L-Methylfolate for Depression: Does It Help?

meta-analysis PMID: 34794190

Quick Summary: Research suggests that adding L-methylfolate to your antidepressant medication might help improve your mood if you have major depressive disorder (MDD). This review of studies found that people taking L-methylfolate alongside their antidepressants were more likely to see an improvement in their symptoms.

What The Research Found

This study looked at several other studies to see if L-methylfolate could help people with depression. The main finding? People taking L-methylfolate along with their regular antidepressant medication were more likely to feel better than those taking a placebo (a sugar pill). Specifically, they had a 31% higher chance of seeing their depression symptoms improve. However, the study didn't find a big difference in how many people actually recovered from their depression.

Study Details

Who was studied: Adults diagnosed with major depressive disorder (MDD) who were already taking antidepressant medication.

How long: The length of the studies wasn't specified in the summary.

What they took: Participants took either L-methylfolate (7.5 mg or 15 mg daily) or a placebo, in addition to their regular antidepressant medication.

What This Means For You

Talk to your doctor: If you're struggling with depression and your current medication isn't fully working, talk to your doctor. L-methylfolate might be an option to discuss.

It's not a cure-all: While this research is promising, it's important to remember that L-methylfolate might not work for everyone.

Don't self-medicate: Always consult with a healthcare professional before starting any new supplement or medication.

Study Limitations

More research is needed: The study authors noted that more high-quality research is needed to confirm these findings.

Study quality: Some of the studies included in the review were funded by pharmaceutical companies, which could potentially introduce bias.

Variability: The results varied quite a bit between the different studies, which makes it harder to draw firm conclusions.

Not for everyone: The study only looked at adults with MDD. It's not known if L-methylfolate would have the same effect on other types of depression or in different age groups.

Limited scope: The study only looked at English-language studies, which could have missed important research.

Key Findings

This meta-analysis found that adjunctive L-methylfolate (7.5–15 mg/day) significantly improved antidepressant response rates in adults with major depressive disorder (MDD), with a 31% higher likelihood of response compared to placebo (risk ratio [RR] 1.31, 95% CI 1.10–1.55, p=0.002). However, remission rates were not statistically different between groups. The study concluded that L-methylfolate may offer modest efficacy as an augmentation strategy for MDD but noted limitations in data quality and heterogeneity.

Study Design

The study was a systematic review and meta-analysis of randomized controlled trials (RCTs) published up to December 31, 2020. It followed PRISMA guidelines and included nine peer-reviewed English-language studies (total N=6,707 patients). Meta-analysis focused on three RCTs reporting categorical Hamilton Rating Scale for Depression-17 (HRSD-17) response data. Study durations were not specified in the summary, but all trials evaluated L-methylfolate as adjunctive therapy to antidepressants.

Dosage & Administration

L-methylfolate was administered orally at doses of 7.5 mg/day (low dose) or 15 mg/day (high dose) across studies. The supplement was used alongside antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or other antidepressants) for MDD treatment.

Results & Efficacy

Response Rates: Meta-analysis of three RCTs showed a statistically significant benefit for L-methylfolate (RR 1.31, 95% CI 1.10–1.55, p=0.002), indicating a 31% increased probability of achieving a ≥50% reduction in HRSD-17 scores.
Remission Rates: No significant difference was observed between L-methylfolate and placebo (RR 1.20, 95% CI 0.96–1.50, p=0.10).
Heterogeneity: High variability across studies (I²=63%), suggesting differences in trial design, patient populations, or dosing protocols.

Limitations

Study Quality: Most included trials were funded by pharmaceutical companies, potentially introducing bias.
Heterogeneity: Significant statistical variability (I²=63%) in response outcomes limited confidence in pooled effect sizes.
Sample Demographics: Population was restricted to adults with MDD; no data on adolescents, elderly, or non-MDD depressive disorders.
Duration & Follow-Up: Long-term efficacy and safety beyond trial periods (not specified in summary) remain unclear.
Publication Bias: Only English-language studies were included, risking exclusion of relevant non-English or unpublished research.

Clinical Relevance

For adults with MDD experiencing partial response to antidepressants, adding L-methylfolate (7.5–15 mg/day) may modestly improve symptom reduction. However, the lack of significant remission benefits and high heterogeneity suggest cautious interpretation. Clinicians should consider individual patient factors, such as folate status or genetic polymorphisms (e.g., MTHFR variants), which were not analyzed here. Users should avoid self-medication, as prescription antidepressants and professional monitoring are critical. The study highlights the need for larger, longer-term RCTs to confirm efficacy and guide standardized use.

Source: https://pubmed.ncbi.nlm.nih.gov/34794190/ (PubMed, 2022)

L-Methylfolate for Depression: Does It Help?