Find the peptide you care about, read what each study actually found, then go and read the paper yourself. No summaries you have to take on trust.
How to use this. Search or tap a category, open a peptide, and you will see its studies listed strongest evidence first. Every headline opens into a plain English summary of what was done and what was found, with a link straight to the source.
The tag on each study tells you what kind of evidence it is, because a randomised trial in people and a study in rats are not the same thing and we are not going to pretend they are.
Retatrutide is a once-weekly injection that acts on three metabolic receptors at once (GLP-1, GIP and glucagon), rather than the one or two that current weight-loss drugs target. It has produced the largest weight losses yet recorded for a drug: about 24% of body weight over 48 weeks in phase 2, and roughly 28% over 68 to 80 weeks in phase 3. It is still investigational and is not approved anywhere.
Where the evidence stands. Strong and fast-maturing human evidence, including published phase 3 trials, but the drug remains investigational and unapproved, and several headline phase 3 results are still company press releases rather than peer-reviewed papers.
TRANSCEND-T2D-1, a double-blind randomised phase 3 trial across 48 sites in 537 adults with type 2 diabetes not controlled by diet and exercise alone, comparing retatrutide 4, 9 and 12 mg with placebo over 40 weeks. HbA1c fell by 1.69%, 1.86% and 1.94% across ascending doses versus 0.81% on placebo, and body weight fell by 11.5%, 13.9% and 15.3% versus 2.6% on placebo. Gastrointestinal events were generally mild and transient, discontinuation for adverse events was 2 to 5%, and no severe hypoglycaemia occurred. This is the first peer-reviewed phase 3 publication for retatrutide.
Bajaj HS et al., Lancet 2026;407:2402-2413. Verified against the PubMed record (PMID 42250575). Figures quoted are the treatment-regimen values in the published abstract; slightly higher numbers circulated in conference coverage using the efficacy estimand.
Read the study →TRIUMPH-1 is the pivotal phase 3 obesity trial, randomising 2,339 adults with obesity or overweight plus a weight-related condition, without diabetes, to retatrutide 4, 9 or 12 mg or placebo for 80 weeks. Reported weight loss was 19.0% (4 mg), 25.9% (9 mg) and 28.3% (12 mg) versus 2.2% on placebo, with a 104-week extension in a subgroup reaching 30.3%. These are company-reported topline results only; the full dataset, safety detail and peer review are still outstanding.
IMPORTANT: this is a company press release dated 21 May 2026, not a peer-reviewed paper. Lilly states detailed results will be presented at a future medical meeting and published later. Treat the numbers as provisional.
Read the study →TRIUMPH-4, a 68-week phase 3 trial, randomised 445 adults with obesity or overweight plus knee osteoarthritis to retatrutide 9 mg, 12 mg or placebo. From a mean baseline weight of 112.7 kg, the 12 mg group lost 28.7% of body weight (32.3 kg) and the 9 mg group 26.4%, versus 2.1% on placebo. WOMAC knee pain scores fell by up to 4.5 points (75.8%) versus 2.4 points (40.3%) on placebo, and more than one in eight treated participants ended the trial free of knee pain. This is topline company data, and pain relief here is largely inseparable from the weight loss itself rather than being a direct joint effect.
IMPORTANT: company press release dated 11 December 2025, not peer reviewed. Lilly states detailed results will be published in a peer-reviewed journal in future. Corroborated by independent coverage in Healio, Pharmacy Times and Rheumatology Advisor.
Read the study →A randomised, double-blind, placebo-controlled phase 2a substudy of 98 adults who had at least 10% liver fat on MRI at baseline, treated for 48 weeks with retatrutide 1, 4, 8 or 12 mg or placebo. At 24 weeks mean relative liver fat fell by 42.9%, 57.0%, 81.4% and 82.4% across ascending doses, versus a 0.3% rise on placebo, with normal liver fat (under 5%) reached by 86% of the 12 mg group and 0% of placebo. Liver fat reductions tracked closely with weight and abdominal fat loss, so this is not clearly a liver-specific effect, and the study measured fat content by imaging rather than biopsy-confirmed disease resolution.
Sanyal AJ et al., Nat Med 2024;30:2037-2048. Verified against the PubMed record (PMID 38858523). This is a substudy of the phase 2 obesity trial, not an independent trial.
Read the study →A randomised, double-blind, placebo-controlled phase 2 trial in 338 adults with obesity, testing once-weekly retatrutide at 1, 4, 8 and 12 mg against placebo for 48 weeks. Mean weight change at 48 weeks ranged from -8.7% (1 mg) to -24.2% (12 mg) versus -2.1% for placebo; at 24 weeks the 12 mg group was already at -17.5% versus -1.6%. Gastrointestinal side effects were dose-dependent and mostly mild to moderate, and heart rate rose before declining after week 24. As a phase 2 trial it was not powered or designed to show long-term safety or hard clinical outcomes.
Jastreboff AM et al., N Engl J Med 2023;389:514-526. Verified against the PubMed record (PMID 37366315).
Read the study →A randomised, double-blind, placebo and active-controlled phase 2 trial in 281 US adults with type 2 diabetes, comparing retatrutide doses against placebo and against dulaglutide 1.5 mg. At 24 weeks HbA1c fell by up to 2.02% (12 mg) versus 0.01% with placebo and 1.41% with dulaglutide. Body weight fell by up to 16.94% at 36 weeks versus 3.00% with placebo. Mild to moderate gastrointestinal events occurred in 35% of retatrutide recipients, the same rate as dulaglutide; there was no severe hypoglycaemia and no deaths.
Rosenstock J et al., Lancet 2023;402:529-544. Verified against the PubMed record (PMID 37385280).
Read the study →GLP-1 is a hormone your gut releases after you eat. It tells the pancreas to release insulin only when glucose is high, slows how fast the stomach empties, and signals fullness to the brain. Drugs that mimic it (semaglutide, liraglutide, dulaglutide) or that hit both the GLP-1 and GIP receptors (tirzepatide) are by a wide margin the most rigorously tested peptide medicines in existence: tens of thousands of people in multi-year randomised placebo-controlled trials measuring hard outcomes like heart attack, stroke, kidney failure and death, not just weight on a scale. Side effects are real and mostly gastrointestinal, and discontinuation rates in the big trials were roughly double placebo.
Where the evidence stands. The strongest evidence base of any peptide class by a wide margin: multiple large, multi-year, randomised, double-blind, placebo-controlled trials with hard cardiovascular, kidney and mortality endpoints.
FLOW randomised 3,533 people with type 2 diabetes and chronic kidney disease to weekly semaglutide 1.0 mg or placebo, median follow-up 3.4 years. The trial was stopped early for benefit. Major kidney disease events fell 24% (hazard ratio 0.76), cardiovascular death fell 29%, major cardiovascular events fell 18%, and death from any cause fell 20%. Kidney function declined more slowly on semaglutide. Serious adverse events were actually less frequent on semaglutide (49.6% vs 53.8%). Applies specifically to diabetic kidney disease, not the general population.
Citation as printed matches exactly: Perkovic V et al., N Engl J Med 2024;391(2):109-121, PMID 38785209.
Read the study →SELECT randomised 17,604 people aged 45+ with existing cardiovascular disease and a BMI of 27 or more, but no diabetes, to weekly semaglutide 2.4 mg or placebo, and followed them a mean of 39.8 months. Cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo (hazard ratio 0.80). This is the trial that showed benefit beyond blood sugar. The trade-off: 16.6% permanently stopped semaglutide because of adverse events versus 8.2% on placebo.
CORRECTED. Source list prints 'New England Journal of Medicine, 389(23), 2115-2128'. The correct citation is Lincoff AM et al., N Engl J Med 2023;389(24):2221-2232, PMID 37952131. The DOI as printed is correct. Note the source list prints this same trial twice (references 13 and 20).
Read the study →SURMOUNT-1 randomised 2,539 adults with obesity and without diabetes to weekly tirzepatide 5, 10 or 15 mg or placebo for 72 weeks. Mean weight change was -15.0%, -19.5% and -20.9% across the three doses versus -3.1% on placebo. Strikingly, 57% of people on 15 mg lost at least a fifth of their body weight, versus 3% on placebo. Side effects were mostly gastrointestinal and concentrated during dose escalation; 4.3 to 7.1% discontinued because of adverse events. Weight, not cardiovascular events, was the endpoint here.
Citation as printed matches exactly: Jastreboff AM et al., N Engl J Med 2022;387(3):205-216, PMID 35658024.
Read the study →STEP 1 randomised 1,961 adults with obesity (or overweight plus a weight-related condition) and no diabetes 2:1 to weekly semaglutide 2.4 mg or placebo plus lifestyle support for 68 weeks. Mean weight change was -14.9% with semaglutide versus -2.4% with placebo; 69.1% lost at least 10% of body weight and 50.5% lost at least 15%, against 12.0% and 4.9% on placebo. In kilograms that is -15.3 kg versus -2.6 kg. Nausea and diarrhoea were the commonest side effects, and 4.5% stopped treatment because of gastrointestinal events.
Citation as printed matches exactly: Wilding JPH et al., N Engl J Med 2021;384(11):989-1002, PMID 33567185.
Read the study →STEP 2 randomised 1,210 adults who had both overweight/obesity and type 2 diabetes to weekly semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo for 68 weeks. Weight fell 9.6% on 2.4 mg versus 3.4% on placebo, and 68.8% lost at least 5% of body weight versus 28.5%. This is a useful reality check against the headline STEP 1 figure: the same drug at the same dose produced markedly less weight loss in people with diabetes (9.6% vs 14.9%). Gastrointestinal adverse events affected 63.5% on the 2.4 mg dose.
CORRECTED TRIAL NAME. Source list labels this 'STEP 8' and omits 'and type 2 diabetes' from the title. It is actually STEP 2: Davies M et al., 'Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)', Lancet 2021;397(10278):971-984, PMID 33667417. Journal, year, volume, pages and DOI as printed are correct; only the trial label and title are wrong. STEP 8 is a different trial (semaglutide vs liraglutide, published in JAMA).
Read the study →REWIND randomised 9,901 people with type 2 diabetes at 371 sites in 24 countries to weekly dulaglutide 1.5 mg or placebo, with a median follow-up of 5.4 years - the longest of the major GLP-1 outcome trials. The primary composite of non-fatal heart attack, non-fatal stroke or cardiovascular death occurred in 12.0% versus 13.4% (hazard ratio 0.88). Its distinctive contribution is that most participants had no previous cardiovascular event, so it extends the benefit to primary prevention. All-cause mortality did not differ significantly, and 47.4% reported gastrointestinal side effects versus 34.1% on placebo.
