The relationship between vitamin B9 (folate) supplementation and suicidality: a scoping review

Emerging real-world evidence suggests that folate supplementation may reduce suicidal ideation and behavior. We conducted a scoping review to evaluate current hypothesis-testing literature on folate supplementation and outcomes related to suicide.

We searched PubMed, Cochrane Library, APA PsycNet, ClinicalTrials.gov, and the International Clinical Trials Registry Platform from inception to February 15, 2025, to identify hypothesis-testing studies (ie, randomized, cohort, or case-control studies) that examined any oral folate formulation and reported a suicide-related endpoint.

Five studies met inclusion criteria: 1 randomized controlled trial (n = 475), 2 case-control studies (n < 20 each), and 2 large within-person cohort analyses (>800 000 adults). Interventions included folic acid 1 to 5 mg/day (3 studies) or folinic acid 1 to 2 mg/kg/day (2 studies). Three studies reported significant reductions in suicidal outcomes. One within-person cohort study found a 44% lower hazard of suicide-related emergency or hospital visits after treatment with folic acid (hazard ratio = 0.56) (and none in a parallel analysis of vitamin B12). A second within-person stratified reanalysis showed benefit in both patients with and without psychiatric histories. One case-control study of patients with a history of suicidal behavior and ideation found lower suicidal ideation questionnaire scores with folinic acid (P < 0.01). The randomized controlled trial and the other case-control study reported no significant benefit for suicide-related endpoints.

Evidence linking folate supplementation to reduced suicidal behavior is promising but limited by heterogeneity in design, sample size, folate formulation, and outcome measurement. Robust conclusions await large, pragmatic trials or extended real-world studies that integrate both suicidal behavior and mortality while comparing folate across diverse populations.