneticists. The most useful independent message is different: low vitamin B12 or folate can itself contribute to low mood and should be tested for and treated properly. Our confidence: low that L-methylfolate helps; moderate that folic acid does not help people with normal folate levels.
Table of contents
- Evidence summary
- What folate, folic acid and L-methylfolate are, and their legal status
- How it might work
- What works and what does not
- Benefits by claim
- Risks and all side effects
- All interactions
- Who should avoid high-dose folate
- Doses studied and product quality
- Follow the money: who makes it and who funded the evidence
- Related research
- Frequently asked questions
- Sources and funding notes
Evidence summary
| Claim | Evidence | Source | Funding / conflict | Strength |
|---|---|---|---|---|
| L-methylfolate 15 mg added to an SSRI improves depression that has not responded | Trial 2 (n=75, 60 days): number needed to treat about 6 (abstract). Trial 1 (n=148, 7.5 mg then 15 mg): no significant difference. | Papakostas 2012 | ClinicalTrials.gov lists Pamlab (the maker) as a collaborator on both trials. An independent 2012 review says many methylfolate articles were underwritten by Pamlab. The paper's funding statement is paywalled. | Weak |
| Folate of any kind added to antidepressants helps (pooled trials) | Only folic acid under 5 mg/day, or methylfolate 15 mg with an SSRI, beat placebo. All evidence graded low or very low. No placebo trials of folate alone. | Roberts 2018 | Europe PMC lists an NIHR grant; full author disclosures not accessed. | Weak |
| L-methylfolate augmentation (meta-analysis) | Response RR 1.25 (95% CI 1.08 to 1.46; 3 studies, n=483 for the response analysis): a small effect. The symptom-score figure could not be verified and is not quoted. | Maruf 2022 | Author affiliations and funding statement were not verified in this check. | Weak |
| High-dose folic acid (5 mg) improves antidepressant outcomes | 475 adults, 12 weeks, primary and secondary care in Wales: no improvement on any measure; SF-12 mental health score 3.0% worse (95% CI −5.2% to −0.8%). | FolATED, Bedson 2014 | NIHR Health Technology Assessment programme (UK public funding). | Moderate (against the claim) |
| Folic acid boosts fluoxetine | 127 people, 500 mcg folic acid for 10 weeks: overall benefit, confined to women (good response 93.9% vs 61.1%). | Coppen & Bailey 2000 | Academic (UK); funding statement not accessed. | Weak |
| MTHFR genotype tells you who needs methylfolate | The C677T variant is modestly associated with depression (OR 1.36). No independent trial shows genotype-guided folate improves outcomes. ACMG advises against routine MTHFR testing. | Gilbody 2007; ACMG 2013 | Academic meta-analysis; professional society guideline | Insufficient |
| B12 supplements lift mood in people who are not deficient | Of 16 trials (6,276 people) in the review, six reported depression outcomes (one B12 alone, five B-complex): no overall effect on depression scores. | Markun 2021 | No external funding; no conflicts declared (Switzerland). | Moderate (against the claim) |
| High-dose folic acid can hide B12 deficiency | Folic acid can improve the anaemia and mask B12 deficiency, which can otherwise damage the nervous system (NHS). EFSA keeps an upper limit of 1,000 mcg/day of folic acid and methylfolate combined. | NHS; EFSA 2023 | UK government; EU food-safety agency | Risk |
| Methylfolate may trigger agitation or mood elevation | Three case vignettes of agitation and mood elevation (full text not opened). | Psychiatric Times 2020 | Case vignettes in a trade journal; no systematic data | Risk (low certainty) |
Independent evidence and credibility scorecard
Independence tiers: 1 = regulator or government body; 2 = academic or Cochrane team with no declared commercial funding for the work; 3 = independent authors analysing mostly manufacturer-run trials, or minor declared industry ties; 4 = manufacturer-funded or manufacturer-authored. Credibility runs from A (highest) to D.
