L-Methylfolate in Diabetic Peripheral Neuropathy: A Narrative Review

Objective: One of the most frequently occurring complications of diabetes mellitus is peripheral neuropathy. Despite the painful symptoms associated with diabetic peripheral neuropathy (DPN), the current treatment landscape focuses on managing symptoms without addressing the underlying causes of DPN. This narrative review describes the mechanistic effects and clinical trial data sup-porting the use of L-methylfolate calcium (LMF), the bioactive form of folate, which is available in the United States as a prescription medical food that also contains other B vitamins for the dietary management of DPN.Methods: Preclinical and clinical trial data evaluating the impact of LMF on DPN were identified using PubMed searches for articles published between 2010 and 2023. Search terms included: folate, LMF, diabetes, neuropathy, and neuropathic pain. Additionally, a literature search was conducted to identify studies related to LMF, genetic polymorphisms, and DPN pathophysiology.Results: Several studies show that the C677T variant of the methylenetetrahydrofolate reductase gene is linked to greater risk of DPN than other methylenetetrahydrofolate reductase variants due to its inhibitory effects on several folic acid metabolic pathways. One double-blind, randomized controlled trial, 5 open-label studies, and 1 retrospective study found that LMF has a significant beneficial effect on DPN that extends beyond symptomatic relief to include modulating the under-lying pathophysiology that leads to the progression and symptoms of DPN. LMF also significantly improves patient quality of life, with minimal adverse effects.Conclusion: Preclinical and clinical studies have found that LMF can be used to treat the underlying causes of DPN and provide long-lasting symptomatic relief.& COPY; 2023 AACE. Published by Elsevier Inc. All rights reserved.