Citation as printed matches exactly: Gerstein HC et al., Lancet 2019;394(10193):121-130, PMID 31189511.
Read the study →LEADER randomised 9,340 people with type 2 diabetes at high cardiovascular risk to daily liraglutide or placebo, median follow-up 3.8 years. The composite of cardiovascular death, non-fatal heart attack and non-fatal stroke occurred in 13.0% versus 14.9% (hazard ratio 0.87, significant for superiority). Death from cardiovascular causes fell from 6.0% to 4.7% and all-cause death from 9.6% to 8.2%. The individual components (heart attack, stroke, heart failure hospitalisation) were each lower but not statistically significant on their own; the benefit shows in the composite and in mortality.
Citation as printed matches exactly: Marso SP et al., N Engl J Med 2016;375(4):311-322, PMID 27295427.
Read the study →SUSTAIN-6 randomised 3,297 people with type 2 diabetes to weekly semaglutide (0.5 or 1.0 mg) or placebo for 104 weeks. The composite of cardiovascular death, non-fatal heart attack and non-fatal stroke occurred in 6.6% versus 8.9% (hazard ratio 0.74), driven largely by a reduction in non-fatal stroke. This trial is also the honest counterweight: retinopathy complications (vitreous haemorrhage, blindness, or needing intravitreal treatment or photocoagulation) were significantly MORE common on semaglutide (hazard ratio 1.76). Cardiovascular death rates themselves were similar between groups.
Citation as printed matches exactly: Marso SP et al., N Engl J Med 2016;375(19):1834-1844, PMID 27633186.
Read the study →MOTS-c is a 16-amino-acid peptide encoded inside mitochondrial DNA itself, which was only discovered in 2015. In mice it activates AMPK, improves how skeletal muscle handles glucose, and protects against diet-induced obesity and age-related insulin resistance. In humans the picture is much thinner: we know exercise raises the body's own MOTS-c and that blood levels fall with age, but no published randomised trial has yet tested giving MOTS-c to people.
Where the evidence stands. Consistent and mechanistically detailed rodent and cell evidence; in humans MOTS-c has only been measured, never tested as a therapy in a published randomised trial.
A narrative review of MOTS-c biology covering its discovery, its role in glucose metabolism in skeletal muscle, and proposed applications in ageing, cardiovascular disease, insulin resistance and inflammation. Notably the authors state plainly that MOTS-c has been used very little in treating disease and that no effective method of applying it in the clinic has been developed. Useful as an orientation to the field, but a review summarises other people's data rather than generating new evidence.
Confirmed as Zheng Y, Wei Z, Wang T, Front Endocrinol (Lausanne) 2023;14:1120533, PMID 36761202. Design is a narrative review, not a systematic review or meta-analysis.
Read the study →In mice, MOTS-c injections improved running performance in young (2 months), middle-aged (12 months) and old (22 months) animals, and treatment started very late in life (23.5 months, 3x weekly) still increased physical capacity. The human component is much smaller: exercise was shown to increase MOTS-c expression in skeletal muscle and in the bloodstream. That human part is an observation about the body's own peptide responding to exercise, not a test of MOTS-c as a treatment.
Paper confirmed as Nat Commun 2021;12(1):470, PMID 33473109. The source list prints the pages as '1-14' (and again as '1-11' in a duplicate entry); the correct locator is article number 470. Reference 12 in the source list is a duplicate of reference 2.
Read the study →The paper that discovered MOTS-c. Researchers found a short reading frame inside mitochondrial DNA encoding a 16-amino-acid peptide, then showed in cultured cells that it inhibits the folate cycle and de novo purine synthesis, which activates AMPK. Injecting MOTS-c into mice prevented both age-dependent and high-fat-diet-induced insulin resistance, and prevented diet-induced obesity. Everything here is mice and cell culture; no human dosing was involved.
Citation as printed (Lee C et al., 2015, Cell Metabolism 21(3):443-454) matches the record exactly. PMID 25738459.
Read the study →Showed that MOTS-c, though encoded in the mitochondrial genome, physically relocates into the cell nucleus when the cell is starved of glucose, and there switches on stress-response genes via AMPK and the transcription factor NRF2. This was the first demonstration that a mitochondrially-encoded factor directly regulates nuclear genes. It is cell-biology work, so it explains a mechanism rather than showing any health outcome.
CORRECTED. Source list prints 'Kim, K. H., et al., (2019) ... Cell Metabolism, 30(5), 898-909.e5'. The real paper is Kim KH, Son JM, Benayoun BA, Lee C, Cell Metabolism 2018;28(3):516-524.e7, PMID 29983246. Year, volume and pages as printed are all wrong; the PubMed link printed alongside it is correct.
Read the study →AOD-9604 is a short piece of the tail end of human growth hormone, built to keep the fat-burning signal while dropping the growth and blood-sugar effects of the full hormone. In rodents it reliably slows weight gain and increases fat breakdown without harming insulin sensitivity. In humans it has been tested mainly for safety, and it has never been shown in a published, peer-reviewed trial to produce meaningful weight loss.
Where the evidence stands. Rodent evidence is genuine and consistent; human evidence is limited to a pooled safety analysis. The one human weight-loss trial (about 300 obese adults) was only ever released as a 2005 conference abstract and a company press release, never as a peer-reviewed paper. Note also that this section's reference list is heavily unreliable: 11 of its 20 references could not be found to exist at all, and several carry links pointing to unrelated papers.
Pooled report of six randomized, double-blind, placebo-controlled trials covering roughly 900 healthy and obese adults, testing 25-400 mcg/kg intravenously and 0.25-54 mg orally. Safety and tolerability were indistinguishable from placebo, no treatment-related serious adverse events occurred, and no anti-AOD9604 antibodies were detected. Critically, there were no clinically significant changes in IGF-1, glucose tolerance, or insulin resistance, which is what separates it from full-length growth hormone. Limitation: this is a safety and tolerability paper, not an efficacy paper, and it was authored by parties connected to the compound's developer, so it does not establish that AOD-9604 causes weight loss.
Cited in the source as 'O'Sullivan, A. J., et al. (2015). Clinical Endocrinology, 82(6), 854-862'. The linked paper is actually Stier H, Vos E, Kenley D (2013), 'Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans', J Endocrinol Metab 3(1-2):7-15. The paper is real and is the best human evidence available; the author, year, journal, volume and pages given in the citation are all wrong.
Read the study →Obese (ob/ob) and lean mice were treated with human growth hormone, AOD9604 or saline for 14 days via mini-osmotic pump. Both compounds significantly reduced body weight gain, increased in vivo fat oxidation and raised plasma glycerol, but unlike growth hormone, AOD9604 caused no hyperglycaemia and did not suppress insulin secretion. In vitro, AOD9604 did not compete for the growth hormone receptor and did not induce cell proliferation. Limitation: mouse study in a genetically obese strain; the absence of proliferation was shown only in one transfected cell line.
Cited in the source as 'AOD9604, a novel orally active growth hormone fragment, can reduce body weight and fat mass in obese mice. Int J Obes 25(8), 1246-1253'. No such paper exists. The real 2001 Heffernan paper is 'Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment', Int J Obes Relat Metab Disord 2001;25(10):1442-9, PMID 11673763.
Read the study →Fourteen days of intraperitoneal human growth hormone or AOD9604 reduced body weight and body fat in obese mice, and raised the suppressed levels of beta-3 adrenergic receptor RNA back toward lean-mouse levels. In beta-3 receptor knockout mice, chronic treatment failed to produce the weight and lipolysis changes seen in wild-type controls, though acutely AOD9604 still raised energy expenditure and fat oxidation in the knockouts. The authors conclude the lipolytic action is not mediated directly through the beta-3 receptor. Limitation: purely mechanistic mouse work with no body-composition relevance to humans.
Citation matches the real paper exactly (Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM; Endocrinology 2001;142(12):5182-9).
Read the study →Obese Zucker rats were given 500 mcg/kg oral AOD9604 daily for 19 days. Treated animals gained 15.8 +/- 0.6 g versus 35.6 +/- 0.8 g in controls, a reduction of over 50 percent in body weight gain, with increased lipolytic activity in adipose tissue. Unlike intact human growth hormone, chronic AOD9604 showed no adverse effect on insulin sensitivity as measured by euglycemic clamp. Limitation: a small, short rodent study in a genetically obese strain, at a dose far above human exposure.
Cited in the source as 'Lipolytic domain of human growth hormone (AOD9604): Activity in vitro and in vivo. Metabolism, 49(9), 1124-1130'. The linked PMID is real but is a different paper: Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R, 'Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone', Horm Res 2000;53(6):274-8. Title, journal, volume and pages in the citation are wrong.
Read the study →C57BL/6J (ob/ob) mice were treated orally with saline (n=8) or the peptide (n=10) for 30 days. From day 16 onward, treated animals gained significantly less weight than controls despite identical food consumption, with reduced lipogenic and increased lipolytic activity in adipose tissue and an acute rise in energy expenditure and fat oxidation. The same lipolytic and antilipogenic effects were reproduced in isolated adipose tissue from obese rodents and from humans. Limitation: the human element is isolated fat tissue in a dish, not people, and the peptide studied is AOD-9401, a closely related but not identical hGH fragment.
Citation details are correct (Heffernan MA, Jiang WJ, Thorburn AW, Ng FM; Am J Physiol Endocrinol Metab 2000;279(3):E501-7). Important caveat the source section does not mention: this paper studies AOD-9401 (hGH 177-191), not AOD-9604 (hGH 176-191).
Read the study →Cerebrolysin is a mixture of small peptides and amino acids made from pig brain tissue, given by infusion and studied mainly in stroke, traumatic brain injury and dementia. It has by far the largest genuine clinical trial record of any peptide on this page, including trials with over a thousand patients and independent Cochrane review. The results are genuinely mixed: some trials show clear functional gains, the largest stroke trial missed its main endpoint, and reviewers rate the overall evidence quality as low.
Where the evidence stands. Strong by peptide standards but genuinely mixed: multiple large multicentre RCTs and independent meta-analyses exist, yet the biggest stroke trial was negative on its primary endpoint and Cochrane graded the vascular dementia evidence 'very low' quality.