| Source | Who funds it | Country | Independence tier (1–4) | Credibility (A–D) | Why it would tell the truth / residual bias |
|---|---|---|---|---|---|
| FDA: Frequently Asked Questions About Medical Foods (3rd edition, 2023) | US government | US | 1 | A | Sets the legal rules for medical foods. Says nothing about whether any product works. |
| CDC: MTHFR gene variant and folic acid facts | US government | US | 1 | A | No product to sell. Written mainly to defend folic acid for preventing birth defects, not about depression. |
| NICE NG239: Vitamin B12 deficiency in over 16s (2024) | UK Department of Health and Social Care (via NICE) | UK | 1 | A | Independent guideline committee with a declared-interests process. Covers B12, not folate treatment of depression. |
| EFSA: Tolerable upper intake level for folate (2023) | EU agency (public body) | EU | 1 | A | Systematic review of harms with formal uncertainty analysis. Most data concern folic acid rather than methylfolate. |
| FolATED trial (Bedson 2014) | NIHR Health Technology Assessment programme | UK | 2 | A | Publicly funded (NIHR) trial that published a null result. Tested folic acid, not methylfolate, and excluded people who were deficient. |
| Taylor et al., Cochrane review (2003) | Funding statement not checked | UK | 2 | B− | No folate-industry ties declared; one author reported funding from SSRI makers. Only 3 trials (247 people). It predates the 2012 methylfolate trials. |
| Roberts, Carter & Young 2018 meta-analysis | NIHR grant (per Europe PMC record) | UK | 2 | B | Graded evidence with GRADE and tested dose subgroups openly. Questioned on language bias by the Cochrane lead author (Taylor 2018). |
| Markun et al. 2021 (B12 meta-analysis) | No external funding; University of Zurich | Switzerland | 2 | B+ | No conflicts declared, data openly shared. Looked at people without overt deficiency, so it does not test treatment of real deficiency. |
| ACMG practice guideline on MTHFR testing (2013; addendum 2020) | American College of Medical Genetics and Genomics (professional society) | US | 2 | A− | Geneticists recommending against a genetic test, which is an admission against professional interest. Its focus is clotting risk, not depression. |
| CANMAT 2023 depression guideline update | Funding statement not checked in this review | Canada | 2 | B | Funding and author ties not checked in this review. Guideline grades not checked in this review. |
| Maruf et al. 2022 meta-analysis | Funding statement not accessed; author affiliations not verified in this check | Canada (author affiliations) | 2 | B− | Small, pre-specified pooled effects reported honestly as "modest". |
| Papakostas et al. 2012 (two trials) | Pamlab listed as collaborator on both registry entries (NCT00955955; NCT00321152) | US | 3 | B− | Double-blind, and both trials were published together. But the positive trial had only 75 people, and the maker's role is unverified in this check. |
Note on clustering: the placebo-controlled L-methylfolate trials pooled in the reviews we read come mainly from one US network of academic psychiatrists whose maker involvement we could not confirm in this check. The independent trial evidence (FolATED, Cochrane, Roberts) is almost entirely from the UK and is about folic acid. No large publicly funded trial of L-methylfolate itself exists that we could find.
What folate, folic acid and L-methylfolate are, and their legal status
"Folate" is the umbrella name for vitamin B9. It comes in several forms:
- Folic acid: the synthetic form used in supplements and fortified food. In the UK it is available on prescription, and some folic acid supplements can be bought in shops and pharmacies (NHS).
- L-methylfolate (also called 5-MTHF, L-5-methyltetrahydrofolate or levomefolate): the main form of folate in blood. Calcium L-methylfolate is an authorised nutrient source for food supplements and fortified foods in the EU (EFSA 2023). The best-known branded ingredient is Metafolin.
- Deplin: a US product containing L-methylfolate. Its maker's website was not opened in this check (Deplin website). Product strengths were not verified in this check (Deplin FC). A separate product, DeplinPRO, was not checked in this review (DeplinPRO).
What "medical food" means
The term comes from the US Orphan Drug Act. A medical food is meant for a disease with "distinctive nutritional requirements" established by medical evaluation, used under a doctor's supervision (FDA medical-foods FAQ). FDA says it reads this definition narrowly. Key points from the same FDA guidance and its consumer advice:
- Medical foods do not undergo FDA premarket approval (FDA consumer update).
- The statutory definition describes a medical food as used under a physician's supervision for a condition with "distinctive nutritional requirements" (FDA FAQ). We could not verify the FAQ's labelling wording in this check.
- FDA does not maintain a comprehensive list of medical food products (same source).
