An antioxidant studied in research on sensory discomfort tied to diabetic nerve challenges, and for oxidative stress around nerves.

• Meta-analysis

  600 mg/day IV ALA for 3 weeks in symptomatic diabetic polyneuropathy.

  Diabet Med · 2004

  Full citation

  Meta-analysis of 4 RCTs (n=1,258): 600 mg/day IV ALA for 3 weeks in symptomatic diabetic polyneuropathy.

  Ziegler D et al. · Diabet Med · 2004 · PMID 14984445

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Favorable for Total Symptom Score (dose-related trend), NDS and global satisfaction.

  Nutrients · 2023

  Full citation

  Meta-analysis of 10 RCTs (1,242 patients) of oral ALA: favorable for Total Symptom Score (dose-related trend), NDS and global satisfaction.

  Hsieh RY et al. · Nutrients · 2023 · PMID 37630823

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  IV ALA 600 mg/day for 3 weeks gave a significant, clinically relevant reduction in neuropathic pain.

  Int J Endocrinol · 2012

  Full citation

  Meta-analysis of RCTs: IV ALA 600 mg/day for 3 weeks gave a significant, clinically relevant reduction in neuropathic pain.

  Mijnhout GS et al. · Int J Endocrinol · 2012 · PMID 22331979

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  IV ALA 300–600 mg/day for 2–4 weeks improved nerve conduction velocity and positive symptoms; most included studies were of poor methodological quality.

  Eur J Endocrinol · 2012

  Full citation

  Systematic review/meta-analysis: IV ALA 300–600 mg/day for 2–4 weeks improved nerve conduction velocity and positive symptoms; most included studies were of poor methodological quality.

  Han T et al. · Eur J Endocrinol · 2012 · PMID 22837391

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Cochrane systematic review of alpha-lipoic acid for diabetic neuropathy.

  Cochrane Database Syst Rev · 2024

  Full citation

  Cochrane systematic review of alpha-lipoic acid for diabetic neuropathy.

  Baicus C et al. · Cochrane Database Syst Rev · 2024 · PMID 38205823

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Neuropathic-impairment scores (NIS, NIS-LL) favored ALA.

  Diabetes Care · 2011

  Full citation

  NATHAN 1 RCT (n=460, 4 years) of oral ALA 600 mg/day: neuropathic-impairment scores (NIS, NIS-LL) favored ALA.

  Ziegler D et al. · Diabetes Care · 2011 · PMID 21775755

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral ALA 600, 1,200 or 1,800 mg once daily each improved Total Symptom Score vs placebo (−51%, −48%, −52% vs −32%); authors judged 600 mg once daily the best risk-to-benefit dose.

  Diabetes Care · 2006

  Full citation

  SYDNEY 2 RCT (n=181, 5 weeks): oral ALA 600, 1,200 or 1,800 mg once daily each improved Total Symptom Score vs placebo (−51%, −48%, −52% vs −32%); authors judged 600 mg once daily the best risk-to-benefit dose.

  Ziegler D et al. · Diabetes Care · 2006 · PMID 17065669

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  3 weeks IV then 6 months oral ALA had no clinically meaningful effect on symptoms vs placebo, with a favorable effect on neuropathic deficits.

  Diabetes Care · 1999

  Full citation

  ALADIN III RCT (n=509): 3 weeks IV then 6 months oral ALA had no clinically meaningful effect on symptoms vs placebo, with a favorable effect on neuropathic deficits.

  Ziegler D et al. · Diabetes Care · 1999 · PMID 10480774

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Methylcobalamin and ALA both reduced neuropathy scores; ALA reduced burning and pain more, methylcobalamin slightly more for numbness and paresthesia.

  Minerva Endocrinol · 2018

  Full citation

  RCT (n=40, 2 weeks): methylcobalamin and ALA both reduced neuropathy scores; ALA reduced burning and pain more, methylcobalamin slightly more for numbness and paresthesia.

  Han Y et al. · Minerva Endocrinol · 2018 · PMID 27901334

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  RCT of oral ALA in chemotherapy-induced (oxaliplatin/cisplatin) neuropathy.

  Support Care Cancer · 2014

  Full citation

  RCT of oral ALA in chemotherapy-induced (oxaliplatin/cisplatin) neuropathy.

  Guo Y et al. · Support Care Cancer · 2014 · PMID 24362907

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  IV ALA rapidly improved positive neuropathic sensory symptoms such as pain.

  Diabetes Care · 2003

  Full citation

  SYDNEY RCT: IV ALA rapidly improved positive neuropathic sensory symptoms such as pain.

  Ametov AS et al. · Diabetes Care · 2003 · PMID 12610036

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  800 mg/day oral ALA for 4 months in cardiac autonomic neuropathy (heart-rate variability) in type 2 diabetes.

  Diabetes Care · 1997

  Full citation

  DEKAN RCT: 800 mg/day oral ALA for 4 months in cardiac autonomic neuropathy (heart-rate variability) in type 2 diabetes.

  Ziegler D et al. · Diabetes Care · 1997 · PMID 9051389

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  ALA 600 mg/day was superior to placebo for symptoms.

  Diabetologia · 1995

  Full citation

  ALADIN RCT (3 weeks IV): ALA 600 mg/day was superior to placebo for symptoms.

  Ziegler D et al. · Diabetologia · 1995 · PMID 8786016

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  ALA and nerve conduction / endoneurial blood flow in diabetic rats.

  Diabetologia · 1998

  Full citation

  Animal study: ALA and nerve conduction / endoneurial blood flow in diabetic rats.

  Cameron NE et al. · Diabetologia · 1998 · PMID 9562342

  Read on PubMed ↗ (opens in a new tab)

A fat-soluble form of B1 (a thiamine prodrug) studied for higher bioavailability than standard thiamine: in a pharmacokinetic study, oral benfotiamine produced much higher plasma thiamine bioavailability than thiamine hydrochloride. Trials have used 150–600 mg/day.

• Meta-analysis

  B-vitamin supplementation may improve some neuropathy scores and sural nerve function in DPN.

  J Clin Med · 2026

  Full citation

  Review and meta-analysis: B-vitamin supplementation may improve some neuropathy scores and sural nerve function in DPN.

  Mandra EV et al. · J Clin Med · 2026 · PMID 42452619

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  One small alcoholic-neuropathy trial favored oral benfotiamine for vibration threshold over 8 weeks.

  Cochrane Database Syst Rev · 2008

  Full citation

  Cochrane review (vitamin B for peripheral neuropathy): one small alcoholic-neuropathy trial favored oral benfotiamine for vibration threshold over 8 weeks.

  Ang CD et al. · Cochrane Database Syst Rev · 2008 · PMID 18646107

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine 300 mg/day raised blood thiamine.

  Diabetes Care · 2012

  Full citation

  24-month RCT in type 1 diabetes (n=67): benfotiamine 300 mg/day raised blood thiamine.

  Fraser DA et al. · Diabetes Care · 2012 · PMID 22446172

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine 300 or 600 mg/day; Neuropathy Symptom Score improved in the per-protocol population, more at the higher dose.

  Exp Clin Endocrinol Diabetes · 2008

  Full citation

  BENDIP RCT (165 randomised, 6 weeks): benfotiamine 300 or 600 mg/day; Neuropathy Symptom Score improved in the per-protocol population, more at the higher dose.

  Stracke H et al. · Exp Clin Endocrinol Diabetes · 2008 · PMID 18473286

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine 400 mg/day improved the neuropathy score vs placebo (p=0.029), most for pain.

  Int J Clin Pharmacol Ther · 2005

  Full citation

  BEDIP 3-week randomized pilot (n=40): benfotiamine 400 mg/day improved the neuropathy score vs placebo (p=0.029), most for pain.

  Haupt E et al. · Int J Clin Pharmacol Ther · 2005 · PMID 15726875

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Study on different benfotiamine dosage regimens in diabetic neuropathy research.

  Arzneimittelforschung · 1999

  Full citation

  Study on different benfotiamine dosage regimens in diabetic neuropathy research.

  Winkler G et al. · Arzneimittelforschung · 1999 · PMID 10219465

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine was well tolerated.

  BMJ Open Diabetes Res Care · 2026

  Full citation

  12-month phase II RCT in type 2 diabetes with mild-to-moderate symptomatic DSPN: benfotiamine was well tolerated.

  Ziegler D et al. · BMJ Open Diabetes Res Care · 2026 · PMID 41571333

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine was safe and well tolerated.

  Drug Des Devel Ther · 2021

  Full citation

  Phase I single- and multiple-ascending-dose study in healthy subjects: benfotiamine was safe and well tolerated.

  Sheng L et al. · Drug Des Devel Ther · 2021 · PMID 33727798

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral benfotiamine gave much higher plasma thiamine (~1,147%) and erythrocyte TDP (~196%) bioavailability than thiamine hydrochloride.

  J Clin Pharmacol · 2014

  Full citation

  Pharmacokinetic study: oral benfotiamine gave much higher plasma thiamine (~1,147%) and erythrocyte TDP (~196%) bioavailability than thiamine hydrochloride.

  Xie F et al. · J Clin Pharmacol · 2014 · PMID 24399744

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine studied in alcoholic polyneuropathy over 8 weeks.

  Alcohol Alcohol · 1998

  Full citation

  BAP I RCT: benfotiamine studied in alcoholic polyneuropathy over 8 weeks.

  Woelk H et al. · Alcohol Alcohol · 1998 · PMID 9872352

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Benfotiamine–vitamin B combination studied in diabetic polyneuropathy research.

  Exp Clin Endocrinol Diabetes · 1996

  Full citation

  Benfotiamine–vitamin B combination studied in diabetic polyneuropathy research.

  Stracke H et al. · Exp Clin Endocrinol Diabetes · 1996 · PMID 8886748

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Benfotiamine studied in diabetic polyneuropathy research.

  Srp Arh Celok Lek · 2009

  Full citation

  Benfotiamine studied in diabetic polyneuropathy research.

  Nikolić A et al. · Srp Arh Celok Lek · 2009 · PMID 20069914

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  Benfotiamine’s pharmacological profile vs thiamine disulfides.

  BMC Pharmacol · 2008

  Full citation

  Benfotiamine’s pharmacological profile vs thiamine disulfides.

  Volvert ML et al. · BMC Pharmacol · 2008 · PMID 18549472

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  Benfotiamine, but not thiamine, improved nerve function measures and inhibited neural AGE formation.

  Exp Clin Endocrinol Diabetes · 2001

  Full citation

  Animal study (diabetic rats): benfotiamine, but not thiamine, improved nerve function measures and inhibited neural AGE formation.

  Stracke H et al. · Exp Clin Endocrinol Diabetes · 2001 · PMID 11571671

  Read on PubMed ↗ (opens in a new tab)

An active form of B12. Observational studies and trials link diabetes and long-term metformin use to lower B12 status, and B12 deficiency is associated with neuropathy measures.

• Meta-analysis

  Mecobalamin in combination may improve clinical efficacy and nerve conduction; evidence for mecobalamin alone is not clear.

  J Altern Complement Med · 2020

  Full citation

  Systematic review/meta-analysis of RCTs: mecobalamin in combination may improve clinical efficacy and nerve conduction; evidence for mecobalamin alone is not clear.

  Sawangjit R et al. · J Altern Complement Med · 2020 · PMID 32716261

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Metformin associated with lower B12 and higher risk of deficiency (RR 2.09), dose- and duration-dependent.

  J Diabetes · 2019

  Full citation

  Meta-analysis of 31 studies: metformin associated with lower B12 and higher risk of deficiency (RR 2.09), dose- and duration-dependent.

  Yang W et al. · J Diabetes · 2019 · PMID 30615306

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Metformin lowered serum B12 vs comparators, with a larger drop at ≥2,000 mg/day.

  PLoS One · 2014

  Full citation

  Systematic review/meta-analysis of 6 RCTs: metformin lowered serum B12 vs comparators, with a larger drop at ≥2,000 mg/day.

  Liu Q et al. · PLoS One · 2014 · PMID 24959880

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Some evidence for B12 in post-herpetic neuralgia (level II) and painful peripheral neuropathy (level III).

  Nutrients · 2020

  Full citation

  Systematic review (24 articles): some evidence for B12 in post-herpetic neuralgia (level II) and painful peripheral neuropathy (level III).

  Julian T et al. · Nutrients · 2020 · PMID 32722436

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  16 weeks of 1,000 µg or 2,000 µg/day oral B12 improved neuropathic symptoms.

  J Nutr · 2026

  Full citation

  RCT in DPN with low serum B12: 16 weeks of 1,000 µg or 2,000 µg/day oral B12 improved neuropathic symptoms.

  Mansour A et al. · J Nutr · 2026 · PMID 41548600

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral methylcobalamin 1 mg/day raised B12 and improved nerve conduction, VPT, sudomotor function, pain and QoL.