Randomised, double-blind, placebo-controlled multicentre trial in 100 acute ischaemic stroke patients enrolled within 18 hours (30 mL/day for 7 days, then 10 mL/day to day 30). The primary endpoint, NIH Stroke Scale at day 30, showed medium-to-large superiority for Cerebrolysin (Mann-Whitney 0.66, 95% CI 0.55-0.78, p=0.005), with no safety differences between groups. Limitation: only 100 patients and a 30-day endpoint, so durable functional recovery was not tested.
Source cited Neural Regeneration Research 12(10):1653-1661 with DOI 10.4103/1673-5374.217333. That DOI resolves to an unrelated paper on calcium dobesilate and retinal neuroprotection. Correct: Gharagozli K et al. J Med Life 2017;10(3):153-160, PMID 29075343.
Read the study →CARS was a multicentre, double-blind RCT giving Cerebrolysin 30 mL/day or saline placebo for 21 days starting 24-72 hours after stroke, on top of standardised rehabilitation. The primary endpoint, Action Research Arm Test score at day 90, favoured Cerebrolysin with a large effect size of 0.71, and a combined analysis across 12 outcome scales showed small-to-medium superiority. Limitation: a single manufacturer-sponsored trial, and the effect is reported as a Mann-Whitney statistic rather than an absolute score difference, which makes the real-world size harder to judge.
Cited details match exactly.
Read the study →Randomised, double-blind, placebo-controlled trial in 70 stroke patients (35 per arm) given a 21-day course plus standardised rehabilitation. Both groups improved significantly on motor function, but there was no significant difference between Cerebrolysin and placebo overall. Only within the severely impaired subgroup did Cerebrolysin show significantly more improvement, alongside imaging changes in corticospinal diffusivity. Limitation: small trial, and a positive subgroup inside a null trial is a lead to follow, not a result to rely on.
Source cited BMC Neurology 16:163; the correct article number is 16:31. DOI 10.1186/s12883-016-0553-z is correct. Source title also differs slightly from the published title.
Read the study →CASTA randomised 1,070 acute ischaemic stroke patients across Asia (529 Cerebrolysin, 541 placebo) to 30 mL/day. The primary composite endpoint showed no significant difference from placebo. A post-hoc look at the more severely affected patients (NIHSS above 12) showed lower 90-day mortality with Cerebrolysin (10.5% vs 20.2%), but this subgroup was not pre-specified and is hypothesis-generating only, not evidence of benefit.
Cited details match exactly. This is a NEGATIVE trial on its primary outcome and should always be reported as such.
Read the study →Multicentre, double-blind, placebo-controlled RCT in 242 vascular dementia patients given intravenous Cerebrolysin 20 mL/day on top of aspirin. At 24 weeks the ADAS-cog+ score improved by 10.6 points with Cerebrolysin versus 4.4 with placebo, the CIBIC+ treatment difference was 0.84 (p<0.0001), and the odds ratio for a favourable combined response was 5.63. Limitation: one manufacturer-sponsored trial, and the unusually large placebo-adjusted gain has not been replicated at this size elsewhere.
Source cited CNS Neuroscience & Therapeutics 17(6):617-623. The PubMed ID given in the source resolves instead to Guekht AB, Moessler H, Novak PH, Gusev EI. J Stroke Cerebrovasc Dis 2011;20(4):310-318, DOI 10.1016/j.jstrokecerebrovasdis.2010.01.012. Title is otherwise correct.
Read the study →Systematic review and meta-analysis of ten clinical studies covering 8,749 traumatic brain injury patients. Cerebrolysin was associated with statistically significant improvement in Glasgow Coma Scale and Glasgow Outcome Scale, but all-cause mortality and length of hospital stay were not affected. Limitation: the pooled studies were heterogeneous in design and many were not blinded, and the flat mortality result is a meaningful negative that should be stated alongside the score improvements.
Source cited International Journal of Molecular Sciences 24(7):6239. Correct: Jarosz K, Kojder K, Andrzejewska A, Solek-Pastuszka J, Jurczak A. Brain Sciences 2023;13(3):507, DOI 10.3390/brainsci13030507.
Read the study →Independent Cochrane systematic review pooling six randomised trials and 597 participants with vascular dementia. Cerebrolysin improved cognition and global function with no difference in adverse event rates, but the reviewers graded the certainty of evidence as 'very low' and warned that the effects may be too small to be clinically meaningful. They explicitly called for methodologically robust trials before any routine use.
Source cited review CD007480 (DOI 10.1002/14651858.CD007480.pub3). That is the wrong review number. Correct: Cui S, Chen N, Yang M, Guo J, Zhou M, Zhu C, He L. Cochrane Database Syst Rev 2019;2019(11):CD008900, DOI 10.1002/14651858.CD008900.pub3.
Read the study →Meta-analysis of six randomised, double-blind, placebo-controlled trials of Cerebrolysin 30 mL/day in mild-to-moderate Alzheimer's disease. Cerebrolysin beat placebo on cognitive function at 4 weeks and on global clinical change at both 4 weeks and 6 months, with the authors concluding an overall beneficial effect and favourable benefit-risk ratio. Limitation: only six trials, all at a single dose, and the pooled trials share heavy manufacturer involvement, so funding and publication bias cannot be ruled out.
All cited details confirmed. Actual DOI is 10.1159/000377672.
Read the study →Epitalon is a synthetic four-amino-acid peptide modelled on epithalamin, an extract of the pineal gland. Almost all of its research comes from one St Petersburg group and consists of rodent lifespan and tumour studies, cell-culture work on telomerase, and a small number of long-running trials in elderly heart patients. Those human trials used epithalamin (the crude gland extract), not the Epitalon tetrapeptide, which is an important distinction that is often blurred.
Where the evidence stands. Concentrated almost entirely in a single Russian research group (Khavinson, Anisimov and colleagues, St Petersburg Institute of Bioregulation and Gerontology), much of it published in Russian-language or low-circulation journals. The telomerase and Hayflick-limit results are real published findings but have not been reproduced by any independent laboratory in over twenty years, and the human data tested the crude pineal extract rather than the peptide itself.
A long-running randomised study in elderly people with accelerated cardiovascular ageing gave repeat courses of epithalamine alongside standard therapy. Over 12 years of follow-up the treated group showed reduced functional age and improved exercise capacity, a roughly 28% lower overall mortality, about half the cardiovascular mortality of controls, and halved rates of cardiovascular failure and respiratory disease. The critical caveat is that the agent tested was epithalamine, a crude pineal gland extract, not the synthetic Epitalon tetrapeptide; group sizes and full methods are not available in the English abstract, and the trial was run by the group that developed the product.
Source cited this as 'Advances in Gerontology, 18(4), 495-502' with the title 'Geroprotective effect of epithalamin ... with accelerated aging of the cardiovascular system'. The PMID supplied (17426848) actually resolves to Korkushko OV et al., 'Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging', Bull Exp Biol Med 2006;142(3):356-359.
Read the study →Thirty-nine elderly patients with coronary heart disease received six courses of epithalamin over three years on top of standard therapy and were followed for 15 years; 40 comparable patients received standard therapy alone. The treated group showed slower cardiovascular ageing, better preserved physical endurance, a restored melatonin rhythm and significantly lower mortality. This is a very small sample from a single centre, the agent is again the pineal extract rather than the Epitalon tetrapeptide, and the study has never been replicated elsewhere.
Source cited 'Advances in Gerontology, 1(1), 29-35' and described it as a 3-year randomized study. The PMID supplied (22451889) resolves to Bull Exp Biol Med 2011;151(3):366-369, 'Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up'. The word 'pituitary' in the published English title appears to be a translation error: the abstract describes a pineal (epithalamin) preparation.
Read the study →Female Swiss-derived SHR mice received monthly subcutaneous Epitalon from 3 months of age until death. Epitalon did not change food intake, body weight or mean lifespan, but it slowed the decline of oestrous function, cut chromosomal aberrations by 17.1%, increased survival of the longest-lived 10% by 13.3% and maximum lifespan by 12.3%, and reduced leukaemia 6-fold. The honest reading is that average lifespan was unchanged, which is a far weaker result than 'life extension' claims usually imply, and the work is from the peptide's originating group.
Title, journal, year, volume 4 and pages 193-202 all match; the source's shortened author list omits several co-authors (Alimova, Rosenfeld, Zavarzina, Semenchenko, Yashin).
Read the study →Female HER-2/neu transgenic mice were given monthly courses of saline, Epitalon or the dipeptide Vilon. Epitalon reduced the cumulative number and maximum size of mammary tumours (p<0.05), reduced multiple-tumour incidence and lung metastasis size, and was associated with a 3.7-fold reduction in HER-2/neu mRNA expression in the tumours. Notably the comparator peptide Vilon made things worse, accelerating tumour development, which is a useful reminder that 'peptide' is not a synonym for 'safe'. This is a cancer-prone mouse strain, not a model of healthy human ageing.
Title, authors, journal, volume 101(1), pages 7-10 and year all match the source citation exactly.
Read the study →Female macaques of different ages were given Epitalon and their melatonin and cortisol secretion patterns measured. The peptide significantly increased evening melatonin synthesis in the senescent animals and helped restore a normal daily cortisol rhythm. This is one of very few non-rodent studies of Epitalon and the only primate one, but animal numbers and full statistics are not reported in the abstract and no independent group has repeated it.
Title, authors, journal, volume 22(4), pages 251-254 and year all match the source citation exactly.
Read the study →An independent Chinese group cultured mouse oocytes for 6, 12 and 24 hours past ovulation with and without Epitalon, using at least 30 oocytes per group across repeated experiments. At 0.1 mM, Epitalon cut reactive oxygen species by roughly 86%, reduced fragmentation from 13% to 5.8% at 24 hours, lowered early apoptosis by about 34%, preserved mitochondrial membrane potential and raised mitochondrial DNA copy number. This is the most useful entry in the Epitalon list because it is the one substantial finding from outside the originating group, but it is still mouse cells in a dish.
Source cited 'Li, L., Shi, Y., Zhang, W., et al. ... 14(7), 2824-2842'. The correct record is Yue X, Liu SL, Guo JN, et al., 'Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro', Aging (Albany NY) 2022;14(7):3191-3202. Authors and page range in the source are wrong; the article itself is real and matches the described content.
Read the study →Human fetal lung fibroblasts normally stopped dividing at passage 34. With Epitalon added, telomeres were restored towards early-passage length and the cells completed about 10 further divisions, reaching passage 44, while untreated controls stopped. This is the direct follow-up to the telomerase paper from the same group. It is a single cell line in one laboratory, and pushing cells past their normal division limit is a double-edged result: it is also a feature of cancer cells.
Journal, volume 137(5), pages 503-506, authors and year match. Published title is 'Peptide promotes overcoming of the division limit in human somatic cell' (singular).