So "prescription medical food" is a marketing and pharmacy-channel description, not an FDA approval. FDA has not formally ruled, as far as we could find, on whether depression has "distinctive nutritional requirements". An independent critic argued in 2012 that it does not (Carlat Report).
Status by country
| Place | Status | Source |
|---|---|---|
| United States | L-methylfolate is sold as a dietary supplement and as "medical foods" such as Deplin. No folate product is FDA-approved for depression. | FDA |
| European Union | Calcium L-methylfolate and a glucosamine salt of 5-MTHF are authorised folate sources in supplements. The 1,000 mcg/day upper limit covers folic acid and these forms combined. | EFSA 2023 |
| United Kingdom | Folic acid is available on prescription and in shops. We could not open NICE's adult depression guideline (NG222) recommendations page (403), so we could not confirm whether it mentions folate or methylfolate. | NHS; NICE NG222 |
| Canada (clinical guidance) | CANMAT 2023 placement of L-methylfolate was not checked in this review. | CANMAT 2023 |
How it might work
The idea is biologically reasonable but unproven as an explanation for any benefit in depression.
- The theory: folate is needed for the "one-carbon" cycle that makes S-adenosylmethionine (SAMe) and helps recycle a cofactor (BH4) used to make serotonin, dopamine and noradrenaline. Low folate has long been linked with depression and poorer antidepressant response (Coppen 2000).
- The marketing extension: promotional material has implied that L-methylfolate is essential for BH4 and is the only form of folate that crosses into the brain. An independent review in The Carlat Report called neither claim "entirely true", noting BH4 can be made by other routes (Carlat Report).
- In humans: a post-hoc analysis of the positive 75-person trial suggested methylfolate worked better in people with obesity, higher inflammation markers or certain folate-pathway gene variants (Papakostas 2014). The authors themselves said confirmatory studies were needed. Many subgroups were tested in a small sample, so chance findings are likely.
- Why folic acid might differ: the FolATED team suggested methylfolate might be a better candidate than folic acid after their null result (Bedson 2014). No head-to-head trial of methylfolate vs folic acid in depression has been published that we could find.
What works and what does not
| Claimed benefit | Verdict | Evidence | Key caveat |
|---|---|---|---|
| L-methylfolate 15 mg added to an SSRI | MIXED | Number needed to treat about 6 in 75 people (Papakostas 2012); pooled response RR 1.25 (Maruf 2022) | Maker-linked; 7.5 mg trial negative; 60 days only |
| Folic acid added to antidepressants (not deficient) | DOES NOT WORK | No benefit in 475 people (FolATED) | Older, smaller trials were positive |
| Any folate on its own instead of an antidepressant | INSUFFICIENT | No placebo-controlled monotherapy trials (Roberts 2018) | One study of 96 people compared folate with trazodone; no significant benefit for folate |
| Treating a proven B12 or folate deficiency | WORKS (for the deficiency) | Standard NHS treatment; B12 deficiency can cause depression and anxiety (NHS) | Treats the deficiency; mood effects not trial-proven |
| B12 in people without deficiency | DOES NOT WORK | No effect on depression in the six trials that measured it (Markun 2021) | Short trials, mostly older adults |
| MTHFR test to choose treatment | INSUFFICIENT | Not recommended by ACMG (ACMG) | Only post-hoc, maker-linked data |
Benefits by claim
Does L-methylfolate (Deplin) work as an add-on to antidepressants?
Possibly, a little, at 15 mg a day. The 2012 paper reported two trials in outpatients whose depression had partly or fully failed to respond to an SSRI (Papakostas 2012). Both used a "sequential parallel comparison design", a two-phase method meant to reduce the placebo effect.
- Trial 1 (148 people): L-methylfolate 7.5 mg a day (one group stepped up to 15 mg for the second 30 days). No significant difference from placebo.
- Trial 2 (75 people): 15 mg a day throughout. Response was higher than on placebo, with a number needed to treat of about 6 (abstract). In plain terms, about 1 extra person in 6 responded.
Pamlab, which made Deplin, is listed as a collaborator on both registry entries (NCT00955955; NCT00321152). A 12-month open-label extension reported full recovery in 38% (26 of 68) with no control group (Zajecka 2016). With no control group, this cannot separate the effect of methylfolate from time, the SSRI or natural recovery.