  Nutrients · 2021

  Full citation

  1-year RCT (n=90, type 2 diabetes on metformin ≥4 years, B12 <400 pmol/L): oral methylcobalamin 1 mg/day raised B12 and improved nerve conduction, VPT, sudomotor function, pain and QoL.

  Didangelos T et al. · Nutrients · 2021 · PMID 33513879

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Acetyl-L-carnitine was as effective as methylcobalamin (the active comparator) on symptoms and neurophysiology in DPN.

  J Diabetes Investig · 2016

  Full citation

  Multicenter RCT (24 weeks): acetyl-L-carnitine was as effective as methylcobalamin (the active comparator) on symptoms and neurophysiology in DPN.

  Li S et al. · J Diabetes Investig · 2016 · PMID 27180954

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Long-term metformin use was associated with biochemical B12 deficiency and anemia.

  J Clin Endocrinol Metab · 2016

  Full citation

  DPP/DPPOS secondary analysis of an RCT: long-term metformin use was associated with biochemical B12 deficiency and anemia.

  Aroda VR et al. · J Clin Endocrinol Metab · 2016 · PMID 26900641

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Metformin 850 mg three times daily lowered B12 by 19% vs placebo and raised the absolute risk of B12 deficiency by 7.2 points; authors link the deficiency to raised homocysteine.

  BMJ · 2010

  Full citation

  RCT (n=390 on insulin, 4.3 years): metformin 850 mg three times daily lowered B12 by 19% vs placebo and raised the absolute risk of B12 deficiency by 7.2 points; authors link the deficiency to raised homocysteine.

  de Jager J et al. · BMJ · 2010 · PMID 20488910

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Methylcobalamin improved somatic and autonomic symptoms in diabetic neuropathy.

  Clin Neurol Neurosurg · 1992

  Full citation

  Double-blind study: methylcobalamin improved somatic and autonomic symptoms in diabetic neuropathy.

  Yaqub BA et al. · Clin Neurol Neurosurg · 1992 · PMID 1324807

  Read on PubMed ↗ (opens in a new tab)
• Observational

  B12/folate deficiency linked to higher homocysteine and oxidative stress.

  Nutrition · 2012

  Full citation

  B12/folate deficiency linked to higher homocysteine and oxidative stress.

  Al-Maskari MY et al. · Nutrition · 2012 · PMID 22595450

  Read on PubMed ↗ (opens in a new tab)
• Observational

  Functional B12 deficiency (high MMA) was common in older adults with diabetes; neuropathy was present in 62% with high MMA vs 18% with normal MMA, and B12 therapy improved MMA in 88%.

  Diabetes Care · 2011

  Full citation

  Functional B12 deficiency (high MMA) was common in older adults with diabetes; neuropathy was present in 62% with high MMA vs 18% with normal MMA, and B12 therapy improved MMA in 88%.

  Solomon LR et al. · Diabetes Care · 2011 · PMID 21421801

  Read on PubMed ↗ (opens in a new tab)
• Observational

  Metformin use was associated with lower B12, higher MMA/homocysteine, and more severe neuropathy measures.

  Diabetes Care · 2010

  Full citation

  Metformin use was associated with lower B12, higher MMA/homocysteine, and more severe neuropathy measures.

  Wile DJ et al. · Diabetes Care · 2010 · PMID 19846797

  Read on PubMed ↗ (opens in a new tab)
• Not in PubMed

  24-week study using 1500 mcg methylcobalamin daily.

  J Diabetes Mellitus · 2012

  Full citation

  24-week study using 1500 mcg methylcobalamin daily.

  Dominguez JC et al. · J Diabetes Mellitus · 2012 · not indexed in PubMed

  Publisher PDF ↗ (opens in a new tab)

L-methylfolate (5-MTHF) is the active form of folate the body uses directly and its main circulating form; it is not folic acid. The MTHFR enzyme makes 5-MTHF, and common MTHFR variants (C677T, A1298C) have been linked to reduced enzyme activity, which reduces the ability to make 5-MTHF. Supplemental 5-MTHF is already past that step. See the methylation deep-dive below.

• Randomized trial

  L-methylfolate 3 mg + methylcobalamin 2 mg + P-5-P 35 mg improved NTSS-6 symptom scores at weeks 16 and 24 and lowered homocysteine (−2.7 vs +0.5 µmol/L).

  Am J Med · 2013

  Full citation

  Multicenter RCT (n=214, 24 weeks): L-methylfolate 3 mg + methylcobalamin 2 mg + P-5-P 35 mg improved NTSS-6 symptom scores at weeks 16 and 24 and lowered homocysteine (−2.7 vs +0.5 µmol/L).

  Fonseca VA et al. · Am J Med · 2013 · PMID 23218892

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  400 µg/day folic acid or equimolar [6S]-5-MTHF both lowered homocysteine.

  Int J Food Sci Nutr · 2018

  Full citation

  RCT in older adults (n=40, 4 weeks): 400 µg/day folic acid or equimolar [6S]-5-MTHF both lowered homocysteine.

  Sicińska E et al. · Int J Food Sci Nutr · 2018 · PMID 28460586

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  MTHF raises plasma folate better than folic acid in MTHFR variants.

  Br J Pharmacol · 2009

  Full citation

  MTHF raises plasma folate better than folic acid in MTHFR variants.

  Prinz-Langenohl R et al. · Br J Pharmacol · 2009 · PMID 19917061

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Low-dose L-MTHF equals or beats folic acid for lowering homocysteine.

  Am J Clin Nutr · 2003

  Full citation

  Low-dose L-MTHF equals or beats folic acid for lowering homocysteine.

  Venn BJ et al. · Am J Clin Nutr · 2003 · PMID 12600857

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Folic acid handling by the human gut.

  Am J Clin Nutr · 2014

  Full citation

  Folic acid handling by the human gut.

  Patanwala I et al. · Am J Clin Nutr · 2014 · PMID 24944062

  Read on PubMed ↗ (opens in a new tab)
• Observational

  Serum 5-MTHF was inversely associated with homocysteine at ≤10 ng/mL, and the association was modified by MTHFR C677T genotype.

  Nutr J · 2022

  Full citation

  Cross-sectional analysis in hypertensive adults: serum 5-MTHF was inversely associated with homocysteine at ≤10 ng/mL, and the association was modified by MTHFR C677T genotype.

  Cheng Y et al. · Nutr J · 2022 · PMID 35562805

  Read on PubMed ↗ (opens in a new tab)
• Observational

  5-MTHF + methylcobalamin + P-5-P studied in diabetic peripheral neuropathy research.

  Curr Med Res Opin · 2016

  Full citation

  5-MTHF + methylcobalamin + P-5-P studied in diabetic peripheral neuropathy research.

  Trippe BS et al. · Curr Med Res Opin · 2016 · PMID 26439233

  Read on PubMed ↗ (opens in a new tab)
• Review

  Narrative review of preclinical and clinical data on L-methylfolate (in a combination B-vitamin medical food) in DPN, including MTHFR C677T literature.

  Endocr Pract · 2023

  Full citation

  Narrative review of preclinical and clinical data on L-methylfolate (in a combination B-vitamin medical food) in DPN, including MTHFR C677T literature.

  Christofides EA et al. · Endocr Pract · 2023 · PMID 37088147

  Read on PubMed ↗ (opens in a new tab)
• Review

  Folate, folic acid, and 5-MTHF are not the same.

  Xenobiotica · 2014

  Full citation

  Folate, folic acid, and 5-MTHF are not the same.

  Scaglione F et al. · Xenobiotica · 2014 · PMID 24494987

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  The L-methylfolate/P-5-P/methylcobalamin combination at a human-equivalent dose improved sensory nerve conduction, hypoalgesia and intraepidermal nerve fiber density.

  Diabetes · 2012

  Full citation

  Animal study (ZDF rats): the L-methylfolate/P-5-P/methylcobalamin combination at a human-equivalent dose improved sensory nerve conduction, hypoalgesia and intraepidermal nerve fiber density.

  Shevalye H et al. · Diabetes · 2012 · PMID 22751692

  Read on PubMed ↗ (opens in a new tab)

B6 already in its active form. With methyl-B12 and L-methylfolate, it’s the trio studied in small-fiber nerve research.

• Meta-analysis

  Neuropathy associated with lower B12 and higher MMA and homocysteine.

  Eur J Neurol · 2021

  Full citation

  Systematic review/meta-analysis (46 observational, 7 interventional studies): neuropathy associated with lower B12 and higher MMA and homocysteine.

  Stein J et al. · Eur J Neurol · 2021 · PMID 33619867

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Evidence supports a neurotoxic role of B6 at high levels; low B6 may also be a risk factor—dose context for B6.

  Nutrients · 2023

  Full citation

  Systematic review: evidence supports a neurotoxic role of B6 at high levels; low B6 may also be a risk factor—dose context for B6.

  Muhamad R et al. · Nutrients · 2023 · PMID 37447150

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Double-blind RCT (n=18, 4 months) of pyridoxine 50 mg three times daily in diabetic neuropathy.

  Diabetes Care · 1981

  Full citation

  Double-blind RCT (n=18, 4 months) of pyridoxine 50 mg three times daily in diabetic neuropathy.

  Levin ER et al. · Diabetes Care · 1981 · PMID 6751736

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Study on thiamine and pyridoxine in diabetic peripheral neuropathy research.

  East Afr Med J · 1997

  Full citation

  Study on thiamine and pyridoxine in diabetic peripheral neuropathy research.

  Abbas ZG et al. · East Afr Med J · 1997 · PMID 9557427

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  That combination studied for cutaneous sensitivity in diabetic neuropathy research.

  Rev Neurol Dis · 2010

  Full citation

  That combination studied for cutaneous sensitivity in diabetic neuropathy research.

  Walker MJ Jr et al. · Rev Neurol Dis · 2010 · PMID 21206429

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  L-methylfolate + methylcobalamin + P-5-P in diabetic small-fiber nerve research.

  Rev Neurol Dis · 2011

  Full citation

  L-methylfolate + methylcobalamin + P-5-P in diabetic small-fiber nerve research.

  Jacobs AM et al. · Rev Neurol Dis · 2011 · PMID 21769070

  Read on PubMed ↗ (opens in a new tab)
• Review

  Review of proposed mechanisms of pyridoxine (B6)-induced peripheral neuropathy—safety context for high-dose B6.

  Adv Nutr · 2021

  Full citation

  Review of proposed mechanisms of pyridoxine (B6)-induced peripheral neuropathy—safety context for high-dose B6.

  Hadtstein F et al. · Adv Nutr · 2021 · PMID 33912895

  Read on PubMed ↗ (opens in a new tab)

Research found 81% of people with neuropathy were vitamin D deficient, versus 60% without. High-dose D3 has been studied alongside diabetic nerve discomfort.

• Meta-analysis

  Vitamin D reduced short-term pain in painful diabetic neuropathy vs placebo (SMD −0.85); small, variable-quality trials, so authors call for larger RCTs before routine use.

  Endocrinol Diabetes Metab · 2025

  Full citation

  Meta-analysis of RCTs (4 trials, n=320): vitamin D reduced short-term pain in painful diabetic neuropathy vs placebo (SMD −0.85); small, variable-quality trials, so authors call for larger RCTs before routine use.

  Gilbody A et al. · Endocrinol Diabetes Metab · 2025 · PMID 41139799

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Vitamin D deficiency was more prevalent in diabetic patients with neuropathy (pooled OR 1.84 fixed-effects; 2.87 random-effects).

  Br J Nutr · 2022

  Full citation

  Meta-analysis: vitamin D deficiency was more prevalent in diabetic patients with neuropathy (pooled OR 1.84 fixed-effects; 2.87 random-effects).

  Yammine K et al. · Br J Nutr · 2022 · PMID 34024290

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Lower 25(OH)D was associated with type 2 DPN; more high-quality research needed.

  Medicine (Baltimore) · 2019

  Full citation

  Systematic review/meta-analysis: lower 25(OH)D was associated with type 2 DPN; more high-quality research needed.

  Zhang B et al. · Medicine (Baltimore) · 2019 · PMID 31770239

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Vitamin D deficiency is very likely associated with DPN in type 2 diabetes; further validation needed.

  J Endocrinol Invest · 2015

  Full citation

  Systematic review/meta-analysis: vitamin D deficiency is very likely associated with DPN in type 2 diabetes; further validation needed.

  Lv WS et al. · J Endocrinol Invest · 2015 · PMID 25527161

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Vitamin D supplementation could add value in painful DPN; pain improvement may relate to the vitamin D level attained.

  Clin Nutr · 2020

  Full citation

  Systematic review: vitamin D supplementation could add value in painful DPN; pain improvement may relate to the vitamin D level attained.

  Yammine K et al. · Clin Nutr · 2020 · PMID 32089370

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Cholecalciferol 40,000 IU/week improved neuropathy scores, cutaneous microcirculation and IL-6/IL-10.

  Nutrients · 2020

  Full citation

  RCT (n=67, 24 weeks): cholecalciferol 40,000 IU/week improved neuropathy scores, cutaneous microcirculation and IL-6/IL-10.