Read the study →Epitalon was added to cultures of telomerase-negative human fetal fibroblasts. The peptide induced expression of the catalytic subunit of telomerase, produced measurable telomerase activity, and lengthened telomeres. This is the single most-quoted Epitalon finding, and it is a genuine published paper, but it is a short in-vitro report in a Russian journal, it uses fetal cells rather than adult tissue, and in more than two decades no independent laboratory has published a replication. It says nothing about telomerase in a living human being.
Title, authors, journal, volume 135(6), pages 590-592 and year all match the source citation exactly.
Read the study →Semax is a synthetic peptide based on a fragment of ACTH, modified so it no longer triggers the adrenal hormone response. It is registered and used in Russia for stroke and cognitive indications, and preclinical work shows it switching on neurotrophin, immune and vascular genes in the injured brain. The human clinical literature is almost entirely Russian, and the specific human studies cited in this source could not be verified to exist.
Where the evidence stands. Preclinical rodent and in vitro evidence is real and reproducible; the human clinical evidence sits almost entirely in Russian-language journals, none of the human studies listed in this source could be verified, and there is no independent Western replication.
Review of neuroprotective peptides and drug-discovery strategies for ischaemic stroke, covering blood-brain barrier penetration and protein-protein interaction blocking, with Semax as a worked example. Limitation: a review rather than new data, written by the laboratory that developed Semax, so it should be read as an argument for the approach rather than independent assessment.
Source cited 'Filippenkov, I. B., & Limborska, S. A.' as the authors. Correct author order is Dergunova LV, Filippenkov IB, Limborska SA, Myasoedov NF, Genes 2023;14(5):953. Design field is a poor fit: this is a narrative review, not an original study.
Read the study →Review of the physiological activity spectrum of Semax, concluding it retains a significant share of the neurotropic effects of native melanocortins while having no hormonal activity, with reported nootropic, neuroprotective, anxiolytic, antidepressant and analgesic effects. Limitation: this is a narrative review by the developing laboratory, not primary data, and it aggregates mostly Russian preclinical work.
Source gave DOI 10.1134/S1819712408010182, which returns 404. Correct DOI is 10.1007/s11710-008-1018-0, Neurochemical Journal 2008;2(2):95-101, authors Levitskaya NG, Glazova NY, Sebentsova EA, Manchenko DM, Vilensky DA, Andreeva LA, Kamensky AA, Myasoedov NF. Design field is a poor fit: this is a narrative review, not an original study.
Read the study →Genome-wide transcriptional analysis of rat brain after focal ischaemia found Semax altered expression of genes tied to the immune and vascular systems, supporting a multi-pathway rather than single-target mechanism. Limitation: a descriptive transcriptomic study in rats; changed gene expression is not the same as improved outcome, and no behavioural recovery data are reported here.
Cited details confirmed via Crossref and PubMed (15:228, DOI 10.1186/1471-2164-15-228). Full author list begins Medvedeva EV, Dmitrieva VG, Povarova OV.
Read the study →Rats underwent permanent middle cerebral artery occlusion and were treated with Semax or the PGP tripeptide, with mRNA measured at 3, 24 and 72 hours. Both increased transcription of neurotrophins and their receptors in the damaged cortex, but Semax acted selectively on ischaemic tissue while PGP produced broader, less specific effects. Limitation: a rodent gene-expression study with no functional recovery endpoint reported.
All cited details confirmed (30(1):71-79, DOI 10.1007/s10571-009-9432-0).
Read the study →Study of Semax's effect on brain monoamine systems in rodents. The fuller companion paper by the same group (Eremin KO et al., Neurochemical Research 2005;30(12):1493-500) reports that Semax alone did not change dopamine levels but raised striatal 5-HIAA by about 25% within two hours, and strongly potentiated amphetamine-induced dopamine release. Limitation: rodent neurochemistry, and the fact that Semax alone did not move dopamine is an important null detail often left out of marketing claims.
Source cited volume 394(1):130-132 with a PDF link on a private clinic website. PubMed records this as Dokl Biol Sci 2004;394:1-3, authors Eremin KO, Kudrin VS, Grivennikov IA, Miasoedov NF, Rayevsky KS (the source omits several). Numeric findings quoted here are taken from the group's fuller 2005 Neurochemical Research paper, PMID 16362768, because the 2004 Doklady record carries no abstract.
Read the study →Spectroscopic and cell assays in artificial membrane models tested whether Semax could interfere with copper-induced amyloid-beta aggregation, a process implicated in Alzheimer's disease. Semax prevented formation of amyloid-beta:copper complexes and showed anti-aggregating and cell-protective properties. Limitation: purely in vitro with artificial membranes, and anti-aggregation in a tube has repeatedly failed to translate into clinical benefit for other compounds.
All cited details confirmed (13(4):486-496, DOI 10.1021/acschemneuro.1c00707).
Read the study →Selank is a synthetic seven-amino-acid peptide based on the immune molecule tuftsin, developed in Russia and studied mainly as a non-sedating anxiety and stress-adaptation agent. Laboratory work consistently shows it modulating the GABA system indirectly rather than acting on receptors the way benzodiazepines do. Human data exist but are small, Russian-language, and not placebo-controlled, and there is essentially no independent Western clinical replication.
Where the evidence stands. Mostly rodent and cell-culture work from a small number of Russian laboratories; the single human study located is a 70-patient unblinded Russian-language comparison, and Western independent replication is effectively absent.
Comparative clinical study in 70 patients with anxiety-phobic, hypochondriacal and somatoform disorders: 30 received phenazepam alone, 40 received phenazepam plus Selank, assessed with HDRS, CGI, Spielberger, Stroop, verbal fluency and SF-36. The combination reduced unwanted effects such as attention impairment, sedation and sexual dysfunction, accelerated the therapeutic response and improved quality-of-life scores. Limitation: Russian-language, unequal groups, and not described as randomised or placebo-controlled, so this is supportive rather than definitive evidence.
Cited details match. Publication is in Russian with an English abstract; full author list is Medvedev VE, Tereshchenko ON, Kost NV, Ter-Israelyan AY, Gushanskaya EV, Chobanu IK, Sokolov OY, Myasoedov NF.
Read the study →Morphine-dependent rats given naloxone to precipitate withdrawal showed a 39.6% reduction in the total withdrawal syndrome index after a single 0.3 mg/kg Selank injection, plus substantially raised tactile sensitivity thresholds. The effect was comparable to diazepam at 2 mg/kg. Limitation: an acute single-dose rodent model; no human opioid withdrawal data exist for Selank.
All cited details confirmed.
Read the study →Study of Selank's effect on cytokine levels in a rat model of chronic social stress, published in a low-impact pharmacology review journal. The paper's existence, title, journal, year and page range were confirmed via Crossref, but the full abstract could not be retrieved, so no numeric results are quoted here. Limitation: rodent immune markers only, a journal with limited reach, and the source citation lists the wrong co-authors.
Correct title is 'The Influence of Selank on the Level of Cytokines Under the Conditions of Social Stress'; correct authors are Yasenyavskaya AL, Samotrueva MA, Tsibizova AA, Bashkina OA, Myasoedov NF, Andreeva LA. The source's co-author list (Zhuravleva NS, Narkevich VB, Volodina MA) does not match the record. Abstract not retrieved, so no numbers are asserted.
Read the study →Rats chronically exposed to ethanol over 30 weeks were treated with Selank, which prevented the development of ethanol-induced memory and attention disturbances and normalised BDNF content in the hippocampus and prefrontal cortex. Limitation: a long-exposure rodent model, and BDNF is a mechanistic marker rather than a clinical outcome, so this does not show cognitive benefit in people.
All cited details confirmed.
Read the study →Rats exposed to unpredictable chronic mild stress were tested on the elevated plus maze after Selank, diazepam, or both. The diazepam-plus-Selank combination was the most effective at reducing anxiety-like behaviour under chronic stress, while Selank alone was most effective against the stress-induced rise in anxiety. Limitation: a rodent behavioural model with no absolute effect sizes reported, and elevated plus maze results translate poorly to human anxiety disorders.
Source cited Evidence-Based Complementary and Alternative Medicine. The DOI 10.1155/2017/5091027 is correct, but the journal is Behavioural Neurology 2017:5091027 (both are Hindawi titles).
Read the study →Real-time PCR of 84 neurotransmission-related genes in rat frontal cortex after Selank administration found significant expression changes in 45 genes at 1 hour and 22 genes at 3 hours. The authors read this as complex modulation of the GABAergic system rather than direct receptor agonism. Limitation: gene expression in rat cortex is several steps removed from any human anxiety outcome.
All cited details confirmed.
Read the study →Receptor-binding experiments on brain cell plasma membranes found Selank acts as a positive allosteric modulator of GABA binding, interacting non-additively with benzodiazepines and able to block the modulatory effects of both diazepam and olanzapine. This supports a binding site that partly overlaps with, but is distinct from, the benzodiazepine site. Limitation: isolated membrane preparations with no behavioural or clinical endpoint.
Source cited this as Medvedev, A. E., & Gusev, E. I. (2016), Bulletin of Experimental Biology and Medicine 161(2):245-248. The title is real but the authors, journal, year and volume are all wrong. Correct: Vyunova TV, Andreeva L, Shevchenko K, Myasoedov N. Protein Pept Lett 2018;25(10):914-923, DOI 10.2174/0929866525666180925144642.
Read the study →In cultured IMR-32 human neuroblastoma cells, 84 GABAergic-system genes were profiled by qPCR. Selank on its own had no direct effect on the mRNA levels of these genes. It did suppress the changes produced by GABA and amplified the number of genes affected by olanzapine. Limitation: an in vitro cell line, and the headline direct result is null, which supports a modulator role rather than an independently active drug.
All cited details confirmed.
Read the study →DSIP is a naturally occurring nine-amino-acid peptide first isolated in the 1970s after it appeared to promote delta (deep) sleep in rabbits. Fifty years on, its receptor has never been identified and its actual physiological role remains unresolved, with most of the usable data coming from rodent stress and oxidative-stress experiments. Of the four peptides reviewed here, DSIP has by far the weakest evidence base, and the reference list supplied for it is largely padded with general sleep-science reviews that never test DSIP at all.
Where the evidence stands. Very weak: no verifiable human trial of DSIP appears anywhere in the source list, the DSIP-specific citations that were checked could not be confirmed to exist, and most of the list is general sleep and immunology reviews containing no DSIP data.
