Methylcobalamin, the active form of vitamin B12, shows promise in managing peripheral nerve discomfort. Multiple studies indicate its effectiveness in improving clinical signs and symptoms, with better outcomes compared to other B vitamins (Jia Hai-yan, 2016; Yu Sun et al., 2005). Methylcobalamin's mechanism of action involves modulating neuroinflammation, regulating immune cell activity, and reducing pain symptoms by affecting ion channels and receptors in dorsal root ganglion neurons (Amilia Ramadhani et al., 2024). It has demonstrated positive effects on both somatic and autonomic symptoms, including pain and paresthesia (Yu Sun et al., 2005). Additionally, methylcobalamin appears to be safe for long-term use with minimal adverse effects (Suresh Vyloppilli et al., 2021).

• Hai-yan, Jia. “Effects of Methylcobalamin on Diabetic Peripheral Neuropathy: A Systematic Review.” Chinese Journal of Evidence-Based Medicine (2016): n. Pag.
  
• Sun, Y., Lai, M. S., & Lu, C. J. (2005). Effectiveness of Vitamin B12 on Diabetic Neuropathy: Systematic Review of Clinical Controlled Trials. Acta Neurologica Taiwanica, 14(2), 48-54.
• Ramadhani, Amilia et al. “Methylcobalamin as a candidate for chronic peripheral neuropathic pain therapy: review of molecular pharmacology action.” The Korean Journal of Pain 37 (2024): 299 - 309.
• Vyloppilli, Suresh et al. “Safety and Efficacy of Methylcobalamin in the Treatment of Peripheral Nerve Injuries and Diabetic Neuropathies - A Systematic Review.” Acta Scientific Pharmaceutical Sciences (2021): n. pag.

Additional Studies

"Ultra-high dose methylcobalamin promotes nerve health. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis." - Source: Ultra-high dose methylcobalamin promotes nerve regeneration (Department of Neurology, Kyoto University Hospital, Japan.)

"These findings indicate that methyl-B12 promotes the health of nerve terminals." - Source: Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals (Laboratory Animal Research Center, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.)

Benfotiamine, a lipid-soluble thiamine derivative, has shown promising effects on peripheral nerve health. High-dose benfotiamine (320 mg/day) demonstrated significant improvement in pain sensation and vibration perception in diabetic patients with painful neuropathy over a 6-week period (Winkler et al., 1999). Studies have demonstrated that benfotiamine can significantly improve motor nerve conduction velocity, inhibit advanced glycation end-product (AGE) formation, and prevent glycoxidation products in diabetic rats (Stracke et al., 2001; Cameron et al., 2005). These effects are attributed to benfotiamine's ability to activate transketolase, redirecting excess glucose metabolites to the pentose phosphate pathway (Cameron et al., 2005). Benfotiamine's higher bioavailability and tissue penetration compared to thiamine contribute to its potential neuroprotective effects (Bozic & Lavrnja, 2023).

• Winkler, Gábor et al. “Effectiveness of Different Benfotiamine Dosage Regimens in the Treatment of Painful Diabetic Neuropathy.” Arzneimittelforschung 49 (1999): 220 - 224.
• Stracke, H. et al. “Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats.” Exp Clin Endocrinol Diabetes 109 (2001): 330 - 336.
• Cameron, Norman E et al. “Inhibitors of Advanced Glycation End Product Formation and Neurovascular Dysfunction in Experimental Diabetes.” Annals of the New York Academy of Sciences 1043 (2005): n. Pag.
• Bozic, Iva and Irena Lavrnja. “Thiamine and benfotiamine: Focus on their therapeutic potential.” Heliyon 9 (2023): n. pag.

