Metformin & B12: Could Your Diabetes Meds Be Causing Nerve Pain?

review PMID: 40697600

Quick Summary: Research shows that a common diabetes medication, metformin, can lower vitamin B12 levels. This can lead to nerve damage and pain, especially in the feet and legs. Taking B12 supplements may help.

Metformin, B12, and Nerve Pain: What's the Link?

If you take metformin for type 2 diabetes, you could be at risk for low vitamin B12. This is because metformin can interfere with how your body absorbs B12. Low B12 can damage nerves, leading to a condition called diabetic neuropathy. This can cause:

Pain, tingling, or numbness in your feet and legs

Weakness in your muscles

Problems with balance

Study Details

Who was studied: People with type 2 diabetes who take metformin.

How long: The research looked at studies over various time periods.

What they took: Some studies used oral cyanocobalamin (a type of B12) at a dose of 500 mcg to 1 mg daily for 12-24 weeks.

What This Means For You

Talk to your doctor: If you take metformin and have nerve pain, ask your doctor to check your B12 levels.

Consider B12 supplements: If your B12 is low, taking a supplement could help reduce your nerve pain and improve nerve function.

Don't self-treat: Always talk to your doctor before starting any new supplements.

Early detection is key: Addressing B12 deficiency early can help prevent nerve damage from getting worse.

Study Limitations

More research is needed: While the link between metformin, B12, and nerve pain is clear, more studies are needed to confirm the best dosage and long-term effects of B12 supplements.

Small studies: Some of the studies on B12 supplements were small, so the results may not apply to everyone.

Not a cure: B12 supplements may help, but they may not completely reverse nerve damage.

Clinical Evidence

The 2025 review “Metformin‑induced vitamin B12 deficiency: An underdiagnosed cause of diabetic neuropathy” synthesizes data from observational cohorts, case‑control studies, and a limited number of interventional trials that examined vitamin B12 status in patients with type 2 diabetes mellitus (T2DM) receiving metformin. The authors report that up to 30 % of long‑term metformin users develop biochemical B12 deficiency (serum B12 < 200 pg/mL), and that deficiency correlates with higher neuropathy scores (e.g., Michigan Neuropathy Screening Instrument mean difference ≈ 2.1 points, p < 0.01) compared with metformin‑treated patients with normal B12 levels. Several small supplementation trials (n = 30–120 participants) demonstrated that oral cyanocobalamin (500 µg daily) for 12–24 weeks improved nerve conduction velocity (average increase 2.5 m/s, p = 0.04) and reduced neuropathic pain scores (mean reduction 1.5 points on a 10‑point VAS, p = 0.03) in deficient individuals. The review emphasizes that these improvements are observed only when deficiency is confirmed; borderline B12 levels (200–300 pg/mL) show variable response. The authors conclude that systematic B12 screening in T2DM patients with neuropathy is warranted, and that supplementation is a low‑cost, safe intervention that can mitigate neuropathy progression when deficiency is present.

Mechanisms of Action

Metformin interferes with the calcium‑dependent absorption of the B12‑intrinsic factor complex in the terminal ileum, leading to reduced serum B12 and subsequent impairment of myelin synthesis and neuronal repair. B12 deficiency reduces methylmalonyl‑CoA mutase activity, leading to accumulation of methylmalonic acid, which is neurotoxic. Additionally, B12 is a co‑factor for methionine synthase; its deficiency reduces S‑adenosyl‑methionine (SAM) production, compromising phospholipid synthesis essential for myelin integrity. The review cites mechanistic studies showing that B12 repletion restores methylmalonic acid levels, improves mitochondrial function in peripheral nerves, and enhances nerve conduction by supporting myelin sheath regeneration.

Safety Profile

The review reports that oral cyanocobalamin at doses up to 1 mg daily is well tolerated, with adverse events reported in <2 % of participants (mild gastrointestinal upset). No serious adverse events or clinically relevant drug‑drug interactions were identified in the cited trials. The review notes that high‑dose parenteral B12 (≥1 mg intramuscularly) may cause transient hyper‑methylation in rare cases, but no adverse outcomes were reported in the included studies. Contraindications are limited to known hypersensitivity to cobalamin preparations.

Dosage Information

The review summarizes that most interventional studies used oral cyanocobalamin 500 µg daily for 12–24 weeks, with some trials employing 1 mg daily for severe deficiency. Administration was oral, with no requirement for fasting. In cases of severe deficiency (serum B12 < 100 pg/mL), some studies employed intramuscular 1 mg weekly for 4 weeks followed by oral maintenance, though data are limited. The review suggests that supplementation be initiated once serum B12 < 200 pg/mL or when functional markers (elevated methylmalonic acid) indicate deficiency.

Evidence Quality Assessment

The evidence derives primarily from observational studies and a few small‑scale randomized controlled trials (RCTs) with limited sample sizes (n ≈ 30–120). While the association between metformin use and B12 deficiency is consistently reported across cohorts, the interventional data on neuropathy improvement are limited to short‑term, low‑power RCTs. Consequently, the evidence for clinical benefit of B12 supplementation in metformin‑induced deficiency is moderate: strong observational support for the deficiency‑neuropathy link, but limited high‑quality RCT data on therapeutic efficacy. Further large‑scale, double‑blind RCTs are needed to confirm dose‑response relationships and long‑term outcomes.