Review in a major neurochemistry journal assessing the accumulated DSIP literature since its 1977 isolation. The authors conclude that despite decades of work, no DSIP receptor has been identified, the sleep-promoting findings have not been consistently reproduced, and the peptide's physiological role is still unresolved - hence the title. This is the single most honest and most citable reference on DSIP in the entire source list, and it is a sceptical one.
All cited details confirmed (97(2):303-309). Design field is a poor fit: this is a critical narrative review, not an original study. Its conclusion is deflationary and should be represented as such.
Read the study →Male Wistar rats under restraint stress were given DSIP at several doses. At 40 micrograms/kg the peptide increased catalase and superoxide dismutase activity during acute stress, and under chronic stress the same dose reduced enzyme activity and oxidative markers while preserving protein levels; higher doses were less effective. Limitation: a rodent liver biochemistry endpoint with a non-linear dose response, entirely unrelated to sleep, and no human equivalent exists.
NOT the paper cited in the source. Located during verification as the nearest genuine, indexed publication by the same authors (Bobyntsev II, Kryukov AA, Belykh AE, Dudka VT) that the source's untraceable reference 1 attributes work to. Cited details: 160(4):421-424.
Read the study →Male Wistar rats exposed to electrical foot-shock stress received DSIP across several doses. The 120 micrograms/kg dose normalised the rise in malondialdehyde during acute stress, and across all doses the peptide raised antioxidant enzyme activity and normalised liver protein production under chronic stress, though effects on oxidative markers varied by dose. Limitation: rodent liver chemistry in a Russian-language physiology journal, with inconsistent dose-response and no clinical endpoint.
NOT in the source list. Located during verification; authors Belykh AE, Bobyntsev II, Kryukov AA, Dudka VT, 101(6):700-707. Included because the source's reference 1 by the same authors could not be traced.
Read the study →In male Wistar rats undergoing immobilisation stress, DSIP reduced the number of Fos-immunoreactive cells in the hypothalamic paraventricular nucleus. Blocking NMDA receptors with dizocilpine, or blocking protein synthesis with cycloheximide, each prevented this suppression, implicating NMDA-receptor signalling in the mechanism. Limitation: a mechanistic rodent study using an immediate-early-gene marker, not a behavioural or sleep outcome.
NOT in the source list. Located during verification as genuine indexed DSIP research by the Sudakov group, whom the source cites via two references that could not be confirmed to exist. Cited details: 506(2):184-187, authors Umriukhin PE, Koplik EV, Sudakov KV.
Read the study →Comparison of DSIP and an ACTH(4-10) analogue on Fos induction in limbic structures of the rat brain under emotional stress, from the Russian group that produced most of the DSIP stress literature. Metadata were confirmed via Crossref but the abstract was not retrieved, so no numeric findings are asserted here. Limitation: rodent immediate-early-gene mapping from a single laboratory, published over two decades ago and not independently replicated.
NOT in the source list. Located during verification. Cited details: Sudakov KV et al., Stress 2001;4:143-153. Existence and bibliographic details confirmed via Crossref; abstract not retrieved, so no results are quoted.
Read the study →Cortagen is a synthetic four-amino-acid peptide derived from Cortexin, a brain-cortex extract that has been used clinically in Russia since the late 1980s. The research on Cortagen itself is small and almost entirely in rats and mice: nerve regeneration, brain gene expression, behaviour and chronic ischaemia models. There are no published human trials of Cortagen.
Where the evidence stands. Small, preclinical and mostly Russian. PubMed indexes only about fifteen papers mentioning Cortagen at all, nearly all from the Khavinson group, and none are human trials of Cortagen. Several references in the source list are actually studies of Cortexin (a different, whole-extract product) rather than Cortagen, and one independent mouse study exists but was co-authored by an employee of the manufacturer.
Rats with chronic brain ischaemia were treated with cortexin or the synthetic peptide cortagen. Both accelerated recovery of disturbed individual behaviour and prevented excessive lipid peroxidation and the fall in brain antioxidant activity seen in untreated ischaemic animals. The paper is in Russian, group sizes and effect sizes are not available in the English abstract, and cortagen is tested alongside rather than against its parent extract.
Source cited 'Zarubina, I. V., & Makul'kin, R. F. (2011) ... 74(3), 3-5'. The correct record is Zarubina IV, Shabanov PD, Eksp Klin Farmakol 2011;74(2):8-15. Second author, issue and page numbers in the source are all wrong.
Read the study →An Italian group at the Istituto Superiore di Sanita tested cortagen (0.01, 0.03 or 0.10 mg/kg i.p.) against cortexin and vehicle in CD-1 mice using the elevated plus maze and locomotor habituation paradigms. The 0.03 mg/kg cortagen dose increased locomotion both acutely and after five days of dosing, with little effect on anxiety-related behaviour, whereas cortexin was anxiolytic acutely but anxiogenic on repeat dosing. This is the closest thing to an independent Cortagen study, though a co-author was affiliated with Geropharm Ltd, which manufactures cortexin, and it is published in a small open-access journal not indexed in PubMed.
Full-text PDF retrieved and checked. Correct authors are Adriani W, Granstrem O, Romano E, Koroleva S, Laviola G; journal, volume 2, pages 22-29 and year all match the source citation.
Read the study →Six-month-old female CBA mice received cortagen injections for five days, after which cardiac gene expression was profiled across 15,247 transcripts by cDNA microarray. 234 clones (1.53% of the total) showed significant expression changes, corresponding to 110 known genes, with regulation ranging from +5.42 to -2.86 fold. This demonstrates the peptide does reach tissue and alter transcription, which is the core bioregulator claim; it does not show any functional or health benefit, and the tissue studied was heart rather than brain.
Title, authors, journal, volume 25(1-2), pages 87-93 and year all match the source citation exactly.
Read the study →A follow-up from the same Pavlov Institute group examined whether cortagen's effect on injured nerve function lasted beyond the treatment window, and reported a delayed, persisting improvement in restoration of nerve function. The English abstract carries no numerical results, so the size of the effect cannot be assessed from the record; it is included only as evidence that the nerve finding was pursued rather than published once and abandoned.
Title, authors, journal, volume 384, pages 183-184 and year confirmed via PubMed (DOI 10.1023/a:1016098302564). Not in the source reference list under this exact form but directly continues its reference 2.
Read the study →Rats had the sciatic nerve cut and sutured, then received 10 micrograms/kg cortagen intramuscularly daily for 10 days. Compared with controls, the regenerating nerve fibres showed a 27% higher growth rate and 40% faster conduction velocity. These are the clearest quantitative numbers in the whole Cortagen literature, but this is a small rat surgical model from the peptide's originating institute with no independent replication and no human equivalent.
Title, authors, journal, volume 130, pages 1172-1174 and year all match; PubMed lists the issue as 12 rather than the 6 given in the source.
Read the study →NAD+ is a coenzyme every cell uses to turn food into energy, and levels fall as we age. NAD+ itself is poorly absorbed by mouth, so supplements use precursors, mainly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which do reliably push blood NAD+ back up. What is far less settled is whether that rise makes healthy people measurably better off.
Where the evidence stands. Raising blood NAD+ with oral NR or NMN is well proven and well tolerated in humans; turning that into hard clinical benefit is not proven, and intravenous NAD+ specifically has essentially no controlled outcome trials at all.
The NICE trial, a randomised double-blind study of 90 people with peripheral artery disease given 6 months of nicotinamide riboside, with or without resveratrol, versus placebo. NR improved six-minute walk distance by 7.0 metres versus a 10.6 metre decline on placebo, a between-group difference of 17.6 metres; among participants who took at least 75% of their pills the improvement was 31.0 metres, and resveratrol added nothing. This is one of very few trials showing a genuine functional gain from an NAD+ precursor, but it was a small pilot in a diseased population, used a one-sided 90% confidence interval, and the authors call for a larger confirmatory trial.
McDermott MM et al., Nat Commun 2024;15:5046. Verified against the PubMed record (PMID 38871717). Findings apply to people with peripheral artery disease, not to healthy adults.
Read the study →A randomised, multicentre, double-blind, placebo-controlled dose-response trial in 80 healthy middle-aged adults given placebo or 300, 600 or 900 mg NMN daily for 60 days. Blood NAD+ rose significantly in every NMN group at both day 30 and day 60, and six-minute walk distance improved significantly versus placebo across the dose groups. NMN was safe and well tolerated up to 900 mg daily. The trial was industry-sponsored, ran only 60 days, and walking distance in already-healthy adults is a soft endpoint, so this is supportive rather than decisive.
Yi L et al., GeroScience 2023;45:29-43. Verified against the PubMed record (PMID 36482258). Sponsored by a supplement manufacturer; interpret effect sizes cautiously.
Read the study →A 10-week randomised, placebo-controlled, double-blind trial of 250 mg per day NMN in 25 postmenopausal women with prediabetes who were overweight or obese (13 NMN, 12 placebo). Insulin-stimulated glucose disposal measured by hyperinsulinaemic-euglycaemic clamp, the gold-standard method, rose by about 25% with NMN and did not change on placebo, alongside increased muscle insulin signalling. This is the strongest mechanistic human result in the field, but the sample was very small, single-sex and specifically prediabetic, so it does not generalise to healthy people, and body weight and other metabolic markers did not improve.
Yoshino M et al., Science 2021;372:1224-1229. Verified against the PubMed record (PMID 33888596). A published technical comment questioned aspects of the analysis, so the finding is best treated as promising rather than settled.
Read the study →A randomised, double-blind, placebo-controlled crossover trial of 1,000 mg per day nicotinamide riboside for 6 weeks in 13 healthy overweight or obese adults. NR did raise skeletal muscle NAD+ metabolites and produced small changes in body composition and sleeping metabolic rate. However there was no effect on insulin sensitivity measured by hyperinsulinaemic-euglycaemic clamp, nor on mitochondrial function, liver or muscle fat, cardiac function, ambulatory blood pressure, inflammation or energy metabolism. This is the clearest demonstration that raising NAD+ does not automatically deliver metabolic benefit.
Remie CME et al., Am J Clin Nutr 2020;112:413-426. Verified against the PubMed record (PMID 32320006). Included deliberately as a negative result to balance the positive trials.
Read the study →A randomised, double-blind, placebo-controlled crossover trial of 1,000 mg per day of nicotinamide riboside for two 6-week periods in healthy middle-aged and older adults (30 randomised, 24 completed). NR was well tolerated and raised NAD+ in peripheral blood mononuclear cells by roughly 60%. Systolic blood pressure fell by about 3.9 mmHg and aortic stiffness trended downward, but neither reached statistical significance; the authors framed these as exploratory findings needing larger trials. This is the foundational human NR trial and it is honest that the functional benefits were not demonstrated.