Pooled analyses agree on a small effect. Maruf and colleagues found a response risk ratio of 1.25 (95% CI 1.08 to 1.46) (Maruf 2022; a secondary review reports the same figure; we could not confirm their symptom-score result). A separate review mixing methylfolate and folic acid reported a 2.16-point larger fall on the Hamilton scale (95% CI 0.69 to 3.62) and a response RR of 1.36 (Altaf 2021; funding statement not accessed). Guideline bodies have reviewed it, but we could not confirm their grades in this check: the WFSBP/CANMAT nutraceutical taskforce (Sarris 2022) and CANMAT 2023 (CANMAT 2023).
Does folic acid help depression?
Not in people with normal folate levels, on the best evidence. The 2003 Cochrane review found only three trials with 247 people. In the two add-on trials (151 people), adding folate to other treatment cut Hamilton scores by a further 2.65 points (95% CI 0.38 to 4.93). A separate outcome, a 50% fall in score at ten weeks, had relative risk 0.47 (95% CI 0.24 to 0.92) and a number needed to treat of 5 (Taylor 2003, Cochrane). The reviewers said folate may have a role but that it was unclear whether this applied to people without folate deficiency.
The biggest contributing trial gave 500 mcg folic acid with fluoxetine to 127 people. The benefit was confined to women (Coppen & Bailey 2000).
The UK's FolATED trial then tested 5 mg folic acid in 475 adults starting or taking antidepressants. People who were folate- or B12-deficient were excluded. After 12 weeks there was no improvement on any depression, health or cost measure (Bedson 2014). The authors wrote that the result undermines guidelines that recommend folic acid for depression.
A later meta-analysis found a benefit only in narrow subgroups: folic acid below 5 mg a day, or methylfolate 15 mg with an SSRI. All the evidence was graded low or very low quality (Roberts 2018). The Cochrane review's lead author published a response on language bias in this meta-analysis (Taylor 2018). We could not access those trials.
Does an MTHFR gene variant mean you need methylfolate?
No reliable evidence says so. MTHFR is the enzyme that turns folate into L-methylfolate. The common C677T variant is very common: the CDC says more people in the US carry one or two copies than carry none (CDC).
- Association, not prediction: people with two copies (TT) had 1.36 times the odds of depression compared with CC (95% CI 1.11 to 1.67) in a meta-analysis of 1,280 cases (Gilbody 2007). That is a modest link and does not show that the variant causes depression in any one person.
- Folic acid still works in carriers: the CDC says people with MTHFR variants can process all types of folate, including folic acid. The CDC says daily folic acid intake matters more for blood folate levels than the MTHFR variant (CDC).
- Testing not recommended: the ACMG concluded that MTHFR testing has minimal clinical utility for its main use, clotting risk, and reaffirmed this in 2020 (ACMG 2013; 2020 addendum).
- Only maker-linked data on genotype and response: the claim that gene variants predict methylfolate response comes from a post-hoc analysis of the 75-person, Pamlab-collaborator trial (Papakostas 2014). FolATED planned to test genetic predictors of folic-acid response, but its main results showed no benefit to predict (FolATED report).
More broadly, the FDA warned in November 2018 that the link between DNA variations and antidepressant effectiveness "has never been established". In April 2019 it sent a warning letter to a Virginia lab over pharmacogenetic tests with unapproved claims about antidepressants (BioPharma Dive, 2019).
Can low vitamin B12 cause depression?
It can contribute. NICE NG239 notes that B12 deficiency can be associated with depression, anxiety and psychosis (NICE NG239). But in people who are not deficient, B12 or B-complex supplements did not improve depression scores in the six trials that measured mood, within a review of 16 trials and 6,276 people (Markun 2021). The practical point is testing, not routine supplementing.
Does it help schizophrenia or bipolar depression?
These are outside the scope of this review. We could not verify the grade the WFSBP/CANMAT taskforce gave methylfolate for negative symptoms in schizophrenia (Sarris 2022). For bipolar disorder, see the safety section below.
Risks and all side effects
Other effects:
- Common, with folic acid tablets: bloating, wind, nausea and loss of appetite. Liquids can also cause diarrhoea, vomiting and an itchy rash (NHS).