Additional Studies

"An overall beneficial therapeutic effect was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy. The greatest change occurred in the group of patients receiving the high dose of benfotiamine." - Source: Effectiveness of different benfotiamine dosage regimens (2nd Department of Internal Medicine, Municipal St. John's Hospital, Budapest, Hungary)

"It is quite clear that benfotiamine is absorbed much better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine. The bioavailability is at maximum about 3.6 times as high as that of thiamine." - Source: Pharmacokinetics of thiamine derivatives especially of benfotiamine Intl Journal of Clinical Pharmacology & Therapeutics, 1996 Feb;34(2):47-50.)

Research suggests that riboflavin (vitamin B2) may be effective in managing peripheral nerve discomfort. Animal studies demonstrated that riboflavin supplementation significantly reduced mechanical and cold-induced hyperalgesia (Hristov et al., 2024). In mice, riboflavin showed antinociceptive effects and reduced visceral pain (Luca et al., 2015). Avian models have shown that riboflavin deficiency leads to a demyelinating peripheral neuropathy, characterized by endoneurial edema, Schwann cell hypertrophy, and demyelination (Cai et al., 2009; Johnson & Storts, 1988). This avian model provides a reliably reproducible method to study peripheral nerve demyelination and remyelination upon riboflavin supplementation (Cai et al., 2023). In humans, riboflavin's role in myelin formation and its deficiency have been implicated as risk factors for multiple sclerosis (MS) (Naghashpour et al., 2017). Riboflavin supplementation or higher dietary intake has shown improvements in neurological motor disability in MS patients (Naghashpour et al., 2017). The vitamin's importance is linked to its role as a cofactor for xanthine oxidase and glutathione reductase, affecting myelin integrity and oxidative stress (Naghashpour et al., 2017). These findings underscore the potential of riboflavin in supporting peripheral nerve health.

• Hristov M, Sabit Z, Kirilov T, Bakalov D, Tzoneva R, Apostolova S, Georgieva I, Andreeva-Gateva P (2024) Effects of riboflavin on hyperalgesia and serum glutamine-to-glutamate ratio in rats with painful diabetic neuropathy. Pharmacia 71: 1-7
• Luca, Andrei et al. “THE EFFECTS OF RIBOFLAVIN AND METHYLENE BLUE ON NOCICEPTION AND VISCERAL PAIN.” Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi 119 2 (2015): 466-72 .
• Johnson WD, Storts RW. Peripheral Neuropathy Associated with Dietary Riboflavin Deficiency in the Chicken I. Light Microscopic Study. Veterinary Pathology. 1988;25(1):9-16. doi:10.1177/030098588802500102
• Cai Z, Finnie J, Manavis J, Blumbergs P. Avian riboflavin deficiency causes reliably reproducible peripheral nerve demyelination and, with vitamin supplementation, rapid remyelination. Human & Experimental Toxicology. 2023;42. doi:10.1177/09603271231188970
• Mahshid Naghashpour; Sima Jafarirad; Reza Amani; Alireza Sarkaki; Ahmad Saedisomeolia. "Update on riboflavin and multiple sclerosis: a systematic review", Iranian Journal of Basic Medical Sciences, 20, 9, 2017, 958-966. doi: 10.22038/ijbms.2017.9257

Recent studies suggest that vitamin D supplementation may be effective in managing peripheral nerve discomfort. Cholecalciferol (vitamin D3) has been shown to reduce neuropathic pain in rat models by modulating opioid signaling and gene expression related to nociception and allodynia (Poisbeau et al., 2019). It also improves myelination and nerve regeneration after injury (Chabas et al., 2013). In humans, vitamin D supplementation has demonstrated promising effects on muscular pain, particularly in patients with insufficient levels (Helde-Frankling & Björkhem-Bergman, 2017). High-dose vitamin D supplementation (40,000 IU/week) in diabetic neuropathy patients significantly improved neuropathy symptoms, cutaneous microcirculation, and inflammatory markers (Karonova et al., 2020). The anti-inflammatory effects of vitamin D, mediated by reduced cytokine and prostaglandin release, may contribute to its pain-relieving properties (Helde-Frankling & Björkhem-Bergman, 2017). While more research is needed, these studies suggest that vitamin D supplementation may be a safe and potentially beneficial approach for supporting peripheral nerve health and function.