Martens CR et al., Nat Commun 2018;9:1286. Verified against the PubMed record (PMID 29599478) and the full text. The blood pressure result is frequently over-quoted in marketing; it was not statistically significant.
Read the study →A PRISMA-guided systematic review covering 113 eligible studies, comprising 33 human intervention studies (28 randomised) and 80 rodent studies of NAD+ boosting. In humans, oral NR and NMN consistently hit their biochemical target, raising circulating and cellular NAD+ metabolites, and were generally well tolerated over weeks to months; but effects on functional, metabolic, vascular and other healthspan outcomes were heterogeneous and often null. Critically, the review found no eligible outcomes trials evaluating intravenous or intramuscular NAD+ itself for anti-ageing or wellness indications, despite it being widely sold in clinics.
Gallagher C et al., Ageing Res Rev 2026;116:103057. Verified against the PubMed record (PMID 41655607). This is the key citation for the honest position on IV NAD+ specifically.
Read the study →A systematic review and meta-analysis of 12 randomised controlled trials covering 513 adults, pooling the effects of oral NMN on fasting glucose, triglycerides, total cholesterol, LDL and HDL. NMN significantly raised blood NAD+ levels, but most clinically relevant metabolic outcomes showed no significant difference from control. Risk-of-bias assessment flagged concerns in seven studies and high risk in five. The authors conclude directly that an exaggeration of the benefits of NMN supplementation may exist in the field.
Zhang J et al., Crit Rev Food Sci Nutr 2025;65:4382-4400. Verified against the PubMed record (PMID 39116016). The single most useful citation for setting honest expectations.
Read the study →A retrospective review of records from a commercial wellness clinic comparing 500 mg intravenous NAD+ (6 clients) against 500 mg intravenous nicotinamide riboside (8 clients), each given daily for four consecutive days. Every one of the six people receiving IV NAD+ reported moderate to severe abdominal cramping, diarrhoea, nausea, vomiting and raised heart rate, whereas the IV NR group reported only minor tingling; average infusion time was 97 minutes for NAD+ versus 37 minutes for NR. The authors are explicit that the retrospective design, tiny sample and complete absence of a placebo arm limit any interpretation, and NAD+ concentration changes could not even be measured.
Reyna et al., Front Aging 2026, article 1652582. Verified against the PubMed Central record (PMC12907335). This is a retrospective chart review with no control group, included only because it is among the very little direct human data on IV NAD+.
Read the study →NMN is not a peptide at all: it is a vitamin B3 derivative and one step away from NAD+, the coenzyme every cell uses for energy production, DNA repair and switching on the sirtuin repair enzymes. NAD+ itself cannot usefully be swallowed, so people take precursors instead: NMN and nicotinamide riboside (NR) are the two most studied, and both reliably raise blood NAD+ in humans. What is genuinely unsettled is whether raising NAD+ produces the health outcomes people take it for, and even how it gets there: 2025 mouse work suggests most oral NMN is broken down by gut bacteria first rather than absorbed intact. Human trials to date are small, short (30 to 90 days) and mostly measure surrogate markers rather than hard outcomes.
Where the evidence stands. Human randomised trials consistently show oral NMN raises blood NAD+ and is well tolerated up to 900 mg/day; evidence that this translates into meaningful clinical benefit is early, small-scale, short-term and often industry-funded.
A randomised, multicentre, double-blind, placebo-controlled trial in 80 healthy middle-aged adults taking placebo, 300, 600 or 900 mg NMN daily for 60 days. Blood NAD rose significantly in all three NMN groups at day 30 and day 60, highest at 600 and 900 mg, with no safety issues at any dose. Six-minute walking distance improved significantly versus placebo at both timepoints. Caveats: it was analysed per-protocol, ran only 60 days, the endpoints are surrogate or soft (walking distance, an online 'biological age' calculator, a self-reported health questionnaire), and insulin resistance (HOMA-IR) did not improve.
CORRECTED. Source list prints 'Yi, L., et al. (2022) ... Frontiers in Aging, 3, 945188'. There is no article at Frontiers in Aging 3:945188. The PubMed link printed alongside (PMID 36482258) is correct and resolves to Yi L, Maier AB, Tao R, Lin Z et al., GeroScience 2023;45(1):29-43. Journal, year, volume and pages as printed are all wrong.
Read the study →A randomised, double-blind, placebo-controlled trial in 66 healthy adults aged 40 to 65 taking 300 mg NMN daily for 60 days. Serum NAD+/NADH rose 11.3% by day 30 and 38% by day 60 in the NMN group, against 14.3% at day 60 on placebo, with self-reported health scores (SF-36) rising 6.5% versus 3.4%. The honest limitations: this was a trial of a specific commercial product funded by its manufacturer, it reports a NAD+/NADH ratio rather than absolute NAD+, and there are no hard clinical endpoints.
CORRECTED. Source list prints 'Niu, Y., et al. (2022) ... Endocrine, Metabolic & Immune Disorders Drug Targets, 22(7), 777-787'. No article exists at that journal/volume/page. The PubMed link printed alongside (PMID 35821806) is correct and resolves to Huang H, Frontiers in Aging 2022;3:851698 (the 'Uthever' NMN trial). Author, journal, volume and pages as printed are all wrong.
Read the study →A 10-week randomised, double-blind, placebo-controlled trial in 25 postmenopausal women with prediabetes who were overweight or obese, taking 250 mg NMN daily. Insulin-stimulated glucose disposal measured by hyperinsulinaemic-euglycaemic clamp (the gold-standard method) rose roughly 25% with NMN and did not change on placebo, alongside increased muscle AKT and mTOR signalling. Limitations are real: only 25 people, women only, one site, and no improvement in body weight, blood pressure, liver fat or most other metabolic measures. The result was publicly contested in a technical comment in the same journal.
Citation as printed matches exactly: Yoshino M et al., Science 2021;372(6547):1224-1229, PMID 33888596. Readers should be aware of the published Comment (Brenner C, Science 2021;373(6554)) and the authors' Response.
Read the study →A placebo-controlled, randomised, double-blind crossover trial giving 12 aged men 1 g of nicotinamide riboside daily for 21 days. NR did raise the NAD+ metabolome in skeletal muscle, confirming the supplement genuinely reaches the target tissue, and it lowered circulating inflammatory cytokines. Crucially it did NOT alter mitochondrial bioenergetics, and muscle gene expression for energy metabolism and mitochondrial pathways was actually downregulated. This is one of the more important honest results in the field: the precursor gets in, but the expected mitochondrial payoff did not appear. Only 12 men, 21 days.
CORRECTED, AND THE PRINTED TITLE IS MISLEADING. Source list prints 'Elhassan, Y. S., et al. (2019). Nicotinamide riboside enhances exercise performance in humans. Cell Reports, 26(7), 1973-1983.e8'. The real paper is 'Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures', Cell Reports 2019;28(7):1717-1728.e6, PMID 31412242. It did not measure or demonstrate enhanced exercise performance. Do not repeat the printed title's claim.
Read the study →Eleven healthy volunteers took 250 mg NMN each morning for 12 weeks, with plasma measured monthly. Plasma NMN and NAD+ both rose, as did postprandial serum insulin, and no adverse symptoms were reported. The size of the NMN and insulin rise varied widely between individuals. This is the weakest design of the human studies here: 11 people, no control group, no randomisation and no blinding, so it can show that NAD+ goes up but cannot attribute any benefit to the supplement.
CORRECTED, AND THE PRINTED DESIGN IS WRONG. Source list prints 'Yamane, T., et al. (2023). Nicotinamide mononucleotide intake increases plasma NMN and NAD+ in healthy adults: A randomized, double-blind, placebo-controlled trial. Nutrition and Healthy Aging, 9(3), 177-189.' No such article exists. The PubMed link printed alongside (PMID 37344088) resolves to Yamane T et al., Clin Nutr ESPEN 2023;56:83-86, 'Nicotinamide mononucleotide (NMN) intake increases plasma NMN and insulin levels in healthy subjects' - an OPEN-LABEL, SINGLE-ARM study in 11 people, not a randomised double-blind placebo-controlled trial. Never describe this one as an RCT.
Read the study →Researchers traced orally and intravenously dosed NMN and NR in mice using NAD+ metabolomics. Only a small fraction of oral NMN and NR was absorbed intact from the small intestine; most was deamidated by gut microbiota into nicotinic acid, which then reached the liver via enterohepatic circulation. Even intravenous NMN and NR were rapidly broken down to nicotinamide and secreted into bile. This complicates the simple 'NMN goes in, NAD+ goes up' story and is a mouse study, so how closely it applies to humans is unknown.
CORRECTED. Source list prints the title as 'Nicotinamide riboside and nicotinamide mononucleotide: Distinct routes to NAD+ repletion' in Science Advances 11(31). The real title is 'Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation', Sci Adv 2025;11(12):eadr1538, PMID 40117359. The DOI as printed is correct.
Read the study →Reported that the Slc12a8 gene encodes a specific, sodium-dependent NMN transporter that is highly expressed in the mouse small intestine, and that knocking it down reduced NMN uptake and lowered NAD+ in the jejunum and ileum. If correct, this would explain how NMN gets into cells intact rather than being broken down first. Important caveat: the finding was directly challenged in the same journal by an independent group (Schmidt & Brenner, Nature Metabolism 2019), and the mechanism remains contested. Mouse tissue only.
Citation as printed matches exactly: Grozio A et al., Nature Metabolism 2019;1(1):47-57, PMID 31131364. Flagged as scientifically contested: see 'Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter' (Nat Metab 2019;1(7):660-661) and the authors' Reply (1(7):662-665).
Read the study →Identified ACMSD as the rate-limiting brake on de novo NAD+ synthesis, and showed that inhibiting it genetically or pharmacologically raises NAD+, activates SIRT1 and improves mitochondrial function in both C. elegans and mice. Because ACMSD is expressed mainly in kidney and liver, the authors propose it as a target for protecting those organs. This is an alternative route to raising NAD+ that does not involve taking NMN at all, and it has not been tested in humans.
CORRECTED. Source list prints the year as 2020; the paper is Katsyuba E et al., Nature 2018;563(7731):354-359, PMID 30356218. Volume, issue and pages as printed are correct; only the year is wrong.