  Karonova T et al. · Nutrients · 2020 · PMID 32825324

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  High-dose vitamin D studied alongside diabetic neuropathy discomfort.

  BMJ Open Diabetes Res Care · 2016

  Full citation

  High-dose vitamin D studied alongside diabetic neuropathy discomfort.

  Basit A et al. · BMJ Open Diabetes Res Care · 2016 · PMID 27026808

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Vitamin D3 supplementation studied in neuropathy research.

  Med Princ Pract · 2015

  Full citation

  Vitamin D3 supplementation studied in neuropathy research.

  Shehab D et al. · Med Princ Pract · 2015 · PMID 25720672

  Read on PubMed ↗ (opens in a new tab)
• Observational

  81% with neuropathy were vitamin D deficient vs 60% without in one study.

  Diabet Med · 2012

  Full citation

  81% with neuropathy were vitamin D deficient vs 60% without in one study.

  Shehab D et al. · Diabet Med · 2012 · PMID 22050401

  Read on PubMed ↗ (opens in a new tab)
• Observational

  Vitamin D insufficiency and peripheral neuropathy.

  Diabet Med · 2012

  Full citation

  NHANES 2001–2004 analysis (n=591 adults with diabetes): vitamin D insufficiency and peripheral neuropathy.

  Soderstrom LH et al. · Diabet Med · 2012 · PMID 21726279

  Read on PubMed ↗ (opens in a new tab)
• Letter

  Type 2 diabetics had lower pain scores after 3 months of vitamin D.

  Arch Intern Med · 2008

  Full citation

  Type 2 diabetics had lower pain scores after 3 months of vitamin D.

  Lee P et al. · Arch Intern Med · 2008 · PMID 18413561

  Read on PubMed ↗ (opens in a new tab)

The cooling topical analgesic. Research has looked at topical menthol in nerve-related discomfort and musculoskeletal pain, including its action on the TRPM8 cold receptor.

• Randomized trial

  RCT of topical menthol for chemotherapy-related neuropathy symptoms.

  BMJ Support Palliat Care · 2024

  Full citation

  RCT of topical menthol for chemotherapy-related neuropathy symptoms.

  Ozdemir D et al. · BMJ Support Palliat Care · 2024 · PMID 39038990

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  5% menthol gel increased skin blood flow at the treated site and modestly across the dermatome, consistent with TRPM8 activation.

  Microvasc Res · 2022

  Full citation

  Randomized crossover study (n=15 healthy adults): 5% menthol gel increased skin blood flow at the treated site and modestly across the dermatome, consistent with TRPM8 activation.

  Dillon GA et al. · Microvasc Res · 2022 · PMID 34717968

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  0.5%, 4.6% and 10% menthol gels all cooled the skin; 4.6% felt coolest.

  Skin Res Technol · 2016

  Full citation

  Randomized study (n=10 healthy men): 0.5%, 4.6% and 10% menthol gels all cooled the skin; 4.6% felt coolest.

  Lasanen R et al. · Skin Res Technol · 2016 · PMID 25773465

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  3.5% menthol gel reduced perceived discomfort more than ice and allowed greater evoked force.

  Int J Sports Phys Ther · 2012

  Full citation

  Randomized study (n=16, delayed-onset muscle soreness): 3.5% menthol gel reduced perceived discomfort more than ice and allowed greater evoked force.

  Johar P et al. · Int J Sports Phys Ther · 2012 · PMID 22666646

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  A menthol-based topical analgesic reduced pain sensitivity (pressure-pain threshold) similarly whether applied to the upper or lower body.

  J Sport Rehabil · 2022

  Full citation

  RCT: a menthol-based topical analgesic reduced pain sensitivity (pressure-pain threshold) similarly whether applied to the upper or lower body.

  Behm DG et al. · J Sport Rehabil · 2022 · PMID 34552033

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Topical menthol dose-dependently increased cutaneous blood flow; sensory-nerve inhibition attenuated the effect.

  Microvasc Res · 2016

  Full citation

  Randomized human study: topical menthol dose-dependently increased cutaneous blood flow; sensory-nerve inhibition attenuated the effect.

  Craighead DH et al. · Microvasc Res · 2016 · PMID 27131832

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Topical menthol vs placebo for chronic arm/hand pain.

  Rehabil Res Pract · 2014

  Full citation

  Triple-blind RCT: topical menthol vs placebo for chronic arm/hand pain.

  Sundstrup E et al. · Rehabil Res Pract · 2014 · PMID 25298894

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  L-menthol and pain-related somatosensory-evoked potentials.

  Brain Sci · 2023

  Full citation

  L-menthol and pain-related somatosensory-evoked potentials.

  Makibuchi T et al. · Brain Sci · 2023 · PMID 37371396

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Topical 1% menthol cream in treatment-related neuropathic pain.

  Support Care Cancer · 2015

  Full citation

  Proof-of-concept: topical 1% menthol cream in treatment-related neuropathic pain.

  Fallon MT et al. · Support Care Cancer · 2015 · PMID 25680765

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  3.5% topical menthol gel studied in knee osteoarthritis functional tasks.

  J Geriatr Phys Ther · 2013

  Full citation

  3.5% topical menthol gel studied in knee osteoarthritis functional tasks.

  Topp R et al. · J Geriatr Phys Ther · 2013 · PMID 22976810

  Read on PubMed ↗ (opens in a new tab)
• Observational

  Menthol cream titrated 1%→10%; 12/21 met the responder criterion at 10%. Exploratory.

  J Pain Palliat Care Pharmacother · 2026

  Full citation

  Retrospective chart review (n=21, refractory localized neuropathic pain, 71% chemotherapy-induced): menthol cream titrated 1%→10%; 12/21 met the responder criterion at 10%. Exploratory.

  Treillet E et al. · J Pain Palliat Care Pharmacother · 2026 · PMID 42627361

  Read on PubMed ↗ (opens in a new tab)
• Review

  Role and mechanism of menthol in topical analgesic products.

  J Clin Pharm Ther · 2018

  Full citation

  Role and mechanism of menthol in topical analgesic products.

  Pergolizzi JV Jr et al. · J Clin Pharm Ther · 2018 · PMID 29524352

  Read on PubMed ↗ (opens in a new tab)
• Review

  Review of menthol’s role in pain and analgesia, including TRPM8.

  Front Mol Neurosci · 2022

  Full citation

  Review of menthol’s role in pain and analgesia, including TRPM8.

  Li Z et al. · Front Mol Neurosci · 2022 · PMID 36277488

  Read on PubMed ↗ (opens in a new tab)

Most MSM research is oral — knee comfort, physical function, and quality of life. Cited here as ingredient research, not a claim that this cream treats arthritis.

• Meta-analysis

  Meta-analysis of DMSO and MSM in osteoarthritis of the knee.

  Evid Based Complement Alternat Med · 2011

  Full citation

  Meta-analysis of DMSO and MSM in osteoarthritis of the knee.

  Brien S et al. · Evid Based Complement Alternat Med · 2011 · PMID 19474240

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  MSM and knee quality of life in people with mild knee pain.

  Nutrients · 2023

  Full citation

  RCT: MSM and knee quality of life in people with mild knee pain.

  Toguchi A et al. · Nutrients · 2023 · PMID 37447322

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Randomized controlled study of MSM supplementation in knee osteoarthritis.

  BMC Complement Altern Med · 2011

  Full citation

  Randomized controlled study of MSM supplementation in knee osteoarthritis.

  Debbi EM et al. · BMC Complement Altern Med · 2011 · PMID 21708034

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral MSM in osteoarthritis pain of the knee.

  Osteoarthritis Cartilage · 2006

  Full citation

  Pilot RCT: oral MSM in osteoarthritis pain of the knee.

  Kim LS et al. · Osteoarthritis Cartilage · 2006 · PMID 16309928

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  RCT of oral glucosamine, MSM, and the combination in osteoarthritis.

  Clin Drug Investig · 2004

  Full citation

  RCT of oral glucosamine, MSM, and the combination in osteoarthritis.

  Usha PR et al. · Clin Drug Investig · 2004 · PMID 17516722

  Read on PubMed ↗ (opens in a new tab)

An antioxidant researched (mostly orally or IV) for sensory findings, neuropathic symptoms, and idiopathic pain — ingredient research, not a claim that this cream treats disease.

• Meta-analysis

  600 mg/day IV ALA for 3 weeks in symptomatic diabetic polyneuropathy.

  Diabet Med · 2004

  Full citation

  Meta-analysis of 4 RCTs (n=1,258): 600 mg/day IV ALA for 3 weeks in symptomatic diabetic polyneuropathy.

  Ziegler D et al. · Diabet Med · 2004 · PMID 14984445

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral ALA in symptomatic diabetic polyneuropathy.

  Diabetes Care · 2006

  Full citation

  SYDNEY 2: oral ALA in symptomatic diabetic polyneuropathy.

  Ziegler D et al. · Diabetes Care · 2006 · PMID 17065669

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  RCT of oral ALA for pain of unknown etiology (not a disease-treatment claim for this cream).

  Biomed Pharmacother · 2021

  Full citation

  RCT of oral ALA for pain of unknown etiology (not a disease-treatment claim for this cream).

  Esposito C et al. · Biomed Pharmacother · 2021 · PMID 34649217

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Sensory findings studied with ALA in diabetic polyneuropathy research.

  Diabetes Care · 2003

  Full citation

  Sensory findings studied with ALA in diabetic polyneuropathy research.

  Ametov AS et al. · Diabetes Care · 2003 · PMID 12610036

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  3-week multicenter RCT of IV alpha-lipoic acid in symptomatic diabetic polyneuropathy.

  Diabetologia · 1995

  Full citation

  ALADIN: 3-week multicenter RCT of IV alpha-lipoic acid in symptomatic diabetic polyneuropathy.

  Ziegler D et al. · Diabetologia · 1995 · PMID 8786016

  Read on PubMed ↗ (opens in a new tab)

Nitric-oxide precursor. A small topical pilot looked at blood flow and temperature in the feet; a 12-patient pain study gave L-arginine by IV infusion (not by mouth or topically); a 3-month placebo-controlled RCT (3 g three times daily) found no microcirculation or neuropathy effect. Ingredient background, not trials of this cream.

• Randomized trial

  Placebo-controlled L-arginine RCT (n=30, 3 g three times daily, 3 months) in people with neuropathic diabetic foot.

  Diabet Med · 2010

  Full citation

  Placebo-controlled L-arginine RCT (n=30, 3 g three times daily, 3 months) in people with neuropathic diabetic foot.

  Jude EB et al. · Diabet Med · 2010 · PMID 20121898

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Temperature and blood flow in the feet (pilot).

  Diabetes Care · 2004

  Full citation

  Transdermal L-arginine cream: temperature and blood flow in the feet (pilot).

  Fossel ET et al. · Diabetes Care · 2004 · PMID 14694013

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  IV L-arginine infusion (30 g) and pain scores in 12 patients with persistent pain.

  Eur Neuropsychopharmacol · 1991

  Full citation

  IV L-arginine infusion (30 g) and pain scores in 12 patients with persistent pain.

  Harima A et al. · Eur Neuropsychopharmacol · 1991 · PMID 1822318

  Read on PubMed ↗ (opens in a new tab)

Urea is a small, water-loving molecule the skin already makes as part of natural moisturizing factor (NMF); dry, thickened skin often runs low on it. At high concentrations, topical urea is researched as both a humectant (pulls and holds water) and a keratolytic (helps loosen hard keratin so thick, dry skin can soften). Ingredient research, not a claim that Derm 42 treats a disease.

• Meta-analysis

  Functional creams, primarily urea-containing, outperformed standard bases.

  Front Clin Diabetes Healthc · 2026

  Full citation

  Systematic review/meta-analysis of RCTs (diabetic foot xerosis): functional creams, primarily urea-containing, outperformed standard bases.

  Borgström K et al. · Front Clin Diabetes Healthc · 2026 · PMID 42755659

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Urea cream and celecoxib both helped prevent hand-foot syndrome/skin reaction from cancer therapy; urea especially for moderate-to-severe sorafenib reactions.

  Support Care Cancer · 2022

  Full citation

  Meta-analysis of RCTs: urea cream and celecoxib both helped prevent hand-foot syndrome/skin reaction from cancer therapy; urea especially for moderate-to-severe sorafenib reactions.

  Pandy JGP et al. · Support Care Cancer · 2022 · PMID 35655045

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Systematic review of moisturisers for foot xerosis; urea was the most researched ingredient (14 studies).

  J Foot Ankle Res · 2017

  Full citation

  Parker et al. 2017 — systematic review of moisturisers for foot xerosis; urea was the most researched ingredient (14 studies).

  Parker J et al. · J Foot Ankle Res · 2017 · PMID 28191040

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  A comprehensive review of the clinical literature (systematic review).

  Dermatol Online J · 2013

  Full citation

  Pan et al. 2013 — urea: a comprehensive review of the clinical literature (systematic review).