• Poisbeau, P., Aouad, M., Gazzo, G. et al. Cholecalciferol (Vitamin D3) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling. Mol Neurobiol 56, 7208–7221 (2019).
• Chabas, Jean et al. “Cholecalciferol (Vitamin D3) Improves Myelination and Recovery after Nerve Injury.” PLoS ONE 8 (2013): n. Pag.
• Helde-Frankling, Maria and Linda Björkhem-Bergman. “Vitamin D in Pain Management.” International Journal of Molecular Sciences 18 (2017): n. Pag.
• Karonova, Tatiana L et al. “High-Dose Vitamin D Supplementation Improves Microcirculation and Reduces Inflammation in Diabetic Neuropathy Patients.” Nutrients 12 (2020): n. Pag.

Vitamin B6, particularly as pyridoxine hydrochloride, has shown potential benefits for nerve health. Studies have demonstrated neuroprotective effects of pyridoxine in rat models of mononeuropathy, improving thermal hyperalgesia and motor function (Morani & Bodhankar, 2007). In diabetic neuropathy patients, pyridoxine deficiency was prevalent and correlated with reduced nerve conduction velocity (Khobrani et al., 2023).

• Morani, Aashish S. and Subhash Laxmanrao Bodhankar. “Pharmacologyonline 2 : 147-157 ( 2007 ) Morani and Bodhankar 147 Neuroprotective Effect of Pyridoxine Hydrochloride in Models of Mononeuropathy in Rats.” (2007).
• Khobrani, Moteb A. et al. “Impact of vitamin B6 deficiency on the severity of diabetic peripheral neuropathy – A cross sectional study.” Saudi Pharmaceutical Journal : SPJ 31 (2023): 655 - 658.

Feverfew (Tanacetum parthenium) has shown promise in managing various types of pain, including peripheral nerve pain. Studies have demonstrated its effectiveness in relieving diabetic neuropathic pain in rats, with efficacy comparable to clinically used antihyperalgesic drugs (Galeotti et al., 2014). The plant's active compound, parthenolide, exhibits strong analgesic effects in neuropathic pain models (Popiołek-Barczyk, 2023). A flower extract of Feverfew has been found to alleviate acute, inflammatory, articular, and neuropathic pain in various animal models, including chemotherapy-induced neuropathic pain (di Cesare Mannelli et al., 2015). The extract's potency was similar to that of gabapentin in neuropathic pain models. While Feverfew has traditionally been used for migraine prophylaxis (Palevitch et al., 1997), these recent findings suggest its potential as a widespread pain reliever, particularly for peripheral nerve pain management.

• Galeotti, Nicoletta et al. “St. John's Wort seed and feverfew flower extracts relieve painful diabetic neuropathy in a rat model of diabetes.” Fitoterapia 92 (2014): 23-33 .
• Popiołek-Barczyk, Katarzyna. “Pyrethrum maruna – an ancient medicine for modern diseases.” Modern Medicine (2023): n. Pag.
• di Cesare Mannelli, Lorenzo et al. “Widespread pain reliever profile of a flower extract of Tanacetum parthenium.” Phytomedicine : international journal of phytotherapy and phytopharmacology 22 7-8 (2015): 752-8 .
• Palevitch, Dan et al. “Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double‐blind placebo‐controlled study.” Phytotherapy Research 11 (1997): n. pag.

Passionflower extract (Passiflora incarnata) has been shown to support the nervous system by enhancing the calming effects of GABA, a key neurotransmitter that helps regulate nerve signals and reduce stress-related discomfort (Appel et al., 2011). Research suggests that passionflower works by increasing GABA activity in the brain, helping to relax the nervous system and ease symptoms of anxiety (Elsas et al., 2010).