- Rare: a more serious allergic reaction called anaphylaxis (NHS).
- In trials: L-methylfolate side-effect rates were no different from placebo over 60 days (Papakostas 2012). The Cochrane review found no evidence of safety problems in the trials it identified (Cochrane).
- Worse mental-health score: in FolATED, the SF-12 mental health score was 3.0% lower on folic acid than on placebo (Bedson 2014). This was a secondary measure and may be chance.
- Delay to effective treatment: using a folate product in place of an antidepressant or therapy has no trial support (Roberts 2018).
All interactions
Interaction data are almost all for folic acid. We found no formal interaction studies for high-dose L-methylfolate.
| Medicine | What can happen | Source |
|---|---|---|
| Epilepsy medicines (phenytoin, phenobarbital, primidone) | Listed by the NHS as medicines that may not mix well with folic acid; ask the prescriber before combining. | NHS |
| Antibiotics (chloramphenicol, co-trimoxazole) | Listed by the NHS as possible interactions. | NHS |
| Sulfasalazine | Listed by the NHS as a possible interaction. | NHS |
| Lithium | Listed by the NHS as a possible interaction. Relevant because lithium is used in bipolar disorder and resistant depression. | NHS |
| Aspirin | Listed by the NHS as a possible interaction. | NHS |
| Methotrexate | Folic acid is deliberately prescribed to reduce methotrexate side effects ; do not add extra folate without the prescriber. | NHS |
| Antidepressants (SSRIs) | No harmful interaction reported in the add-on trials; L-methylfolate was studied alongside unchanged SSRI doses. | Papakostas 2012 |
Who should avoid high-dose folate
- Anyone with vitamin B12 deficiency anaemia or pernicious anaemia: the NHS says folic acid medicines may not be suitable (NHS).
- People with cancer or a coronary stent: both are listed by the NHS as reasons folic acid medicines may not be suitable (NHS).
- People with bipolar disorder: case reports of agitation and mood elevation (Psychiatric Times). Use only with the psychiatrist's knowledge.
- Pregnancy: standard folic acid is recommended before and in early pregnancy. Folic acid is the only form of folate shown to help prevent neural tube defects (Medscape summary citing CDC genetics experts). We found no safety trials of 7.5–15 mg L-methylfolate in pregnancy; the depression trials did not study it.
- Breastfeeding: we found no data on high-dose methylfolate. Ask a doctor or pharmacist before using any folate product.
- Children: The age range on Deplin's label was not verified in this check (Deplin), but the depression trials enrolled adults (Zajecka 2016: adult participants). EFSA's upper limits for children are lower, from 200 to 800 mcg a day by age (EFSA 2023).
- People on the interacting medicines above, especially epilepsy medicines and methotrexate.
Doses studied and product quality
These are doses used in trials or stated on product material, not advice.
- L-methylfolate add-on trials: 7.5 mg a day (not effective) and 15 mg a day (positive trial), for 60 days, alongside an unchanged SSRI (Papakostas 2012). The open-label extension continued 15 mg for up to 12 months (Zajecka 2016).
- Folic acid trials: 500 mcg a day with fluoxetine (Coppen 2000); 5 mg a day for 12 weeks (FolATED).
- Older trial in the Cochrane review: one study of 96 people compared folate with trazodone and found no significant benefit from folate (Cochrane).
- Upper limit for comparison: 1,000 mcg (1 mg) a day for adults from supplements and fortified food, covering folic acid and methylfolate together (EFSA 2023). Studied methylfolate doses are 7.5 to 15 times higher. That is not proof of harm, but it means they should be used with medical supervision and a B12 check.
Product quality and "generic" versions
Because medical foods and supplements do not go through drug approval, dose accuracy and form are not checked by FDA before sale (FDA). Folate exists in two mirror-image forms. We found no independent laboratory survey of L-methylfolate content in US products.
Follow the money: who makes it and who funded the evidence
Who makes and sells it
- Pamlab (US): developed Deplin. Nestlé Health Science bought Pamlab in 2013, describing Deplin as a medical food for "certain people on prescribed antidepressant therapy"; terms were not disclosed (Nestlé USA).
- Alfasigma (Italy): bought Pamlab from Nestlé. Reuters reported the acquisition on 13 January 2017 (Alfasigma press release). Deplin is now made and distributed by Alfasigma USA.