  Pan M et al. · Dermatol Online J · 2013 · PMID 24314769

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  40% urea was the comparator for pedal (heel) fissures; a barrier-repair cream showed minimal statistical difference from urea 40%. Ingredient research, not a Derm 42 outcome claim.

  J Am Podiatr Med Assoc · 2025

  Full citation

  RCT (JAPMA 2025) — double-blind, 48 enrolled, 28 days: 40% urea was the comparator for pedal (heel) fissures; a barrier-repair cream showed minimal statistical difference from urea 40%. Ingredient research, not a Derm 42 outcome claim.

  Ross AJ et al. · J Am Podiatr Med Assoc · 2025 · PMID 41166120

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  A urea/glycerine/petrolatum cream improved fissure closure and xerosis.

  Diabet Med · 2017

  Full citation

  Multicenter RCT (n=167 with diabetes and heel fissures, 4 weeks): a urea/glycerine/petrolatum cream improved fissure closure and xerosis.

  Gin H et al. · Diabet Med · 2017 · PMID 28627029

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  40% urea ointment under occlusion outperformed bifonazole-urea for complete chemical removal of the infected nail.

  Dermatology · 2013

  Full citation

  Multicenter RCT (onychomycosis): 40% urea ointment under occlusion outperformed bifonazole-urea for complete chemical removal of the infected nail.

  Lahfa M et al. · Dermatology · 2013 · PMID 23467055

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  5% urea + arginine + carnosine cream increased skin hydration vs a glycerol-based emollient.

  BMC Dermatol · 2012

  Full citation

  RCT (type 2 diabetes, severe foot xerosis): 5% urea + arginine + carnosine cream increased skin hydration vs a glycerol-based emollient.

  Federici A et al. · BMC Dermatol · 2012 · PMID 23009311

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  40% urea cream vs 12% ammonium lactate for xerosis; day 14 urea superior on roughness, fissures, thickness, and dryness.

  Am J Clin Dermatol · 2002

  Full citation

  Ademola et al. 2002 — RCT: 40% urea cream vs 12% ammonium lactate for xerosis; day 14 urea superior on roughness, fissures, thickness, and dryness.

  Ademola J et al. · Am J Clin Dermatol · 2002 · PMID 11978141

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  10% urea + 4% lactic acid cream reduced foot xerosis more than its vehicle, with benefit persisting 2 weeks after stopping.

  Ostomy Wound Manage · 2002

  Full citation

  Split-foot RCT (n=40 with diabetes, 4 weeks): 10% urea + 4% lactic acid cream reduced foot xerosis more than its vehicle, with benefit persisting 2 weeks after stopping.

  Pham HT et al. · Ostomy Wound Manage · 2002 · PMID 12046488

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  2% butenafine with 20% urea for keratinolysis; well tolerated.

  J Dermatol · 1998

  Full citation

  Double-blind RCT (toenail onychomycosis): 2% butenafine with 20% urea for keratinolysis; well tolerated.

  Syed TA et al. · J Dermatol · 1998 · PMID 9830263

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Two 10% urea creams of different cost both improved foot skin quality.

  Adv Skin Wound Care · 2024

  Full citation

  Double-blind RCT (diabetic foot syndrome): two 10% urea creams of different cost both improved foot skin quality.

  Tejeda Ramírez S et al. · Adv Skin Wound Care · 2024 · PMID 38648245

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Urea-containing cream vs glycerol emollient for severe foot xerosis in type 2 diabetes (urea combo, not 42%). Greater hydration with the urea cream.

  Curr Med Res Opin · 2015

  Full citation

  Federici et al. 2015 — RCT: urea-containing cream vs glycerol emollient for severe foot xerosis in type 2 diabetes (urea combo, not 42%). Greater hydration with the urea cream.

  Federici A et al. · Curr Med Res Opin · 2015 · PMID 25851453

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  10% urea cream three times daily lowered 12-week hand-foot skin reaction incidence (56.0% vs 73.6%) and delayed onset.

  J Clin Oncol · 2015

  Full citation

  Open-label RCT (n=871, sorafenib): 10% urea cream three times daily lowered 12-week hand-foot skin reaction incidence (56.0% vs 73.6%) and delayed onset.

  Ren Z et al. · J Clin Oncol · 2015 · PMID 25667293

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Phase III placebo-controlled RCT of a urea/lactic-acid keratolytic cream for capecitabine hand-foot syndrome.

  J Clin Oncol · 2010

  Full citation

  Phase III placebo-controlled RCT of a urea/lactic-acid keratolytic cream for capecitabine hand-foot syndrome.

  Wolf SL et al. · J Clin Oncol · 2010 · PMID 21060036

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Urea / ammonium lactate combinations studied for skin hydration and protection vs either component alone.

  Skin Pharmacol Appl Skin Physiol · 2002

  Full citation

  Gloor et al. 2002 — urea / ammonium lactate combinations studied for skin hydration and protection vs either component alone.

  Gloor M et al. · Skin Pharmacol Appl Skin Physiol · 2002 · PMID 11803256

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Glycerine and urea moisturizers differed in their effects on skin barrier function.

  Skin Res Technol · 2001

  Full citation

  RCT in atopic dermatitis: glycerine and urea moisturizers differed in their effects on skin barrier function.

  Lodén M et al. · Skin Res Technol · 2001 · PMID 11737814

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Once-weekly 40% urea/1% bifonazole under occlusion was associated with nail removal about 1 week earlier.

  Skin Appendage Disord · 2020

  Full citation

  Clinical analysis (onychomycosis): once-weekly 40% urea/1% bifonazole under occlusion was associated with nail removal about 1 week earlier.

  Shemer A et al. · Skin Appendage Disord · 2020 · PMID 33088816

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Urea nail lacquer allowed easy removal of the affected part of fungal nail plates.

  J Dermatolog Treat · 2002

  Full citation

  Clinical report: urea nail lacquer allowed easy removal of the affected part of fungal nail plates.

  Baran R et al. · J Dermatolog Treat · 2002 · PMID 19753735

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  40% urea was keratolytic in a standardized stratum-corneum test (high-dose urea NRF formulations).

  Pharmazie · 2001

  Full citation

  Gloor et al. 2001 — 40% urea was keratolytic in a standardized stratum-corneum test (high-dose urea NRF formulations).

  Gloor M et al. · Pharmazie · 2001 · PMID 11683130

  Read on PubMed ↗ (opens in a new tab)
• Review

  Emollient, moisturizing, keratolytic, barrier, and antimicrobial roles (review).

  Dermatol Ther (Heidelb) · 2021

  Full citation

  Piquero-Casals et al. 2021 — urea in dermatology: emollient, moisturizing, keratolytic, barrier, and antimicrobial roles (review).

  Piquero-Casals J et al. · Dermatol Ther (Heidelb) · 2021 · PMID 34596890

  Read on PubMed ↗ (opens in a new tab)
• Review

  Clinical evidence for high-concentration urea on hyperkeratotic skin (keratolytic, moisturizing, emollient).

  Int J Clin Pract · 2020

  Full citation

  Starace et al. 2020 — clinical evidence for high-concentration urea on hyperkeratotic skin (keratolytic, moisturizing, emollient).

  Starace M et al. · Int J Clin Pract · 2020 · PMID 33249711

  Read on PubMed ↗ (opens in a new tab)
• Review

  Lower doses moisturize; higher concentrations (>10%) exert keratolytic action.

  Dermatol Ther · 2018

  Full citation

  Celleno 2018 — topical urea in skincare review: lower doses moisturize; higher concentrations (>10%) exert keratolytic action.

  Celleno L et al. · Dermatol Ther · 2018 · PMID 30378232

  Read on PubMed ↗ (opens in a new tab)
• Review

  Review of emollients and moisturizers for dry-skin barrier; urea-containing moisturizers studied for TEWL and irritation resistance.

  Am J Clin Dermatol · 2003

  Full citation

  Loden 2003 — review of emollients and moisturizers for dry-skin barrier; urea-containing moisturizers studied for TEWL and irritation resistance.

  Lodén M et al. · Am J Clin Dermatol · 2003 · PMID 14572299

  Read on PubMed ↗ (opens in a new tab)

Unrefined mango (Mangifera indica) and shea (Butyrospermum parkii) butters — emollients that help seal moisture after urea softens thick, dry skin. Cited as ingredient research, not a claim that Derm 42 treats eczema or any disease.

• Clinical study

  Cream containing shea butter extract studied for skin hydration and acceptability (pediatric eczema; not a Derm 42 disease-treatment claim).

  Hong Kong Med J · 2015

  Full citation

  Hon et al. 2015 — cream containing shea butter extract studied for skin hydration and acceptability (pediatric eczema; not a Derm 42 disease-treatment claim).

  Hon KL et al. · Hong Kong Med J · 2015 · PMID 26314567

  Read on PubMed ↗ (opens in a new tab)

Aloe vera gel juice, glycerin, and tocopheryl acetate support the cream’s moisturizing feel. Glycerin is a classic humectant used in topical skincare.

• Review

  Review of hydration, barrier, and related functions.

  Br J Dermatol · 2008

  Full citation

  Fluhr et al. 2008 — glycerol and the skin: review of hydration, barrier, and related functions.

  Fluhr JW et al. · Br J Dermatol · 2008 · PMID 18510666

  Read on PubMed ↗ (opens in a new tab)

Fat-soluble vitamin used in epithelial tissue maintenance.

• Randomized trial

  Vitamin A (with zinc status considered) associated with shorter ICU/hospital stays; not this dose or product, nutritional-support context only.

  Nutr Hosp · 2012

  Full citation

  CABG RCT: vitamin A (with zinc status considered) associated with shorter ICU/hospital stays; not this dose or product, nutritional-support context only.

  Matos AC et al. · Nutr Hosp · 2012 · PMID 23588448

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  5,000 IU vitamin A/day linked to lower oxidative-stress markers when zinc was adequate; not WoundWorx dose/form and not a wound-healing trial.

  Nutr Hosp · 2018

  Full citation

  Cardiac surgery patients: 5,000 IU vitamin A/day linked to lower oxidative-stress markers when zinc was adequate; not WoundWorx dose/form and not a wound-healing trial.

  Matos A et al. · Nutr Hosp · 2018 · PMID 30070862

  Read on PubMed ↗ (opens in a new tab)

Collagen-synthesis cofactor — featured in wound-nutrition reviews.

• Meta-analysis

  Cochrane review of nutritional interventions for pressure-ulcer prevention and treatment.

  Cochrane Database Syst Rev · 2024

  Full citation

  Cochrane review of nutritional interventions for pressure-ulcer prevention and treatment.

  Langer G et al. · Cochrane Database Syst Rev · 2024 · PMID 38345088

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Wound-nutrition review

  Antioxidants (Basel) · 2022

  Full citation

  Wound-nutrition review

  Bechara N et al. · Antioxidants (Basel) · 2022 · PMID 36009324

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Vitamin C 600 mg/day for 10 days improved early wound-size reduction and pain vs placebo.

  Int J Dent · 2022

  Full citation

  Split-mouth double-blind RCT (n=42, tooth extraction): vitamin C 600 mg/day for 10 days improved early wound-size reduction and pain vs placebo.

  Pisalsitsakul N et al. · Int J Dent · 2022 · PMID 35310461

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  500 mg slow-release vitamin C; 8-week healing median 100% vs −14% on placebo; half had baseline deficiency.

  Br J Nutr · 2021

  Full citation

  Double-blind RCT (n=16, chronic foot ulcers): 500 mg slow-release vitamin C; 8-week healing median 100% vs −14% on placebo; half had baseline deficiency.

  Gunton JE et al. · Br J Nutr · 2021 · PMID 32981536

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Supplements with arginine 9 g, vitamin C 500 mg and zinc 30 mg improved PUSH scores.

  Clin Nutr · 2005

  Full citation

  Small RCT (n=16, pressure ulcers, 3 weeks): supplements with arginine 9 g, vitamin C 500 mg and zinc 30 mg improved PUSH scores.

  Desneves KJ et al. · Clin Nutr · 2005 · PMID 16297506

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Multicenter RCT of ascorbic acid supplementation for pressure-ulcer healing.

  J Clin Epidemiol · 1995

  Full citation

  Multicenter RCT of ascorbic acid supplementation for pressure-ulcer healing.

  ter Riet G et al. · J Clin Epidemiol · 1995 · PMID 8543959

  Read on PubMed ↗ (opens in a new tab)
• Review

  Collagen cofactor / wound-nutrition reviews

  Br J Community Nurs · 2013

  Full citation

  Collagen cofactor / wound-nutrition reviews

  Moores J et al. · Br J Community Nurs · 2013 · PMID 24796079

  Read on PubMed ↗ (opens in a new tab)

Cholecalciferol for everyday vitamin D status during recovery.

• Meta-analysis

  Lower vitamin D in diabetic foot ulcers; severe deficiency associated with higher DFU risk (OR 3.22).

  Nutr Diabetes · 2019

  Full citation

  Systematic review/meta-analysis (1,115 patients): lower vitamin D in diabetic foot ulcers; severe deficiency associated with higher DFU risk (OR 3.22).