Read the study →SS-31 (elamipretide) is a synthetic four-amino-acid peptide that concentrates inside mitochondria and binds cardiolipin, the lipid that holds the cell's energy-producing machinery in shape. It is by a wide margin the best-studied peptide in this group: it has completed registered, placebo-controlled human trials with published results, which almost no other peptide on the market can claim. The results themselves are mixed, and being well studied is not the same as being proven effective.
Where the evidence stands. The strongest evidence base of any peptide covered here, with multiple registered placebo-controlled human trials plus direct work on explanted human heart tissue. Both large randomised trials (mitochondrial myopathy and dry AMD) missed their primary endpoints; the encouraging signals so far come from post-hoc genetic subgroups and secondary imaging measures, which is hypothesis-generating rather than conclusive.
After MMPOWER-3 failed, the investigators re-analysed the data by genotype. In patients with mtDNA maintenance (replisome) defects, 6-minute walk distance at week 24 improved 25.2 +/- 8.7 metres on elamipretide versus 2.0 +/- 8.6 metres on placebo (p=0.06); within the chronic progressive external ophthalmoplegia subset of that group the gap was 37.3 +/- 9.5 versus -8.0 +/- 10.7 metres (p=0.0024). These subgroups were defined after the trial read out negative, so the findings are hypothesis-generating only. To the sponsor's credit, they went on to design a dedicated phase 3 trial (NuPOWER) to test the hypothesis properly.
Title, authors, journal, volume 19, article 431, year and DOI all match the source citation.
Read the study →176 people aged 55 and over with dry age-related macular degeneration and noncentral geographic atrophy were randomised (117 drug, 59 placebo) to 40 mg/day subcutaneous elamipretide or placebo for 48 weeks. The primary endpoints (low-luminance visual acuity and atrophy area) were not met. Prespecified imaging measures did show a 43% reduction in total ellipsoid zone attenuation (nominal p=0.0034) and 47% reduction in partial attenuation (nominal p=0.0040), and 14.6% of treated patients gained 10 or more letters of low-luminance acuity versus 2.1% on placebo (nominal p=0.0404). Every positive number here is a nominal p-value on a secondary measure, and adverse events were more frequent on drug (86% vs 71%).
Source cited 'Ehlers, J. P., Lunasco, L. M., Yordi, S., et al. (2024) ... online ahead of print'. The correct record is Ehlers JP, Hu A, Boyer D, Cousins SW, et al., 'ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation', Ophthalmology Science 2024;5(1):100628.
Read the study →218 adults with genetically confirmed primary mitochondrial myopathy were randomised 1:1 to 40 mg/day subcutaneous elamipretide or placebo for 24 weeks. Neither primary endpoint was met: the treatment difference in 6-minute walk distance was -3.2 metres (95% CI -18.7 to 12.3, p=0.69) and the difference in total fatigue score was -0.07 (p=0.37). The drug was well tolerated, with most adverse events mild to moderate. This is the single largest and most rigorous elamipretide trial, and it is a clearly negative result in the overall population.
Full title is 'Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial'. Journal, volume 101(3), pages e238-e252, year and DOI all match.
Read the study →Nineteen adults aged 55 and over with dry AMD and noncentral geographic atrophy took 40 mg/day subcutaneous elamipretide for 24 weeks in a single-centre, open-label phase 1 safety study. Among the 15 who completed, best-corrected visual acuity improved by 4.6 +/- 5.1 letters (p=0.0032) and low-luminance acuity by 5.4 +/- 7.9 letters (p=0.0245). All 19 participants had at least one non-ocular adverse event, though none were serious. With no placebo group and only 15 completers, these gains cannot be separated from learning effects or chance, and the much larger randomised follow-up (ReCLAIM-2) did not confirm them.
Full title is 'Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study'. Journal, volume 2, article 100086 and DOI match; PubMed dates it 2021 online, 2022 in issue.
Read the study →Mice given lipopolysaccharide developed mitochondrial dysfunction, synaptic damage and learning and memory impairment. Elamipretide treatment significantly reduced those deficits and improved measures of mitochondrial function and oxidative stress in the hippocampus. This is a standard acute inflammation model used to study post-operative cognitive problems; it is a long way from human cognition and the results have not been tested in a cognitive trial.
Title, authors, journal, volume 16, article 230, year and DOI all match the source citation exactly.
Read the study →Researchers took heart muscle from explanted failing human hearts and from non-failing donor hearts, and treated the tissue directly with elamipretide. Failing myocardium showed clearly impaired mitochondrial function at baseline; adding elamipretide significantly improved mitochondrial oxygen flux, complex I and complex IV activity, and supercomplex-associated complex IV activity. This is the cleanest demonstration that the drug's proposed mechanism operates in real human heart muscle, but it is tissue in a dish rather than a treated patient, so it predicts nothing about clinical outcomes.
Title, authors, journal, volume 4(2), pages 147-157, year and DOI all match the source citation exactly.
Read the study →Thymulin is a natural nine-amino-acid hormone made by the thymus gland, the organ that trains T-cells. It only becomes active when bound to zinc, so its function is tied directly to zinc status. Research has focused on its role in calming inflammation and maintaining immune balance, and on the fact that thymulin levels fall sharply with age as the thymus shrinks. Nearly all of the evidence is from mice, rats and cell experiments; there are no controlled human treatment trials.
Where the evidence stands. Almost entirely rodent and cell-based; human data are observational only, with no treatment trials.
A review of thymic peptides - including thymulin - in patients recovering from allogeneic stem cell transplantation, where slow T-cell recovery in the first three to four months predicts relapse, graft-versus-host disease and serious infection. It sets out what is known about how these peptides shape immune reconstitution and what has been tried clinically. It is a narrative review of observational human data, not a trial showing thymulin improves outcomes.
Printed as Kunstek, H. (2025), 'Thymic peptides in immune reconstitution and clinical application', Transplantation and Cellular Therapy Reviews, 2(1), 45-58, DOI 10.1016/j.tctr.2025.01.005. That journal and DOI do not exist. The real paper is Kunstek H, Kieviet J, Lindemans C, de Koning C, Nierkens S, Blood Neoplasia 2025;2(2):100090. It is a narrative review, not a systematic one.
Read the study →A review of hormone-like peptides made by the thymus - thymosin alpha-1, thymosin beta-4, thymulin and thymopoietin - covering how they push T-cells to mature and regulate natural killer and dendritic cells. It surveys clinical applications in cancer, viral infection, autoimmune disease and immunodeficiency and reports a favourable safety record with extended use. Most of the clinical track record described belongs to thymosin alpha-1, not thymulin.
Crossref records first online publication in 2024 with issue-year 2025, volume 31, article 10. Authors are Besman M, Zambrowicz A, Matwiejczyk M. Narrative, not systematic, review.
Read the study →Mice were given streptozotocin to induce type 1 diabetes, then treated with thymulin or with the antioxidant enzyme peroxiredoxin 6. Both reduced the physiological damage - blood glucose, weight loss, immune cell counts and inflammatory signals including TNF-alpha, interleukins and interferon-gamma - though by different mechanisms. It is a chemically induced mouse model of diabetes, and the paper's speculation about COVID-19 treatment is not backed by data in the study.
Exact match: Novoselova EG et al., Int J Immunopathol Pharmacol 2021;35:20587384211005645, PMID 33779346.
Read the study →Rats with induced inflammatory pain were treated with thymulin. Treated animals showed reduced heat sensitivity and less paw swelling, alongside suppressed activation of spinal microglia (the immune cells of the spinal cord), reduced p38 signalling and lower TNF-alpha and IL-6. The mechanism is coherent, but this is an acute rodent pain model and says nothing about chronic pain in humans.
Title, authors, journal, year, volume and pages are all correct, but the printed DOI (10.1016/j.intimp.2019.02.050) resolves to a completely different paper on macrophage polarisation by Wang Y et al. Correct DOI is 10.1016/j.intimp.2019.02.042, PMID 30851702.
Read the study →A review of work in which a viral vector carrying a modified thymulin gene was injected into thymus-deficient and aging rodents, turning muscle cells into an ongoing source of the hormone and restoring blood thymulin to normal. Restoring thymulin corrected several pituitary and hormonal abnormalities that follow thymus loss. This is gene therapy in mice and rats, not injected thymulin in humans, and the two are not interchangeable.
Title, authors, journal, year, volume and pages all correct, but the printed DOI (10.1159/000329515) is wrong by one digit. Correct DOI is 10.1159/000329495, PMID 21952687.
Read the study →A review of thymulin in experimental lung disease, describing broad suppression of pro-inflammatory signalling, blocking of the p38 and NF-kappaB pathways, and selective boosting of anti-inflammatory cytokines. The authors highlight that no toxicity was seen even at high doses and argue thymulin is a good candidate for clinical trials. Fifteen years later those trials have still not been run, which is the honest headline.
Paper is real - Santos M, Henriques-Coelho T, Leite-Moreira A, Expert Opin Ther Targets 2010;14(2):131-141, PMID 20055713 - but the printed DOI (10.1517/14728220903433387) does not resolve to any record. Correct DOI is 10.1517/14728220903512991.
Read the study →Macrophages and fibroblasts - cells with no connection to the thymus - were subjected to oxidative stress, heat, or triggers for programmed and unprogrammed cell death. Thymulin appeared in the culture medium of both cell types within two hours, and western blots suggested a precursor protein, possibly SPATS2L, exists in these cells. This overturns the assumption that thymulin is purely thymic, but it is entirely cell-culture work.
Title, authors, journal, year, volume and pages correct, but the printed DOI (10.1177/0394632016685293) does not resolve. Correct DOI is 10.1177/0394632017694625, PMID 28281875.
Read the study →FOXO4-DRI is a designed peptide that breaks the grip FOXO4 has on p53 inside senescent ('zombie') cells, which pushes those cells to self-destruct while leaving healthy cells alone. The original 2017 Cell paper is a genuinely landmark piece of work in ageing biology and the mechanism has since been confirmed at the structural level. Everything published so far is cell culture and mice, though: there has never been a human trial.
Where the evidence stands. Entirely preclinical. One influential mouse study, several independent in-vitro confirmations in human cells, and structural work confirming the mechanism, but zero human trials, no published human safety or dosing data, and no long-term data on what removing senescent cells does in a healthy adult.
The founding paper identified FOXO4 as the protein keeping senescent cells alive by sequestering p53, then designed FOXO4-DRI to disrupt that interaction. The peptide selectively triggered apoptosis in senescent cells while being tolerated in living mice, and reversed chemotherapy-induced tissue damage, improved fitness and restored kidney function in both naturally aged and fast-ageing (Xpd-progeroid) mice. It is a well-designed and heavily cited study, but it is mouse work from a single laboratory, and the doses and dosing schedule used have never been tested in a person.