Studies have found that passionflower extract can bind to GABA receptors, slowing down nerve overactivity and promoting a sense of calm (Grundmann et al., 2008). Animal studies have shown that it helps reduce anxious behavior, improves memory, and influences brain chemistry in a way that supports relaxation (Jawna-Zboińska et al., 2016). In one study, its effects were even comparable to those of diazepam (a well-known anti-anxiety medication), further demonstrating its nerve-calming properties.

By promoting relaxation and reducing nerve overstimulation, passionflower extract may help soothe nerve discomfort, making it a valuable addition to a nerve health regimen.

• Appel, Kurt et al. “Modulation of the γ‐aminobutyric acid (GABA) system by Passiflora incarnata L.” Phytotherapy Research 25 (2011): n. Pag.
• Elsas, Siegward M. et al. “Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo, varying with extraction method.” Phytomedicine : international journal of phytotherapy and phytopharmacology 17 12 (2010): 940-9 .
• Grundmann, Oliver et al. “Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system.” Planta medica 74 15 (2008): 1769-73 .
• Jawna-Zboińska, Katarzyna et al. “Passiflora incarnata L. Improves Spatial Memory, Reduces Stress, and Affects Neurotransmission in Rats.” Phytotherapy Research 30 (2016): 781 - 78

Research suggests that Skullcap (Scutellaria spp.) may have anxiolytic properties and could potentially calm neurotransmitters. Skullcap has been identified as a GABA-modulating phytomedicine with preclinical and clinical evidence supporting its anxiolytic effects (Savage et al., 2018). The plant contains flavonoids like baicalin and baicalein, which can bind to the benzodiazepine site of GABAA receptors, as well as GABA and glutamine. Animal studies have shown that Scutellaria lateriflora extracts significantly increase exploratory behaviors associated with reduced anxiety (Awad et al., 2003). Skullcap has been traditionally used to treat various nervous disorders, including anxiety (Weeks, 2009). The root extract of Scutellaria baicalensis, known as Huang-Qin in Chinese medicine, has been used for centuries to treat insomnia and other conditions (Zhao et al., 2016). These findings suggest that Skullcap may be a promising natural alternative for managing stress and anxiety.

• Savage, Karen M et al. “GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence.” Phytotherapy Research 32 (2018): 18 - 3.
• Awad, Rosalie et al. “Phytochemical and biological analysis of skullcap (Scutellaria lateriflora L.): a medicinal plant with anxiolytic properties.” Phytomedicine : international journal of phytotherapy and phytopharmacology 10 8 (2003): 640-9 .
• Weeks, Benjamin S.. “Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian.” Medical science monitor : international medical journal of experimental and clinical research 15 11 (2009): RA256-62 .
• Zhao, Qing et al. “Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants.” Science Bulletin 61 (2016): 1391 - 1398.

Recent studies suggest that oat (Avena sativa) extract may have beneficial effects on nerve health and cognitive function. In rats, oat extract demonstrated positive effects on sciatic nerve repair, including increased formation of perineurium and epineurium, reduced inflammation, and improved axon growth (Darzian Rostami et al., 2020). Oats contain various bioactive compounds, including β-glucan, avenanthramides, and flavonoids, which contribute to its potential as a therapeutic agent with antioxidant, anti-inflammatory, and immunomodulatory properties (Singh et al., 2013). These findings suggest that oat extract may have neuroprotective and cognitive-enhancing effects.

• Darzian Rostami, Z et al. “Effect of Oat (Avena Sativa L.) Extract on Experimental Sciatic Nerve Injury in Rats.” Archives of Razi Institute 75 2 (2020): 249-256 .
• Singh, Rajinder et al. “Avena sativa (Oat), A Potential Neutraceutical and Therapeutic Agent: An Overview.” Critical Reviews in Food Science and Nutrition 53 (2013): 126 - 144.