Metformin can affect this through 2 different nutrient pathways: Vitamin B12, Folic Acid. This medication is commonly used for Diabetes.
Each nutrient below contributes to this impact through a different mechanism.
Neurological symptoms like depression, cognitive impairment, and peripheral neuropathy often signal low or deficient vitamin B12 status, with tingling or numbness in extremities being particularly common. These effects stem from B12's vital role in myelin synthesis and nerve protection; without it, demyelination occurs, leading to neurotoxicity via oxidative stress and neuronal damage. Population studies show up to 20% of older adults with low B12 exhibit cognitive decline, underscoring the need for early monitoring to prevent irreversible neurological harm.
Jatoi S, Hafeez A, Riaz SU, Ali A, Ghauri MI, Zehra M. Low Vitamin B12 Levels: An Underestimated Cause Of Minimal Cognitive Impairment And Dementia. Cureus. 2020 Feb 13;12(2):e6976. Boumenna T, Scott TM, Lee JS, Palacios N, Tucker KL. Folate, vitamin B-12, and cognitive function in the Boston Puerto Rican Health Study. Am J Clin Nutr. 2021 Jan 4;113(1):179-186. Nalder L, Zheng B, Chiandet G, Middleton LT, de Jager CA. Vitamin B12 and Folate Status in Cognitively Healthy Older Adults and Associations with Cognitive Performance. J Nutr Health Aging. 2021;25(3):287-294. Esnafoglu, E. and Ozturan, D.D. (2020), The relationship of severity of depression with homocysteine, folate, vitamin B12, and vitamin D levels in children and adolescents. Child Adolesc Ment Health, 25: 249-255. Khosravi M, Sotoudeh G, Amini M, Raisi F, Mansoori A, Hosseinzadeh M. The relationship between dietary patterns and depression mediated by serum levels of Folate and vitamin B12. BMC Psychiatry. 2020 Feb 13;20(1):63. Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Yoon JS. Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry. 2008 Apr;192(4):268-74.
In some adults, chronic folate deficiency has been linked to neurological manifestations such as peripheral neuropathy, gait disturbance, and subtle to more overt cognitive impairment, especially in older age. Cohort studies have reported that low serum or red cell folate, and elevated homocysteine, correlate with worse performance on memory and executive‑function tests, and may be associated with increased risk of vascular dementia. The encouraging aspect is that, when folate deficiency is identified early and corrected alongside vitamin B12 when needed, some patients experience improvement in neuropathic symptoms and stabilization or modest gains in cognitive performance, particularly when other vascular risk factors are also addressed.
Boumenna T, Scott TM, Lee JS, Palacios N, Tucker KL. Folate, vitamin B-12, and cognitive function in the Boston Puerto Rican Health Study. Am J Clin Nutr. 2021 Jan 4;113(1):179-186. Alves Maues AC, Moren Abat MG, Benlloch M, Mariscal G. Folate Supplementation for Peripheral Neuropathy: A Systematic Review. Nutrients. 2025 Oct 20;17(20):3299. Mottaghi T, Khorvash F, Maracy M, Bellissimo N, Askari G. Effect of folic acid supplementation on nerve conduction velocity in diabetic polyneuropathy patients. Neurol Res. 2019 Apr;41(4):364-368. Manzoor M, Runcie J. Folate-responsive neuropathy: report of 10 cases. Br Med J. 1976 May 15;1(6019):1176-8. Kang WB, Chen YJ, Lu DY, Yan JZ. Folic acid contributes to peripheral nerve injury repair by promoting Schwann cell proliferation, migration, and secretion of nerve growth factor. Neural Regen Res. 2019 Jan;14(1):132-139.
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.