  Dai J et al. · Nutr Diabetes · 2019 · PMID 30858355

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  2024 review of RCTs of vitamin D supplementation, postoperative survival and length of stay.

  BMJ Open · 2024

  Full citation

  2024 review of RCTs of vitamin D supplementation, postoperative survival and length of stay.

  Patel A et al. · BMJ Open · 2024 · PMID 38233048

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Low vitamin D status often associated with worse post-surgical outcomes.

  Patient Saf Surg · 2015

  Full citation

  Systematic review: low vitamin D status often associated with worse post-surgical outcomes.

  Iglar PJ et al. · Patient Saf Surg · 2015 · PMID 25926889

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  High-dose D3 (170 µg) vs low-dose improved ulcer healing rates; chronic diabetic ulcers, not elective surgery, and far above this product’s 25 µg.

  Int J Low Extrem Wounds · 2023

  Full citation

  DFU RCT: high-dose D3 (170 µg) vs low-dose improved ulcer healing rates; chronic diabetic ulcers, not elective surgery, and far above this product’s 25 µg.

  Halschou-Jensen PM et al. · Int J Low Extrem Wounds · 2023 · PMID 34213957

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  50,000 IU vitamin D every 2 weeks reduced ulcer length, width and depth and improved glycemic and lipid markers vs placebo.

  J Diabetes Complications · 2017

  Full citation

  RCT (n=60, grade 3 DFU, 12 weeks): 50,000 IU vitamin D every 2 weeks reduced ulcer length, width and depth and improved glycemic and lipid markers vs placebo.

  Razzaghi R et al. · J Diabetes Complications · 2017 · PMID 27363929

  Read on PubMed ↗ (opens in a new tab)

d-alpha-tocopherol succinate — antioxidant vitamin support.

• Randomized trial

  CABG RCT of high-dose vitamin E+zinc combo shortened hospital stay/inflammation markers; combo and doses differ from this bottle—not wound-healing proof.

  Eur J Clin Nutr · 2024

  Full citation

  CABG RCT of high-dose vitamin E+zinc combo shortened hospital stay/inflammation markers; combo and doses differ from this bottle—not wound-healing proof.

  Makiabadi E et al. · Eur J Clin Nutr · 2024 · PMID 37891226

  Read on PubMed ↗ (opens in a new tab)
• Review

  Significant dearth of robust human data that vitamin E improves wound healing.

  Int Wound J · 2016

  Full citation

  Evidence-based review: significant dearth of robust human data that vitamin E improves wound healing.

  Hobson R et al. · Int Wound J · 2016 · PMID 25124164

  Read on PubMed ↗ (opens in a new tab)
• Review

  Perioperative review of vitamin E and platelet function; discuss vitamin E use around surgery with your surgeon.

  Medicines (Basel) · 2015

  Full citation

  Perioperative review of vitamin E and platelet function; discuss vitamin E use around surgery with your surgeon.

  Wang CZ et al. · Medicines (Basel) · 2015 · PMID 26949700

  Read on PubMed ↗ (opens in a new tab)

Active folate form — not folic acid.

• Observational

  Retrospective DFU cohort used high-dose folic acid 5 mg/day—not L-methylfolate and not this product dose; exploratory nutritional context only.

  Wound Repair Regen · 2020

  Full citation

  Retrospective DFU cohort used high-dose folic acid 5 mg/day—not L-methylfolate and not this product dose; exploratory nutritional context only.

  Boykin JV Jr et al. · Wound Repair Regen · 2020 · PMID 32141182

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  Active folate (5-methyltetrahydrofolate) increased wound DNA synthesis; animal data only.

  J Surg Res · 2008

  Full citation

  Rabbit wound model: active folate (5-methyltetrahydrofolate) increased wound DNA synthesis; animal data only.

  Zhang XJ et al. · J Surg Res · 2008 · PMID 18028951

  Read on PubMed ↗ (opens in a new tab)

Active B12 for methylation pathways.

• Systematic review

  N2O anesthesia can unmask B12 deficiency with neurologic injury—supports adequacy of B12 status around surgery, not wound-cure claims for this capsule.

  Clin Neurol Neurosurg · 2018

  Full citation

  Case review: N2O anesthesia can unmask B12 deficiency with neurologic injury—supports adequacy of B12 status around surgery, not wound-cure claims for this capsule.

  Patel KK et al. · Clin Neurol Neurosurg · 2018 · PMID 30144777

  Read on PubMed ↗ (opens in a new tab)

Supports normal cellular energy metabolism.

• Randomized trial

  RCT after periodontal flap surgery used a full B-complex including 50 µg biotin—not biotin alone or this product; attachment-level gains, not systemic surgical wound proof.

  J Periodontol · 2005

  Full citation

  RCT after periodontal flap surgery used a full B-complex including 50 µg biotin—not biotin alone or this product; attachment-level gains, not systemic surgical wound proof.

  Neiva RF et al. · J Periodontol · 2005 · PMID 16018750

  Read on PubMed ↗ (opens in a new tab)

Oxygen transport mineral in a familiar iron salt form.

• Meta-analysis

  Cochrane review of preoperative iron for anemia.

  Cochrane Database Syst Rev · 2019

  Full citation

  Cochrane review of preoperative iron for anemia.

  Ng O et al. · Cochrane Database Syst Rev · 2019 · PMID 31811820

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  IVICA RCT of oral ferrous sulphate vs IV iron for anemia.

  Br J Surg · 2017

  Full citation

  IVICA RCT of oral ferrous sulphate vs IV iron for anemia.

  Keeler BD et al. · Br J Surg · 2017 · PMID 28092401

  Read on PubMed ↗ (opens in a new tab)

Chelated zinc — researched for roles in tissue repair and immune function.

• Meta-analysis

  Meta-analysis of clinical zinc trials suggests possible ulcer-healing benefit with moderate-certainty evidence; not this chelate form/dose and not a treat/cure claim.

  BMJ Nutr Prev Health · 2025

  Full citation

  Meta-analysis of clinical zinc trials suggests possible ulcer-healing benefit with moderate-certainty evidence; not this chelate form/dose and not a treat/cure claim.

  Arribas Lopez E et al. · BMJ Nutr Prev Health · 2025 · PMID 40771531

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Cochrane review of oral zinc sulphate for arterial or venous leg ulcers.

  Cochrane Database Syst Rev · 2014

  Full citation

  Cochrane review of oral zinc sulphate for arterial or venous leg ulcers.

  Wilkinson EA · Cochrane Database Syst Rev · 2014 · PMID 25202988

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Oral nutritional supplements may enhance chronic-wound healing; high-calorie, high-protein formulas with antioxidants favored.

  Nutrition · 2024

  Full citation

  Systematic review: oral nutritional supplements may enhance chronic-wound healing; high-calorie, high-protein formulas with antioxidants favored.

  Santo ACSDE et al. · Nutrition · 2024 · PMID 38696907

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  50 mg elemental zinc/day reduced ulcer length and width and improved glycemic and oxidative-stress markers vs placebo.

  Wound Repair Regen · 2017

  Full citation

  RCT (n=60, grade 3 diabetic foot ulcer, 12 weeks): 50 mg elemental zinc/day reduced ulcer length and width and improved glycemic and oxidative-stress markers vs placebo.

  Momen-Heravi M et al. · Wound Repair Regen · 2017 · PMID 28395131

  Read on PubMed ↗ (opens in a new tab)
• Review

  Zinc physiology in wound healing

  Wounds · 2017

  Full citation

  Zinc physiology in wound healing

  Kogan S et al. · Wounds · 2017 · PMID 28448263

  Read on PubMed ↗ (opens in a new tab)

L-Selenomethionine antioxidant mineral.

• Meta-analysis

  Shorter stay and lower CRP.

  J Cardiothorac Surg · 2024

  Full citation

  Cardiac-surgery selenium meta-analysis: shorter stay and lower CRP.

  Sarhan AM et al. · J Cardiothorac Surg · 2024 · PMID 38659018

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Large RCT of high-dose IV sodium selenite after cardiac surgery.

  JAMA Surg · 2023

  Full citation

  Large RCT of high-dose IV sodium selenite after cardiac surgery.

  Stoppe C et al. · JAMA Surg · 2023 · PMID 36630120

  Read on PubMed ↗ (opens in a new tab)
• Case report

  Correcting zinc+selenium deficiency after RYGB coincided with laparotomy-wound improvement—n=1, combined micronutrients, not this product.

  J Family Med Prim Care · 2023

  Full citation

  Single case: correcting zinc+selenium deficiency after RYGB coincided with laparotomy-wound improvement—n=1, combined micronutrients, not this product.

  Chizooma E et al. · J Family Med Prim Care · 2023 · PMID 38186775

  Read on PubMed ↗ (opens in a new tab)

Trace mineral that pairs with zinc in connective-tissue enzymes.

• Randomized trial

  Cesarean RCT of copper-impregnated dressings (topical)—not oral copper gluconate 1 mg; delivery-route mismatch.

  Eur J Obstet Gynecol Reprod Biol · 2020

  Full citation

  Cesarean RCT of copper-impregnated dressings (topical)—not oral copper gluconate 1 mg; delivery-route mismatch.

  Arendsen LP et al. · Eur J Obstet Gynecol Reprod Biol · 2020 · PMID 32502772

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Prospective copper-dressing study on hard-to-heal wounds; topical copper oxide dressings—not oral gluconate and not this supplement.

  Health Sci Rep · 2024

  Full citation

  Prospective copper-dressing study on hard-to-heal wounds; topical copper oxide dressings—not oral gluconate and not this supplement.

  Gorel O et al. · Health Sci Rep · 2024 · PMID 38226359

  Read on PubMed ↗ (opens in a new tab)

Bovine collagen peptides — types abundant in skin and soft tissue.

• Systematic review

  Oral nutritional supplements had variable effects on wound healing across wound types.

  Ann Otol Rhinol Laryngol · 2022

  Full citation

  Systematic review: oral nutritional supplements had variable effects on wound healing across wound types.

  Daher GS et al. · Ann Otol Rhinol Laryngol · 2022 · PMID 35043693

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Preliminary evidence for oral collagen in wound healing and skin aging; generally safe.

  J Drugs Dermatol · 2019

  Full citation

  Systematic review: preliminary evidence for oral collagen in wound healing and skin aging; generally safe.

  Choi FD et al. · J Drugs Dermatol · 2019 · PMID 30681787

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Pragmatic multicenter RCT of intensive nutrition or wound-healing supplements in hospitalised pressure-ulcer patients.

  J Wound Care · 2023

  Full citation

  Pragmatic multicenter RCT of intensive nutrition or wound-healing supplements in hospitalised pressure-ulcer patients.

  Banks MD et al. · J Wound Care · 2023 · PMID 37094924

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral hydrolyzed collagen-based supplement improved wound-healing rate vs placebo; burn setting and higher protein intake—not this 400 mg dose alone.

  Burns · 2020

  Full citation

  Burn RCT: oral hydrolyzed collagen-based supplement improved wound-healing rate vs placebo; burn setting and higher protein intake—not this 400 mg dose alone.

  Bagheri Miyab K et al. · Burns · 2020 · PMID 31859087

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Collagen peptide supplementation research

  J Cosmet Dermatol · 2015

  Full citation

  Collagen peptide supplementation research

  Asserin J et al. · J Cosmet Dermatol · 2015 · PMID 26362110

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  A fortified collagen protein hydrolysate supplement three times daily roughly doubled the PUSH healing rate vs placebo.

  Adv Skin Wound Care · 2006

  Full citation

  Multicenter RCT (n=89, pressure ulcers, 8 weeks): a fortified collagen protein hydrolysate supplement three times daily roughly doubled the PUSH healing rate vs placebo.

  Lee SK et al. · Adv Skin Wound Care · 2006 · PMID 16557055

  Read on PubMed ↗ (opens in a new tab)
• Animal study

  Dietary collagen hydrolysate increased skin type I/IV collagen and reduced MMP-2 activity

  J Med Food · 2011

  Full citation

  Animal (rat) study: dietary collagen hydrolysate increased skin type I/IV collagen and reduced MMP-2 activity

  Zague V et al. · J Med Food · 2011 · PMID 21480801

  Read on PubMed ↗ (opens in a new tab)

Pineapple enzyme studied in postoperative comfort and wound-care contexts.

• Meta-analysis

  Moderate-quality studies support oral bromelain for pain control and topical bromelain in wound care; no major health risks reported.

  Nutr Health · 2023

  Full citation

  Systematic review/meta-analysis: moderate-quality studies support oral bromelain for pain control and topical bromelain in wound care; no major health risks reported.

  Leelakanok N et al. · Nutr Health · 2023 · PMID 37157782

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Oral bromelain gave moderate relief of postoperative discomfort.

  J Oral Maxillofac Surg · 2019

  Full citation

  Systematic review/meta-analysis (third-molar surgery): oral bromelain gave moderate relief of postoperative discomfort.