Who funded the trials and reviews
- Papakostas 2012: both registry entries list Pamlab as a collaborator (NCT00321152; NCT00955955). The 12-month extension drew on the same trials (Zajecka 2016). A 2012 independent review said many articles promoting the methylfolate story were "underwritten by Pamlab" (Carlat Report).
- FolATED: NIHR Health Technology Assessment programme only (Bedson 2014).
- Cochrane 2003: Funding statement not checked in this review. One author declared research funding from Sanofi-Aventis and GlaxoSmithKline, makers of antidepressants rather than folate (Cochrane).
- Maruf 2022: affiliations and funding statement were not verified in this check (Maruf 2022).
- Guidelines: CANMAT 2023 funding statement not checked in this review (CANMAT 2023).
Documented integrity events and marketing
- FDA and genetic tests: FDA's November 2018 safety communication and April 2019 warning letter to Inova Genomics Laboratory over unapproved claims that tests could guide antidepressant choice (BioPharma Dive). We found no FDA warning letter to Deplin's makers.
Research funding at a glance
12 sources graded. The counts below are the independence tiers assigned in the scorecard above. They count sources, not funding amounts or evidence quality.
Public funding alone does not prove independence, and commercial funding alone does not prove a claim false. Named funders, countries and relationships are in the scorecard and source notes.
The pattern is clear. The trials behind the positive methylfolate claim involved the maker. The independent, publicly funded work tested folic acid and was largely negative, or dealt with safety and B12. That gap, rather than any proof that methylfolate fails, is the main reason our confidence is low.
Related research
For wider, evidence-graded context, see these Pure City Research guides:
- Major depressive disorder: assessment, treatment evidence and safety
- Treatment-resistant depression
- Supplements for stress, anxiety and depression: the evidence
- SAMe (S-adenosylmethionine)
- Saffron for depression
- St John's wort
- Omega-3
- Vitamin D
- Atrophic and autoimmune gastritis: B12 and follow-up
- Bipolar depression
- Perinatal depression
- Lithium
Frequently asked questions
Does L-methylfolate actually work for depression?
It may add a small benefit to an SSRI at 15 mg a day. In the one positive trial the number needed to treat was about 6, but a trial at 7.5 mg found no effect, and the maker was a collaborator (Papakostas 2012). Independent reviewers rate the evidence low or very low quality (Roberts 2018).
Is Deplin FDA-approved?
No. It is sold as a medical food, and medical foods do not undergo FDA premarket approval (FDA). The statutory definition assumes physician supervision (FDA FAQ).
Is L-methylfolate better than folic acid for depression?
Unknown. No published trial has compared them head to head in depression that we could find. Folic acid failed in the large FolATED trial (Bedson 2014), while methylfolate's best data come from small, maker-linked trials.
Should people get an MTHFR test for depression?
Medical geneticists advise against routine MTHFR testing (ACMG). The variant is very common, and the CDC says carriers can still process folic acid (CDC). No independent trial shows that testing improves depression outcomes.
Can low B12 or folate cause depression?
Yes, deficiency can contribute. NICE NG239 notes that B12 deficiency can be associated with depression and anxiety (NICE NG239). A blood test is the way to find out. Extra B12 does not help mood in people who are not deficient (Markun 2021).
Can high-dose folate be harmful?
It can hide B12 deficiency while nerve damage progresses, which is why B12 is checked before folic acid treatment (NHS). The European upper limit is 1,000 mcg a day; studied methylfolate doses are 7,500–15,000 mcg (EFSA 2023).
Can L-methylfolate cause anxiety, agitation or mania?
Clinicians have reported agitation and mood elevation in case reports (Psychiatric Times 2020). These are case reports; in the 60-day trials, side effects were similar to placebo (Papakostas 2012).
Can people take methylfolate instead of an antidepressant?
There is no placebo-controlled evidence for folate of any kind on its own for depression (Roberts 2018). Talk to your prescriber before changing any treatment.
