Folate deficiency has been associated with a higher risk of depressive symptoms, irritability, and other mood disturbances, likely through its role in one‑carbon metabolism, monoamine neurotransmitter synthesis, and methylation processes in the brain. Clinical and epidemiologic studies have found that people with low folate or elevated homocysteine are more likely to experience major depression, and lower folate status has been linked to poorer response to certain antidepressant medications. The encouraging clinical point is that, in folate‑deficient individuals, correcting folate status (often with folic acid or methylfolate, and alongside vitamin B12 when indicated) may improve mood symptoms and, in some cases, enhance antidepressant treatment response, especially when combined with comprehensive psychiatric and lifestyle interventions. This medication is commonly used for Diabetes.
David Mischoulon, Maurizio Fava. Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues. The Journal of Clinical Psychiatry. 2009. Gao S, Khalid A, Amini-Salehi E, Radkhah N, Jamilian P, Badpeyma M, Zarezadeh M. Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses. Food Sci Nutr. 2024 Mar 8;12(6):3806-3818. Reynolds EH, Crellin R, Bottiglieri T, Laundy M, Toone BK, et al. Methylfolate as Monotherapy in Depression. A Pilot Randomised Controlled Trial. J Neurol Psychol. 2015;3(1): 5. Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ. 2002 Jun 22;324(7352):1512-5. Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007 Jul;61(7):631-7.
Some side effects may be linked to nutrient depletion caused by this medication.
Long term treatment with Biguanides, such as Metformin or Metformin combinations with other drugs, are found in research to reduce vitamin B12 absorption due to it hindering the activity of a calcium-dependent mechanism. Insufficient levels of vitamin B12 can lead to higher circulating homocysteine levels and the elevated risk of neurological problems and cardiovascular diseases.
Biguanide (anti-diabetic) drugs have been found in scientific evidence to decrease serum levels of coenzyme Q10. Type 2 diabetes can increase oxidative stress in the body, weakening its defenses and potentially harming cells. CoQ10, a powerful antioxidant, plays a crucial role in protecting cells from this damage. CoQ10 supplementation may help restore these levels, potentially improving mitochondrial function and protecting the kidneys from damage.
Research has shown that anti-diabetic Biguanide drugs may reduce folic acid absorption. Folic acid is a powerful antioxidant and low levels make the body more susceptible to oxidative stress, which can damage enzymes involved in homocysteine metabolism, and subsequently increase its accumulation. Elevated levels of homocysteine (hyperhomocysteinemia) are a risk factor for various health problems including cardiovascular diseases, neurological problems, osteoporosis, and vision problems.
Biguanides, such as Metformin or Metformin combinations with other drugs, may contribute to reduced levels of thiamine (vitamin B1) in end-stage renal failure patients. Research has found metformin encephalopathy present in patients on hemodialysis for end-stage diabetic renal failure (ESRD). Patients with ESRD should consider having thiamine (vitamin B1) status monitored and supplementing with thiamine when levels are insufficient or deficient.