  Liu S et al. · J Oral Maxillofac Surg · 2019 · PMID 30986376

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Tibrolin (trypsin + bromelain + rutoside) RCT in surgical wound management — combination enzyme tablet study, not this bottle

  Cureus · 2025

  Full citation

  Tibrolin (trypsin + bromelain + rutoside) RCT in surgical wound management — combination enzyme tablet study, not this bottle

  Dewan B et al. · Cureus · 2025 · PMID 40351995

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Bromelain alone moderately reduced swelling; best results combined with dexamethasone.

  J Craniofac Surg · 2017

  Full citation

  RCT (third-molar surgery): bromelain alone moderately reduced swelling; best results combined with dexamethasone.

  Ghensi P et al. · J Craniofac Surg · 2017 · PMID 27755433

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Less inflammatory response with bromelain than control.

  Quintessence Int · 2014

  Full citation

  RCT (third-molar surgery): less inflammatory response with bromelain than control.

  Ordesi P et al. · Quintessence Int · 2014 · PMID 25019111

  Read on PubMed ↗ (opens in a new tab)

Curcuma longa — curcuminoids studied in inflammation and nutrition research.

• Randomized trial

  No pain difference at 24 h; lower pain at 72 h with curcuminoids.

  Complement Med Res · 2022

  Full citation

  Open-label RCT (laparoscopic hysterectomy): no pain difference at 24 h; lower pain at 72 h with curcuminoids.

  Ariyasriwatana C et al. · Complement Med Res · 2022 · PMID 34986477

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Curcuminoids reduced postoperative pain severity.

  J Complement Integr Med · 2019

  Full citation

  Pilot RCT (laparoscopic gynecologic surgery): curcuminoids reduced postoperative pain severity.

  Phoolcharoen N et al. · J Complement Integr Med · 2019 · PMID 31150356

  Read on PubMed ↗ (opens in a new tab)
• Review

  Nutrition and wound-healing overview discussing curcumin

  Int J Mol Sci · 2019

  Full citation

  Nutrition and wound-healing overview discussing curcumin

  Barchitta M et al. · Int J Mol Sci · 2019 · PMID 30841550

  Read on PubMed ↗ (opens in a new tab)

Raises plasma arginine more efficiently than oral arginine in published PK work.

• Meta-analysis

  Authors conclude wound healing might be enhanced by supplementation at the right dose.

  Nutrients · 2021

  Full citation

  Systematic review/meta-analysis on arginine and glutamine: authors conclude wound healing might be enhanced by supplementation at the right dose.

  Arribas-López E et al. · Nutrients · 2021 · PMID 34444657

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Arginine shows potential; glutamine was only studied with arginine.

  Wound Repair Regen · 2025

  Full citation

  Systematic review (pressure ulcers): arginine shows potential; glutamine was only studied with arginine.

  Torsy T et al. · Wound Repair Regen · 2025 · PMID 40748005

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  A formula enriched with arginine, zinc and antioxidants reduced ulcer area more (60.9% vs 45.2%).

  Ann Intern Med · 2015

  Full citation

  Arginine-pathway research. Multicenter RCT (n=200 malnourished adults with pressure ulcers, 8 weeks): a formula enriched with arginine, zinc and antioxidants reduced ulcer area more (60.9% vs 45.2%).

  Cereda E et al. · Ann Intern Med · 2015 · PMID 25643304

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Oral citrulline vs arginine / NO metabolism

  Br J Clin Pharmacol · 2008

  Full citation

  Schwedhelm et al., Br J Clin Pharmacol 2008 — oral citrulline vs arginine / NO metabolism

  Schwedhelm E et al. · Br J Clin Pharmacol · 2008 · PMID 17662090

  Read on PubMed ↗ (opens in a new tab)
• Review

  L-citrulline/watermelon supplementation and vascular function via the L-arginine/nitric oxide pathway.

  Curr Opin Clin Nutr Metab Care · 2017

  Full citation

  Review: L-citrulline/watermelon supplementation and vascular function via the L-arginine/nitric oxide pathway.

  Figueroa A et al. · Curr Opin Clin Nutr Metab Care · 2017 · PMID 27749691

  Read on PubMed ↗ (opens in a new tab)
• Review

  Review of the pharmacokinetics of arginine, ornithine and citrulline.

  J Nutr · 2007

  Full citation

  Review of the pharmacokinetics of arginine, ornithine and citrulline.

  Cynober L · J Nutr · 2007 · PMID 17513441

  Read on PubMed ↗ (opens in a new tab)

Amino acid studied in surgical and burn nutrition research.

• Meta-analysis

  Enteral glutamine may be associated with shorter stay and fewer wound infections.

  Chin J Traumatol · 2024

  Full citation

  Systematic review/meta-analysis (severe burns): enteral glutamine may be associated with shorter stay and fewer wound infections.

  Yue HY et al. · Chin J Traumatol · 2024 · PMID 37460347

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Apparent benefits came from small single-centre trials; authors do not recommend routine use.

  J Burn Care Res · 2024

  Full citation

  Systematic review/meta-analysis (burns): apparent benefits came from small single-centre trials; authors do not recommend routine use.

  Tao W et al. · J Burn Care Res · 2024 · PMID 38243579

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Shorter hospital stay but no clear cut in morbidity—IV dipeptide, not 175 mg oral L-glutamine.

  Nutrients · 2015

  Full citation

  Meta-analysis of IV glutamine dipeptide in major abdominal surgery: shorter hospital stay but no clear cut in morbidity—IV dipeptide, not 175 mg oral L-glutamine.

  Sandini M et al. · Nutrients · 2015 · PMID 25584966

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Enteral glutamine reduced hospital stay, with a possible burn benefit.

  Crit Care · 2015

  Full citation

  Systematic review/meta-analysis (critically ill): enteral glutamine reduced hospital stay, with a possible burn benefit.

  van Zanten AR et al. · Crit Care · 2015 · PMID 26283217

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  RE-ENERGIZE RCT (n=1,200, severe burns) of enteral glutamine and time to discharge.

  N Engl J Med · 2022

  Full citation

  RE-ENERGIZE RCT (n=1,200, severe burns) of enteral glutamine and time to discharge.

  Heyland DK et al. · N Engl J Med · 2022 · PMID 36082909

  Read on PubMed ↗ (opens in a new tab)

Sodium hyaluronate — extracellular matrix glycosaminoglycan.

• Randomized trial

  Oral HA RCT improved skin hydration/tone (100–200 mg/day)—skin condition study, not surgical-wound healing; dose above this product’s 15 mg.

  Skin Res Technol · 2023

  Full citation

  Oral HA RCT improved skin hydration/tone (100–200 mg/day)—skin condition study, not surgical-wound healing; dose above this product’s 15 mg.

  Gao YR et al. · Skin Res Technol · 2023 · PMID 38009035

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Topical HA gel after palatal graft surgery improved pain and epithelialization; topical oral-surgery use—not oral sodium hyaluronate capsules.

  J Periodontol · 2018

  Full citation

  Topical HA gel after palatal graft surgery improved pain and epithelialization; topical oral-surgery use—not oral sodium hyaluronate capsules.

  Yıldırım S et al. · J Periodontol · 2018 · PMID 28914592

  Read on PubMed ↗ (opens in a new tab)

Probiotic strain included for gut support during recovery.

No ingredient-specific studies listed.

Companion probiotic in the same serving.

• Meta-analysis

  Probiotics/synbiotics associated with lower infection (OR 0.34) and septicemia incidence.

  Clin Transl Gastroenterol · 2020

  Full citation

  Multi-strain probiotic research. Meta-analysis of placebo-controlled RCTs (colorectal cancer surgery): probiotics/synbiotics associated with lower infection (OR 0.34) and septicemia incidence.

  Amitay EL et al. · Clin Transl Gastroenterol · 2020 · PMID 33512803

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Probiotics reduced overall infection (OR 0.51) and incision infection (OR 0.59).

  Int J Colorectal Dis · 2019

  Full citation

  Systematic review/meta-analysis (colorectal cancer surgery): probiotics reduced overall infection (OR 0.51) and incision infection (OR 0.59).

  Ouyang X et al. · Int J Colorectal Dis · 2019 · PMID 30539265

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Synbiotics ranked first for reducing surgical-site infection, pneumonia, sepsis, stay and antibiotic use.

  Clin Infect Dis · 2017

  Full citation

  Network meta-analysis (surgical patients): synbiotics ranked first for reducing surgical-site infection, pneumonia, sepsis, stay and antibiotic use.

  Kasatpibal N et al. · Clin Infect Dis · 2017 · PMID 28475793

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  4-strain probiotic including L. plantarum UBLP-40 reduced SSI vs placebo; multi-strain (not this bottle alone) and strain mismatch vs unspecified L. plantarum 5 mg.

  Nutrients · 2022

  Full citation

  Trauma ICU RCT: 4-strain probiotic including L. plantarum UBLP-40 reduced SSI vs placebo; multi-strain (not this bottle alone) and strain mismatch vs unspecified L. plantarum 5 mg.

  Tzikos G et al. · Nutrients · 2022 · PMID 35807801

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  4-probiotic mix including L. plantarum cut SSI/pneumonia/leak rates; combo regimen—not single-strain plantarum at this dose.

  World J Surg · 2015

  Full citation

  Colorectal surgery RCT: 4-probiotic mix including L. plantarum cut SSI/pneumonia/leak rates; combo regimen—not single-strain plantarum at this dose.

  Kotzampassi K et al. · World J Surg · 2015 · PMID 25894405

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Elective surgery RCT of L. plantarum 299v on bacterial translocation and septic morbidity.

  Gut · 2002

  Full citation

  Elective surgery RCT of L. plantarum 299v on bacterial translocation and septic morbidity.

  McNaught CE et al. · Gut · 2002 · PMID 12427785

  Read on PubMed ↗ (opens in a new tab)

Piper nigrum — included to support turmeric absorption.

• Clinical study

  2025 crossover pharmacokinetic reappraisal of piperine and unconjugated curcumin exposure.

  iScience · 2025

  Full citation

  2025 crossover pharmacokinetic reappraisal of piperine and unconjugated curcumin exposure.

  Kroon MAGM et al. · iScience · 2025 · PMID 40487425

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  20 mg piperine with 2 g curcumin raised measured curcumin bioavailability; relevant to turmeric co-ingestion—dose far above 2 mg extract, not wound healing.

  Planta Med · 1998

  Full citation

  Classic human PK: 20 mg piperine with 2 g curcumin raised measured curcumin bioavailability; relevant to turmeric co-ingestion—dose far above 2 mg extract, not wound healing.

  Shoba G et al. · Planta Med · 1998 · PMID 9619120

  Read on PubMed ↗ (opens in a new tab)

Published research describes how Ag+ (silver ions) — not solid silver metal — act as a broad-spectrum antiseptic in lab and dressing studies: attaching to and damaging bacterial membranes, binding thiol groups on proteins, and condensing DNA. These papers study Ag+ and silver hydrogels as ingredients or dressings — in-vitro and dressing research, not a claim that this tube treats, cures, or prevents infection.

• Meta-analysis

  Silver dressings improved healing rate, time to healing, hospital stay and infection resolution.

  J Wound Care · 2022

  Full citation

  Meta-analysis of 7 RCTs (650 patients, diabetic foot ulcers): silver dressings improved healing rate, time to healing, hospital stay and infection resolution.

  Luo Y et al. · J Wound Care · 2022 · PMID 36367799

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Nanocrystalline silver vs older silver formulations—infection 9.5% vs 27.8%, lower pain.

  Ann Plast Surg · 2009

  Full citation

  Meta-analysis of 5 RCTs in burns (n=285): nanocrystalline silver vs older silver formulations—infection 9.5% vs 27.8%, lower pain.

  Gravante G et al. · Ann Plast Surg · 2009 · PMID 19571738

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Silver dressings significantly benefited diabetic-foot-ulcer healing.

  Med Princ Pract · 2025

  Full citation

  Meta-analysis of RCTs (lower-extremity ulcers): silver dressings significantly benefited diabetic-foot-ulcer healing.

  Yi Q et al. · Med Princ Pract · 2025 · PMID 39250909

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Silver-containing hydrofiber shortened healing time and reduced inflammatory reactions vs silver sulfadiazine; safety needs further analysis.

  J Cosmet Dermatol · 2023

  Full citation

  Meta-analysis (burns): silver-containing hydrofiber shortened healing time and reduced inflammatory reactions vs silver sulfadiazine; safety needs further analysis.

  Wu JJ et al. · J Cosmet Dermatol · 2023 · PMID 36683314

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Nanocrystalline silver vs silver sulfadiazine/silver nitrate associated with shorter stay, less pain, fewer procedures and lower infection rates.

  Burns · 2017

  Full citation

  Systematic review/meta-analysis (burns): nanocrystalline silver vs silver sulfadiazine/silver nitrate associated with shorter stay, less pain, fewer procedures and lower infection rates.