Sources and funding notes
What we could not verify directly: the Maruf funding statement and affiliation details; the CANMAT 2023 and WFSBP/CANMAT grades; the full author disclosures for Roberts 2018 and Taylor 2018; the full text of the Psychiatric Times case article (summary only); the NICE NG222 page (returned 403); the FDA 2018 safety communication, which we checked through trade-press reporting rather than the FDA page; and the Alfasigma release text (the January 2017 date is from Reuters coverage). Records checked against PubMed or Europe PMC abstracts, ClinicalTrials.gov, the EFSA 2023 opinion summary and the NHS folic acid page include the Papakostas, FolATED, Roberts, Gilbody, Maruf, Cochrane, Coppen, Markun, Zajecka and Altaf records, the Pamlab collaborator listings, and the 2013 Nestlé and 2017 Alfasigma acquisitions.
- Papakostas GI et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012 — key positive trial; Pamlab listed as collaborator on both registry entries.
- ClinicalTrials.gov NCT00955955 and NCT00321152 — trial registrations; sponsors and collaborators.
- Papakostas GI et al. Adjunctive L-methylfolate by biomarker and genotype. J Clin Psychiatry 2014 — post-hoc analysis of trial 2; maker-linked trial.
- Zajecka JM et al. 12-month open-label L-methylfolate 15 mg. J Clin Psychiatry 2016 — uncontrolled extension of maker-linked trials; funding statement not accessed.
- Taylor MJ, Carney S, Geddes J, Goodwin G. Folate for depressive disorders. Cochrane 2003 (PubMed) — University of Oxford / NHS; no external funding; one author with SSRI-maker funding.
- Roberts E, Carter B, Young AH. Caveat emptor: folate in unipolar depressive illness. J Psychopharmacol 2018 — NIHR grant per Europe PMC.
- Taylor MJ. Language bias and comprehensive meta-analysis of folate for unipolar depression. J Psychopharmacol 2018 — published comment.
- Bedson E et al. FolATED: randomised trial and economic evaluation. Health Technol Assess 2014 (full report) — NIHR HTA only.
- Coppen A, Bailey J. Enhancement of fluoxetine by folic acid. J Affect Disord 2000 — academic; funding not accessed.
- Maruf AA et al. Meta-analysis of L-methylfolate augmentation. Pharmacopsychiatry 2022 — funding and affiliations not verified in this check.
- Altaf R et al. Folate as adjunct to SSRI/SNRI: meta-analysis. Complement Ther Med 2021 — US university authors; funding not accessed.
- Sarris J et al. WFSBP and CANMAT taskforce guidelines on nutraceuticals and phytoceuticals. World J Biol Psychiatry 2022 — professional societies; individual disclosures not reviewed here.
- Lam RW et al. CANMAT 2023 update on adult major depressive disorder. Can J Psychiatry 2024 — funding statement not checked in this review.
- Hickey SE et al. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 2013 and 2020 addendum — professional society.
- Gilbody S et al. MTHFR polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 2007 — academic (UK).
- Markun S et al. Vitamin B12 supplementation and depressive symptoms: meta-analysis. Nutrients 2021 — no external funding.
- NICE NG239: Vitamin B12 deficiency in over 16s (March 2024) — UK public body.
- NICE NG222: Depression in adults (June 2022) — UK public body; folate content not checked.
- EFSA NDA Panel. Scientific opinion on the tolerable upper intake level for folate. EFSA Journal 2023 — EU agency.
- FDA. Frequently Asked Questions About Medical Foods; Third Edition (March 2023) and FDA: Is it really FDA approved? — US regulator.
- CDC: MTHFR gene variant and folic acid facts — US government.
- NHS: Folic acid; side effects; B12 or folate deficiency anaemia: symptoms; treatment — UK public health service.
- Balt S. Deplin: is it just folate by another name? The Carlat Psychiatry Report, 2012 — independent clinical newsletter.
- Psychiatric Times, L-methylfolate augmenting agent may contribute to agitation and mania, March 2020 (author names not verified) — clinician case vignettes in a trade publication.
- Nestlé USA: Nestlé Health Science acquires Pamlab (2013) — company release.
- Alfasigma: acquisition of Pamlab from Nestlé Health Science (January 2017) — company release.
- BioPharma Dive: FDA warns Virginia lab over marketing of genetic test (April 2019) — trade press reporting FDA actions.
Educational research reviewed 6 October 2026. This article is not medical advice; talk to a qualified clinician or pharmacist before starting, stopping or combining treatments.
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