Introduction
In mental health, few nutrients are as misunderstood as folate and vitamin B6. Patients and providers alike sometimes worry that folate will “activate” mania or worsen psychiatric symptoms. A new randomized controlled trial (Akbarzadeh et al., 2025) provides important evidence to the contrary: folate supplementation actually improved mania outcomes in patients with bipolar I disorder.
Even more compelling, the trial used synthetic folic acid and standard pyridoxine (B6)—not the advanced forms that we now know are more effective and better tolerated. This distinction highlights both the potential of nutrient-based interventions and the pitfalls of using the wrong form of a vitamin.
What the Trial Found
The study enrolled 43 patients hospitalized with acute mania. All patients received sodium valproate, and were randomized to one of three groups:
- Folate (5 mg/day)
- Folate (5 mg/day) + pyridoxine (80 mg/day)
- Placebo
Results after 6 weeks:
- Folate alone significantly reduced manic symptoms compared to placebo.
- 100% of patients in the folate group achieved a ≥50% reduction in their mania scores, compared to 21.4% in placebo.
- Adding pyridoxine (synthetic B6) blunted folate’s effect, offering no additional advantage.
This study directly challenges the myth that folate “activates” mania. In fact, it showed the opposite: folate was therapeutic and led to recovery (Akbarzadeh et al., 2025).
Why B6 Likely Failed: The Vitamin B6 Paradox
The disappointing results with B6 can be explained by genetics and biochemistry.
- The form used in the trial was pyridoxine hydrochloride, not the active form.
- Pyridoxine must be converted into pyridoxal-5-phosphate (P5P), the metabolically active coenzyme form used in neurotransmitter synthesis.
- Genetic differences in pyridoxal kinase can impair this conversion.
- Worse still, high doses of pyridoxine can actually compete for the enzyme, leading to “enzyme clogging” that blocks activation and induces cellular stress and apoptosis. This phenomenon, known as the Vitamin B6 Paradox, explains why high-dose pyridoxine can mimic symptoms of B6 deficiency—such as numbness, tingling, or neuropathy (Vrolijk et al., 2017).
Thus, what the trial demonstrates is not that B6 is ineffective, but rather that the wrong form of B6 can neutralize the potential benefit of folate.
Genetics Matter: MTHFR, MTHFD1, and FOLR1
Why is folate metabolism so critical in mental health? Genetics help answer this question.
- MTHFR (methylenetetrahydrofolate reductase):
One of the best-known folate-related genes. Variants like C677T and A1298C reduce the conversion of folate into 5-MTHF, the form needed for neurotransmitter methylation. These patients benefit from methylfolate directly, rather than synthetic folic acid (DeVos et al., 2008). - MTHFD1 (methylenetetrahydrofolate dehydrogenase 1):
This gene supports de novo thymidylate biosynthesis, essential for DNA repair and brain health. Mutations can impair folate cycling in the nucleus, limiting neurotransmitter synthesis and increasing psychiatric vulnerability (Field et al., 2015). - FOLR1 (folate receptor alpha):
Critical for transporting folate into the central nervous system. Variants and autoantibodies against FOLR1 are linked to cerebral folate deficiency and neuropsychiatric disorders, including autism. Treatment with folinic acid(reduced folate) has been shown to improve outcomes (Rossignol & Frye, 2021).
When we connect these genetic insights with the trial findings, the case becomes stronger: patients with MTHFR, MTHFD1, and FOLR1 variants would likely not benefit from synthetic folic acid, yet they could respond powerfully to folinic acid or methylfolate, as found in advanced formulations.
Why Active Forms Matter
At Neuro Nutrients, our Complete Methylation Support formula contains:
- Two advanced forms of folate: folinic acid and methylfolate, both bypassing common MTHFR and MTHFD1 gene variants.
- The active form of B6 (P5P), which is ready for cellular use without requiring conversion, avoiding the B6 paradox.
If the trial had used methylated folate plus P5P, the clinical effect might have been even stronger—and without the risks of enzyme competition and paradoxical deficiency.
Key Takeaway for Mental Health
- Folate is not destabilizing. On the contrary, it may help resolve mania.
- The form of B vitamins matters: synthetic folic acid and pyridoxine are outdated and potentially problematic.
- Genetics such as MTHFR, MTHFD1, and FOLR1 explain why some patients fail standard supplementation and highlight the importance of bioactive forms.
- Using methylfolate, folinic acid, and P5P supports neurotransmitter balance, methylation, and mood regulation without the risks seen in older trials.
This new study reinforces the promise of targeted, nutrient-based strategies in psychiatry—when done with the right forms, in the right patients.
References
Akbarzadeh, F., Talaei, A., Nematy, M., Ganji, D., Ebrahimi, A., & Talaei, A. (2025). Short-term effects of folate supplementation in combination with vitamin B6 for treating acute manic episodes in bipolar I disorder: A randomized controlled trial. Brain and Behavior, 15(e70432). https://doi.org/10.1002/brb3.70432
DeVos, L., Chanson, A., Liu, Z., et al. (2008). Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations. American Journal of Clinical Nutrition, 88(4), 1149–1158. https://pmc.ncbi.nlm.nih.gov/articles/PMC2728423/
Field, M. S., Kamynina, E., Watkins, D., Rosenblatt, D. S., & Stover, P. J. (2015). Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proceedings of the National Academy of Sciences, 112(13), 400–409. https://doi.org/10.1073/pnas.1414555112
Rossignol, D. A., & Frye, R. E. (2021). Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: A systematic review and meta-analysis. Journal of Personalized Medicine, 11(8), 686. https://doi.org/10.3390/jpm11080686
Vrolijk, M. F., Opperhuizen, A., Jansen, E. H., Hageman, G. J., Bast, A., & Haenen, G. R. (2017). The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicology in Vitro, 44, 206–212. https://doi.org/10.1016/j.tiv.2017.07.004