  Nherera LM et al. · Burns · 2017 · PMID 28161149

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Antimicrobial dressings vs non-antimicrobial may increase the number of ulcers healed; trials few, small and often poorly designed.

  Cochrane Database Syst Rev · 2017

  Full citation

  Cochrane review (diabetic foot ulcers): antimicrobial dressings vs non-antimicrobial may increase the number of ulcers healed; trials few, small and often poorly designed.

  Dumville JC et al. · Cochrane Database Syst Rev · 2017 · PMID 28613416

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Meta-analysis of RCTs of silver vs silver-free dressings and surgical-site infection in clean/clean-contaminated surgery.

  J Surg Res · 2017

  Full citation

  Meta-analysis of RCTs of silver vs silver-free dressings and surgical-site infection in clean/clean-contaminated surgery.

  Li HZ et al. · J Surg Res · 2017 · PMID 28688669

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Cochrane review of wound dressings, including silver, and surgical-site infection in wounds healing by primary intention.

  Cochrane Database Syst Rev · 2016

  Full citation

  Cochrane review of wound dressings, including silver, and surgical-site infection in wounds healing by primary intention.

  Dumville JC et al. · Cochrane Database Syst Rev · 2016 · PMID 27996083

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  Cochrane review of silver dressings and topical silver agents for wound healing and infection.

  Cochrane Database Syst Rev · 2010

  Full citation

  Cochrane review of silver dressings and topical silver agents for wound healing and infection.

  Storm-Versloot MN et al. · Cochrane Database Syst Rev · 2010 · PMID 20238345

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Silver-nanoparticle gel dressing had a higher weekly healing rate than conventional dressing.

  Int J Low Extrem Wounds · 2023

  Full citation

  Double-blind randomized study (n=80, non-ischemic DFU): silver-nanoparticle gel dressing had a higher weekly healing rate than conventional dressing.

  Essa MS et al. · Int J Low Extrem Wounds · 2023 · PMID 33686887

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  No efficacy or safety difference between nanocrystalline silver and 1% silver sulfadiazine; higher dressing cost.

  Burns · 2022

  Full citation

  RCT (outpatient adult burns): no efficacy or safety difference between nanocrystalline silver and 1% silver sulfadiazine; higher dressing cost.

  Moreira SS et al. · Burns · 2022 · PMID 34688520

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Nano-crystalline silver hydrogel vs silver sulfadiazine in second-degree burns (wound-dressing study).

  J Basic Clin Pharm · 2014

  Full citation

  Adhya et al., 2014 — nano-crystalline silver hydrogel vs silver sulfadiazine in second-degree burns (wound-dressing study).

  Adhya A et al. · J Basic Clin Pharm · 2014 · PMID 25538469

  Read on PubMed ↗ (opens in a new tab)
• Review

  Silver nanoparticles as a new generation of antimicrobials (review).

  Biotechnol Adv · 2009

  Full citation

  Rai et al., 2009 — silver nanoparticles as a new generation of antimicrobials (review).

  Rai M et al. · Biotechnol Adv · 2009 · PMID 18854209

  Read on PubMed ↗ (opens in a new tab)
• Review

  Increasing use of silver-based products as antimicrobial agents (review).

  J Antimicrob Chemother · 2007

  Full citation

  Chopra, 2007 — increasing use of silver-based products as antimicrobial agents (review).

  Chopra I et al. · J Antimicrob Chemother · 2007 · PMID 17307768

  Read on PubMed ↗ (opens in a new tab)
• Review

  Its antibacterial properties and mechanism of action.”

  J Wound Care · 2002

  Full citation

  Lansdown, 2002 — “Silver I: its antibacterial properties and mechanism of action.”

  Lansdown AB et al. · J Wound Care · 2002 · PMID 11998592

  Read on PubMed ↗ (opens in a new tab)
• Lab study

  Electrically generated Ag+; >5-log reduction of S. aureus and E. coli at 90 min with membrane damage.

  Appl Environ Microbiol · 2008

  Full citation

  Jung et al., 2008 — electrically generated Ag+; >5-log reduction of S. aureus and E. coli at 90 min with membrane damage.

  Jung WK et al. · Appl Environ Microbiol · 2008 · PMID 18245232

  Read on PubMed ↗ (opens in a new tab)
• Lab study

  Mechanistic Ag+ study on E. coli and S. aureus (membrane detach, DNA condensation, protein inactivation).

  J Biomed Mater Res · 2000

  Full citation

  Feng et al., 2000 — mechanistic Ag+ study on E. coli and S. aureus (membrane detach, DNA condensation, protein inactivation).

  Feng QL et al. · J Biomed Mater Res · 2000 · PMID 11033548

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HMB is a metabolite of the amino acid leucine. The published research below studied it in older adults, mostly alongside resistance exercise.

• Meta-analysis

  Greater muscle-mass gain in the HMB groups.

  Arch Gerontol Geriatr · 2015

  Full citation

  Wu et al., 2015 — 7 randomized trials in adults 65+ (147 HMB, 140 control): greater muscle-mass gain in the HMB groups.

  Wu H et al. · Arch Gerontol Geriatr · 2015 · PMID 26169182

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  156 women aged 65–79 with low muscle mass, 12 weeks, 1,500 mg calcium-HMB daily with or without resistance training: HMB was associated with a 0.06 m/s difference in usual gait speed vs placebo. Not this dose or product.

  Am J Clin Nutr · 2021

  Full citation

  Osuka et al., 2021 — 156 women aged 65–79 with low muscle mass, 12 weeks, 1,500 mg calcium-HMB daily with or without resistance training: HMB was associated with a 0.06 m/s difference in usual gait speed vs placebo. Not this dose or product.

  Osuka Y et al. · Am J Clin Nutr · 2021 · PMID 34081113

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An essential branched-chain amino acid. The research below looks at leucine and muscle protein synthesis in laboratory and exercise settings.

• Systematic review

  The leucine dose ingested was associated with the muscle-protein-synthesis response in older adults.

  Physiol Rep · 2023

  Full citation

  Wilkinson et al., 2023 — systematic review of post-exercise protein studies in healthy adults: the leucine dose ingested was associated with the muscle-protein-synthesis response in older adults.

  Wilkinson K et al. · Physiol Rep · 2023 · PMID 37537134

  Read on PubMed ↗ (opens in a new tab)
• Clinical study

  Muscle protein synthesis rose in the elderly after the 41% leucine mixture; in young adults both mixtures raised it. Not this dose or form.

  Am J Physiol Endocrinol Metab · 2006

  Full citation

  Katsanos et al., 2006 — controlled study of 6.7 g essential-amino-acid mixtures with 26% vs 41% leucine in young and elderly adults: muscle protein synthesis rose in the elderly after the 41% leucine mixture; in young adults both mixtures raised it. Not this dose or form.

  Katsanos CS et al. · Am J Physiol Endocrinol Metab · 2006 · PMID 16507602

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Ginger root extract studied for its effects on stomach motor function in healthy volunteers. This page reports the study measurements only.

• Randomized trial

  24 healthy volunteers, randomized double-blind crossover, a single 1,200 mg dose of ginger vs placebo, measured by ultrasound: shorter gastric half-emptying time (13.1 vs 26.7 min) and more frequent antral contractions. Different dose and setting from this product.

  Eur J Gastroenterol Hepatol · 2008

  Full citation

  Wu et al., 2008 — 24 healthy volunteers, randomized double-blind crossover, a single 1,200 mg dose of ginger vs placebo, measured by ultrasound: shorter gastric half-emptying time (13.1 vs 26.7 min) and more frequent antral contractions. Different dose and setting from this product.

  Wu KL et al. · Eur J Gastroenterol Hepatol · 2008 · PMID 18403946

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Licorice root extract. The controlled human trial below tested a standardized Glycyrrhiza glabra extract in people with functional dyspepsia, measuring symptom scores.

• Randomized trial

  Adults with functional dyspepsia, randomized double-blind, a standardized G. glabra root extract (75 mg twice daily) vs placebo for 30 days: total symptom scores, a global assessment and a dyspepsia quality-of-life index were lower in the extract group at day 15 and day 30 (P ≤ .05). A named commercial extract; the label does not specify its standardization, and the abstract does not state it was deglycyrrhizinated.

  Evid Based Complement Alternat Med · 2012

  Full citation

  Raveendra et al., 2012 — adults with functional dyspepsia, randomized double-blind, a standardized G. glabra root extract (75 mg twice daily) vs placebo for 30 days: total symptom scores, a global assessment and a dyspepsia quality-of-life index were lower in the extract group at day 15 and day 30 (P ≤ .05). A named commercial extract; the label does not specify its standardization, and the abstract does not state it was deglycyrrhizinated.

  Raveendra KR et al. · Evid Based Complement Alternat Med · 2012 · PMID 21747893

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An enzyme complex from pineapple ( Ananas comosus ). The research below reviews clinical trials of bromelain supplements and markers of inflammation.

• Systematic review

  7 randomized trials of bromelain supplementation in adults (alone or combined with other compounds), about 100–1,200 mg/day for 1–16 weeks: most studies reported lower inflammatory markers. Not a digestion study.

  Clin Nutr ESPEN · 2023

  Full citation

  Pereira et al., 2023 — 7 randomized trials of bromelain supplementation in adults (alone or combined with other compounds), about 100–1,200 mg/day for 1–16 weeks: most studies reported lower inflammatory markers. Not a digestion study.

  Pereira IC et al. · Clin Nutr ESPEN · 2023 · PMID 37202035

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The studies below tested peppermint oil or aroma (inhaled), a different preparation from the leaf extract in this product, and are listed as related ingredient research.

• Meta-analysis

  Lower nausea scores overall (SMD −0.85); the authors note peppermint oil was among the more successful oils. Aromatherapy generally, not peppermint leaf extract.

  Complement Ther Clin Pract · 2024

  Full citation

  Ahn et al., 2024 — 25 randomized trials of aromatherapy (various oils) in patients with cancer: lower nausea scores overall (SMD −0.85); the authors note peppermint oil was among the more successful oils. Aromatherapy generally, not peppermint leaf extract.

  Ahn JH et al. · Complement Ther Clin Pract · 2024 · PMID 38330531

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Lower frequency, duration and severity of nausea, and fewer vomiting episodes, in the first four hours. Inhaled oil, a single exposure, in one surgical setting.

  Complement Ther Clin Pract · 2020

  Full citation

  Maghami et al., 2020 — 60 cardiac-surgery patients, nebulized peppermint essential oil inhaled once before extubation vs control: lower frequency, duration and severity of nausea, and fewer vomiting episodes, in the first four hours. Inhaled oil, a single exposure, in one surgical setting.

  Maghami M et al. · Complement Ther Clin Pract · 2020 · PMID 32891278

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A spore-forming probiotic. The study below tested one named strain, GBI-30, 6086; the Peptalyn label does not name a strain, so results may not carry over.

• Clinical study

  30 adults completed two 2-week protocols with a daily 25 g milk-protein dose with or without B. coagulans GBI-30, 6086: several amino acids showed higher area-under-the-curve and peak blood concentrations (including essential and total amino acids) when taken with the probiotic. Dose not stated in the abstract; strain-specific.

  Nutr Metab (Lond) · 2020

  Full citation

  Stecker et al., 2020 — 30 adults completed two 2-week protocols with a daily 25 g milk-protein dose with or without B. coagulans GBI-30, 6086: several amino acids showed higher area-under-the-curve and peak blood concentrations (including essential and total amino acids) when taken with the probiotic. Dose not stated in the abstract; strain-specific.

  Stecker RA et al. · Nutr Metab (Lond) · 2020 · PMID 33110439

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Menaquinone-7, a long-chain form of vitamin K2. The trial below studied it in relation to bone measures.

• Randomized trial

  A smaller age-related decline in bone mineral content and density at the lumbar spine and femoral neck, and less loss of vertebral height at one thoracic site. Twice this product’s daily amount.

  Osteoporos Int · 2013

  Full citation

  Knapen et al., 2013 — 244 healthy postmenopausal women, 180 µg/day MK-7 or placebo for 3 years: a smaller age-related decline in bone mineral content and density at the lumbar spine and femoral neck, and less loss of vertebral height at one thoracic site. Twice this product’s daily amount.

  Knapen MHJ et al. · Osteoporos Int · 2013 · PMID 23525894

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Vitamin D3. The meta-analysis below pools supplementation trials and bone mineral density.

• Meta-analysis

  Vitamin D3 supplementation was associated with higher bone mineral density at the lumbar spine (SMD 0.06) and femoral neck (SMD 0.25). Effects varied by ethnicity, age, baseline vitamin D level and dosing.

  Nutr Rev · 2023

  Full citation

  Kazemian et al., 2023 — 39 studies in adults: vitamin D3 supplementation was associated with higher bone mineral density at the lumbar spine (SMD 0.06) and femoral neck (SMD 0.25). Effects varied by ethnicity, age, baseline vitamin D level and dosing.

  Kazemian E et al. · Nutr Rev · 2023 · PMID 36308775

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Vitamin B1. The one randomized trial found on thiamin and fatigue used doses far above this product’s and a specific patient group.

• Randomized trial

  40 patients with quiescent inflammatory bowel disease and chronic fatigue, randomized double-blind crossover, 600–1,800 mg/day thiamine for 4 weeks vs placebo: fatigue scores fell 4.5 points on thiamine vs a 0.75-point rise on placebo. This is 120–360 times this product’s thiamin amount, in people with a specific condition, so it does not describe a supplement at this dose.

  Aliment Pharmacol Ther · 2021

  Full citation

  Bager et al., 2021 — 40 patients with quiescent inflammatory bowel disease and chronic fatigue, randomized double-blind crossover, 600–1,800 mg/day thiamine for 4 weeks vs placebo: fatigue scores fell 4.5 points on thiamine vs a 0.75-point rise on placebo. This is 120–360 times this product’s thiamin amount, in people with a specific condition, so it does not describe a supplement at this dose.

  Bager P et al. · Aliment Pharmacol Ther · 2021 · PMID 33210299

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The research below tested B-complex or multivitamin products, so results cannot be assigned to any single B vitamin. Doses, forms and populations differ from this product.

• Meta-analysis

  8 randomized placebo-controlled trials of multivitamin/mineral supplements (at least 28 days) in non-clinical adults: lower perceived stress, mild psychiatric symptoms, anxiety and fatigue scores (fatigue SMD 0.27). The authors suggest supplements with high B-vitamin doses may work better.

  Psychosom Med · 2013

  Full citation

  Long & Benton, 2013 — 8 randomized placebo-controlled trials of multivitamin/mineral supplements (at least 28 days) in non-clinical adults: lower perceived stress, mild psychiatric symptoms, anxiety and fatigue scores (fatigue SMD 0.27). The authors suggest supplements with high B-vitamin doses may work better.

  Long SJ et al. · Psychosom Med · 2013 · PMID 23362497

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  A benefit for stress (SMD 0.23). The authors note B vitamins may matter most for people with poor nutrient or mood status.

  Nutrients · 2019

  Full citation

  Young et al., 2019 — 16 randomized trials of daily supplements with three or more B vitamins (at least 4 weeks): a benefit for stress (SMD 0.23). The authors note B vitamins may matter most for people with poor nutrient or mood status.

  Young LM et al. · Nutrients · 2019 · PMID 31527485

  Read on PubMed ↗ (opens in a new tab)
• Systematic review

  7 randomized placebo-controlled trials of high-dose B-complex multivitamin/mineral supplements in healthy and “at-risk” adults: improvements in perceived stress, physical stamina, concentration and self-reported vigour in several trials. High-dose combination products, not this formula.

  Nutr Hosp · 2021

  Full citation

  Sarris et al., 2021 — 7 randomized placebo-controlled trials of high-dose B-complex multivitamin/mineral supplements in healthy and “at-risk” adults: improvements in perceived stress, physical stamina, concentration and self-reported vigour in several trials. High-dose combination products, not this formula.

  Sarris J et al. · Nutr Hosp · 2021 · PMID 34530623

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Better scores on perceived stress, a general health questionnaire and the “vigour” mood subscale, and lower self-rated mental tiredness during a demanding task battery. Multi-nutrient product, men only, doses not stated in the abstract.

  Psychopharmacology (Berl) · 2010

  Full citation

  Kennedy et al., 2010 — 215 working men aged 30–55, 33 days of a high-dose B-complex plus vitamin C and minerals vs placebo: better scores on perceived stress, a general health questionnaire and the “vigour” mood subscale, and lower self-rated mental tiredness during a demanding task battery. Multi-nutrient product, men only, doses not stated in the abstract.

  Kennedy DO et al. · Psychopharmacology (Berl) · 2010 · PMID 20454891

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  32 healthy adults aged 20–30, randomized double-blind crossover, a 28-day vitamin B1, B2, B6 and B12 tablet vs placebo: longer treadmill running time to exhaustion (1.26-fold) and lower blood lactate and ammonia during and after exercise. Small, one combination tablet, doses not stated in the abstract.

  Int J Med Sci · 2023

  Full citation

  Lee et al., 2023 — 32 healthy adults aged 20–30, randomized double-blind crossover, a 28-day vitamin B1, B2, B6 and B12 tablet vs placebo: longer treadmill running time to exhaustion (1.26-fold) and lower blood lactate and ammonia during and after exercise. Small, one combination tablet, doses not stated in the abstract.

  Lee MC et al. · Int J Med Sci · 2023 · PMID 37786445

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The active, methylated form of folate. The trial below compared how much reached the blood versus folic acid.

• Randomized trial

  The plasma folate response to [6S]-5-MTHF was comparable to folic acid. The specific 5-MTHF salt may differ from this product’s.

  J Nutr · 2004

  Full citation

  Pentieva et al., 2004 — double-blind crossover in 13 men, a single 500 µg dose: the plasma folate response to [6S]-5-MTHF was comparable to folic acid. The specific 5-MTHF salt may differ from this product’s.

  Pentieva K et al. · J Nutr · 2004 · PMID 14988450

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Vitamin B12. The studies below looked at B12 and fatigue, cognition and mood in people without clear deficiency.

• Meta-analysis

  16 randomized trials (6,276 participants) of B12, alone or with folic acid ± B6, in people without overt deficiency, on cognitive function and depressive symptoms.

  Nutrients · 2021

  Full citation

  Markun et al., 2021 — 16 randomized trials (6,276 participants) of B12, alone or with folic acid ± B6, in people without overt deficiency, on cognitive function and depressive symptoms.

  Markun S et al. · Nutrients · 2021 · PMID 33809274

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  95 patients with irritable bowel syndrome or inflammatory bowel disease, fatigue and normal B12 levels, 1,000 µg B12 daily vs placebo for 8 weeks, measuring subjective fatigue, depression and quality of life.

  Clin Nutr ESPEN · 2018

  Full citation

  Scholten et al., 2018 — 95 patients with irritable bowel syndrome or inflammatory bowel disease, fatigue and normal B12 levels, 1,000 µg B12 daily vs placebo for 8 weeks, measuring subjective fatigue, depression and quality of life.

  Scholten AM et al. · Clin Nutr ESPEN · 2018 · PMID 29460813

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Vitamin B7. The studies below looked at biotin and hair or nails.

• Observational

  Biotin deficiency was found in 38%. This measures biotin status; it is not a supplementation trial.

  Int J Trichology · 2016

  Full citation

  Trüeb, 2016 — serum biotin measured in women who complained of hair loss: biotin deficiency was found in 38%. This measures biotin status; it is not a supplementation trial.

  Trüeb RM · Int J Trichology · 2016 · PMID 27601860

  Read on PubMed ↗ (opens in a new tab)
• Observational

  22 (63%) showed clinical improvement. A different dose from this product’s.

  Cutis · 1993

  Full citation

  Hochman et al., 1993 — retrospective chart review of 35 people with brittle nails taking daily biotin: 22 (63%) showed clinical improvement. A different dose from this product’s.

  Hochman LG et al. · Cutis · 1993 · PMID 8477615

  Read on PubMed ↗ (opens in a new tab)
• Review

  18 reported cases, all in people with an underlying cause of poor hair or nail growth, who improved after supplementation.

  Skin Appendage Disord · 2017

  Full citation

  Patel et al., 2017 — review of case reports and trials of biotin for hair and nails: 18 reported cases, all in people with an underlying cause of poor hair or nail growth, who improved after supplementation.

  Patel DP et al. · Skin Appendage Disord · 2017 · PMID 28879195

  Read on PubMed ↗ (opens in a new tab)
• Review

  Clinical trials reported improved firmness, hardness and thickness of brittle nails with oral biotin.

  J Dermatolog Treat · 2018

  Full citation

  Lipner & Scher, 2018 — review of biotin for nail conditions: clinical trials reported improved firmness, hardness and thickness of brittle nails with oral biotin.

  Lipner SR et al. · J Dermatolog Treat · 2018 · PMID 29057689

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Magnesium bound to the amino acid glycine. The trial below compared how much was absorbed.

• Randomized trial

  Double-blind crossover in 12 patients with ileal resection, 100 mg of isotope-labelled magnesium diglycinate vs magnesium oxide: in the four patients with the poorest absorption of the oxide, absorption was higher from the glycinate (23.5% vs 11.8%). A small study in a specific patient group.

  JPEN J Parenter Enteral Nutr · 1994

  Full citation

  Schuette et al., 1994 — double-blind crossover in 12 patients with ileal resection, 100 mg of isotope-labelled magnesium diglycinate vs magnesium oxide: in the four patients with the poorest absorption of the oxide, absorption was higher from the glycinate (23.5% vs 11.8%). A small study in a specific patient group.

  Schuette SA et al. · JPEN J Parenter Enteral Nutr · 1994 · PMID 7815675

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A trace mineral. Studies below tested chromium (mostly as picolinate) on blood-sugar measures, appetite and food intake. Doses in the trials are often higher than this product’s.

• Meta-analysis

  Lower HbA1c (−0.55%) and fasting glucose (−1.15 mmol/L) on average; the abstract notes effects were more evident with picolinate and with doses above 200 µg/day. Participants had diabetes.

  J Clin Pharm Ther · 2014

  Full citation

  Suksomboon et al., 2014 — 25 randomized trials of chromium (mostly alone; chromium picolinate in several) in people with diabetes: lower HbA1c (−0.55%) and fasting glucose (−1.15 mmol/L) on average; the abstract notes effects were more evident with picolinate and with doses above 200 µg/day. Participants had diabetes.

  Suksomboon N et al. · J Clin Pharm Ther · 2014 · PMID 24635480

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Lower fasting glucose, insulin, HbA1c and HOMA-IR on average.

  Pharmacol Res · 2020

  Full citation

  Asbaghi et al., 2020 — 28 randomized trials in people with type 2 diabetes: lower fasting glucose, insulin, HbA1c and HOMA-IR on average.

  Asbaghi O et al. · Pharmacol Res · 2020 · PMID 32730903

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  15 randomized trials with data (618 participants) on chromium and glucose or insulin levels.

  Am J Clin Nutr · 2002

  Full citation

  Althuis et al., 2002 — 15 randomized trials with data (618 participants) on chromium and glucose or insulin levels.

  Althuis MD et al. · Am J Clin Nutr · 2002 · PMID 12081828

  Read on PubMed ↗ (opens in a new tab)
• Meta-analysis

  Average difference in body weight with chromium vs placebo of −0.50 kg.

  Obes Rev · 2013

  Full citation

  Onakpoya et al., 2013 — 11 randomized trials in overweight and obese adults: average difference in body weight with chromium vs placebo of −0.50 kg.

  Onakpoya I et al. · Obes Rev · 2013 · PMID 23495911

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  Acute insulin response to glucose was higher with chromium. Five times this product’s dose.

  Metab Syndr Relat Disord · 2009

  Full citation

  Iqbal et al., 2009 — 63 obese adults with metabolic syndrome, 1,000 µg/day chromium picolinate or placebo for 16 weeks: acute insulin response to glucose was higher with chromium. Five times this product’s dose.

  Iqbal N et al. · Metab Syndr Relat Disord · 2009 · PMID 19422140

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  19 healthy, non-obese adults aged 63–77, 1,000 µg/day chromium picolinate or placebo for 8 weeks, measuring insulin sensitivity, serum lipids and body composition. Five times this product’s dose.

  J Gerontol A Biol Sci Med Sci · 2000

  Full citation

  Amato et al., 2000 — 19 healthy, non-obese adults aged 63–77, 1,000 µg/day chromium picolinate or placebo for 8 weeks, measuring insulin sensitivity, serum lipids and body composition. Five times this product’s dose.

  Amato P et al. · J Gerontol A Biol Sci Med Sci · 2000 · PMID 10819315

  Read on PubMed ↗ (opens in a new tab)
• Randomized trial

  42 overweight women who reported carbohydrate cravings, chromium picolinate (dose printed as “1,000 mg” in the abstract) or placebo for 8 weeks: lower measured food intake, hunger and fat-craving scores. Small trial; the abstract also reports a rat experiment, not described here.

  Diabetes Technol Ther · 2008

  Full citation

  Anton et al., 2008 — 42 overweight women who reported carbohydrate cravings, chromium picolinate (dose printed as “1,000 mg” in the abstract) or placebo for 8 weeks: lower measured food intake, hunger and fat-craving scores. Small trial; the abstract also reports a rat experiment, not described here.

  Anton SD et al. · Diabetes Technol Ther · 2008 · PMID 18715218

  Read on PubMed ↗ (opens in a new tab)
• Review

  Narrative review of 20 randomized trials of chromium and glycemic targets in people with type 2 diabetes.

  Nutr Rev · 2016

  Full citation

  Costello et al., 2016 — narrative review of 20 randomized trials of chromium and glycemic targets in people with type 2 diabetes.

  Costello RB et al. · Nutr Rev · 2016 · PMID 27261273

  Read on PubMed ↗ (opens in a new tab)