Title, authors, journal, volume 169(1), pages 132-147.e16, year and DOI all match the source citation exactly.
Read the study →A 2025 study found keloid scar tissue is enriched in senescent fibroblasts carrying elevated phosphorylated p53 (serine 15). FOXO4-DRI drove those cells into apoptosis and reduced the proportion held in G0/G1 arrest, acting by forcing phospho-p53 out of the nucleus. The finding independently supports the proposed mechanism in a fresh human tissue context, but it is cell-based work aimed at a specific scarring disease, not systemic anti-ageing use.
Source gave the title as '... by blocking p53-FOXO4 interaction' and 'Article xxxx'. The correct title is 'FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation', Communications Biology 2025;8:299 (Kong YX, Li ZS, Liu YB, et al.). The DOI supplied is correct.
Read the study →Using solution NMR, researchers built structural models showing that FOXO4-DRI binds the disordered second transactivation domain of p53 and forms a transiently folded complex, and that both the FOXO4-derived sequence and the cell-penetrating portion contribute to binding. They also showed p53 phosphorylation strengthens the interaction. This confirms the drug does what its designers claimed at the molecular level, which matters because a plausible-sounding mechanism is not the same as a demonstrated one. It is pure biophysics, with no cells or animals involved.
Title, authors, journal, volume 16 and DOI match; article number is 5672 (the source left it as 'Article xxxx').
Read the study →An independent group at Oregon Health & Science University used molecular modelling of the FOXO4-TP53 interface to design improved peptide inhibitors, then tested them against senescent cancer cells. The work both validates the FOXO4-p53 binding site as a genuine drug target and produced candidate peptides intended to be more selective than FOXO4-DRI itself. It is entirely in vitro, in cancer cell models rather than normal ageing tissue.
Source cited 'EBioMedicine, 74, 103716' with DOI 10.1016/j.ebiom.2021.103716. That DOI belongs to an unrelated pancreatic cancer genomics paper. The correct record is Le HH, Cinaroglu SS, Manalo EC, et al., 'Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells', EBioMedicine 2021;73:103646.
Read the study →Human chondrocytes expanded in culture to a high population-doubling level (PDL9) were treated with FOXO4-DRI and compared with young, low-doubling cells (PDL3). The peptide removed more than half the aged cells while leaving cell numbers in the young population essentially unaffected, and senescence markers fell significantly. Honest limitation: it did not improve the cells' ability to form cartilage, so selectivity was demonstrated but functional benefit was not.
Title, authors, journal, volume 9, article 677576, year and DOI all match the source citation exactly.
Read the study →GHK is a short three-amino-acid chain that occurs naturally in human blood and binds copper. Its plasma level falls sharply with age, and laboratory work links the copper complex to collagen production, wound repair and control of inflammation. Most of what is published is mechanism and review work rather than clinical trials.
Where the evidence stands. Mechanistically well-mapped, clinically thin: this reference list contains no primary human trial of GHK-Cu. The strongest primary study is a mouse lung-injury model, and the remainder are narrative reviews, most written by the researcher who discovered the peptide and holds commercial interests in it.
A short review of GHK as a candidate anti-ageing peptide. It documents that plasma GHK sits around 200 ng/mL at age 20 and drops to about 80 ng/mL by age 60, and summarises evidence across tissue remodelling, wound healing, antioxidant and anti-inflammatory action, plus preliminary cognitive findings in aged mice. Limitation: a review article, and the age-related decline is an association, not proof that replacing GHK reverses anything.
CORRECTION: printed as Dou et al. 2022 with no journal named. Actual: Dou Y, Lee A, Zhu L, Morton J, Ladiges W. 'The potential of GHK as an anti-aging peptide.' Aging Pathobiology and Therapeutics, 2020, 2(1), 58-61. Year and journal in the source citation were wrong.
Read the study →The most-cited modern overview of GHK-Cu, published in a peer-reviewed indexed journal. It sets out the peptide's reported actions on collagen, elastin and glycosaminoglycan synthesis, blood-vessel and nerve outgrowth, and anti-inflammatory signalling, and maps these onto the gene pathways GHK appears to regulate. Limitation: it is a narrative review by the peptide's discoverer, with no new data and no meta-analysis of clinical outcomes.
Citation as printed matches exactly: Int J Mol Sci 2018, 19(7), 1987. DOI 10.3390/ijms19071987.
Read the study →A narrative review pulling together gene-expression and tissue-repair data on GHK. It reports that GHK modulates expression of roughly 4,000 human genes in the Broad Institute Connectivity Map dataset, including a set of 47 DNA-repair genes stimulated by at least 50%, and that GHK suppressed RNA production in 70% of 54 genes overexpressed in aggressive metastatic colon cancer. Limitation: this is a review, not an experiment; the gene-expression signals come from cultured cells exposed to GHK, and gene-level changes are not the same as a clinical outcome.
Design is a narrative review, not a systematic review or meta-analysis. Also reports a secondhand human comparison in which collagen production rose in 70% of women using GHK-Cu versus 50% on vitamin C and 40% on retinoic acid; the underlying trial is not in this reference list and was not independently verified.
Read the study →A review arguing that GHK's skin effects run partly through safe transport of copper and through changes in antioxidant gene expression, covering superoxide dismutase, metallothionein and related pathways. It collates in vitro and gene-array data rather than generating new trial evidence. Limitation: review-level synthesis by authors with a commercial stake in the peptide, published in a journal without the citation weight of a clinical dermatology title.
Confirmed via Crossref: Cosmetics 2015, 2(3), 236-247, DOI 10.3390/cosmetics2030236. Matches the printed citation.
Read the study →Mice given a bacterial toxin (LPS) to trigger acute lung injury were treated with the GHK-copper complex, alongside parallel experiments in RAW 264.7 macrophage cell cultures. GHK-Cu reduced reactive oxygen species, raised superoxide dismutase activity, lowered TNF-alpha and IL-6, and visibly reduced inflammatory cell infiltration into lung tissue, acting via suppression of NF-kB p65 and p38 MAPK. Limitation: this is a rodent model of a severe acute illness, injected rather than applied to skin, and says nothing directly about cosmetic or anti-ageing use in people.
Citation as printed matches exactly: Oncotarget 7(36), 58405-58417. DOI 10.18632/oncotarget.11168.
Read the study →OS-01 is a synthetic peptide developed as a 'senotherapeutic', designed to reduce the burden of senescent, worn-out cells in skin rather than to plump or exfoliate it. It is applied topically and works through the PP2A enzyme complex, which is involved in DNA repair and cell-cycle control. It is the only peptide in this group with genuine randomised human trial data behind it.
Where the evidence stands. Small but real randomised human evidence: two double-blind, vehicle- or moisturiser-controlled 12-week facial trials plus mechanistic work in ex vivo human skin. The critical caveat is that every published OS-01 study was designed, funded and authored by OneSkin, the company that owns the patent, with no independent replication.
A randomised, double-blinded 12-week trial in 60 women aged 60 to 90 compared a topical OS-01 formulation against a commercial moisturiser control. The OS-01 group showed significantly improved skin barrier function and hydration, a significant fall in circulating IL-8, and 70% of participants reported improved general skin appearance versus 42% in the control group, while the control group's TNF-alpha and IFN-gamma rose. Limitations: pilot size, a single age band, and all authors are OneSkin employees, co-founders or patent inventors.
Citation as printed matches: J Cosmet Dermatol 2025;24(4):e70169, DOI 10.1111/jocd.70169. Declared conflict of interest: OneSkin owns the patent; several authors are co-founders.
Read the study →A 12-week split-face, double-blinded, vehicle-controlled study in 22 participants applied the OS-01 formulation to one side of the face and an identical peptide-free formulation to the other. The OS-01 side showed significantly reduced trans-epidermal water loss versus both baseline and the vehicle side, and Antera 3D imaging plus expert grading found greater reduction in periorbital wrinkle appearance and indentation on the treated side. Limitations: 22 participants, short duration, and again entirely manufacturer-run.
CORRECTION: printed as 'Zonari, A. (n.d.) ... 2024.pdf' with no year, volume or author list. Actual: Zonari A, Brace LE, Harder NHO, et al. 'Double-blind, vehicle-controlled clinical investigation of peptide OS-01 for skin rejuvenation.' J Cosmet Dermatol 2024;23(6):2135-2144, DOI 10.1111/jocd.16242.
Read the study →Twenty-two participants applied an OS-01 eye formulation twice daily for 12 weeks, with bioinstrumental measurement and expert photographic grading. Transepidermal water loss fell 17.33%, hydration rose 32.49%, firmness improved 10.19% and elasticity rose 25.58% versus baseline, all statistically significant, with 95.46% reporting improved overall appearance. Major limitation: this was a single-arm study with no control group or placebo, so the changes cannot be separated from the effect of any moisturiser or from regression to the mean, and the eye product contains other actives besides OS-01.
Citation as printed matches: Int J Cosmet Sci 2025;47(3):455-465, DOI 10.1111/ics.13042. Not randomised and not controlled, despite the strong percentage figures.
Read the study →A two-step phenotypic screen identified Peptide 14 (OS-01), which reduced senescence burden in human dermal fibroblasts aged by four different routes, progeria mutation, chronological ageing, UVB and etoposide, without measurable toxicity, acting through the PP2A holoenzyme. Applied to aged ex vivo human skin, it produced a structural and molecular profile closer to young skin, reduced senescence markers including SASP, and lowered the skin's DNA methylation age. Limitation: cell culture and donated skin kept alive outside the body, not living people; a formal erratum was published in 2024.
Citation as printed matches: NPJ Aging 2023;9(1):10, DOI 10.1038/s41514-023-00109-1. Erratum: NPJ Aging 2024;10(1):14.
Read the study →CJC-1295 is a long-acting version of the body's own growth hormone releasing hormone. Rather than injecting growth hormone directly, it prompts the pituitary to release more of its own, and a single dose keeps that signal running for over a week. Two published human studies show it raises growth hormone and IGF-1 substantially while keeping the natural pulsing rhythm intact.
Where the evidence stands. Two genuine human trials establish that CJC-1295 raises GH and IGF-1 in healthy adults, but both are short pharmacology studies from 2006 with no body-composition or long-term outcome data, and no human trial has been published since. The remaining strong evidence in this section is for tesamorelin, a different GHRH analogue that is FDA-approved, and for recombinant growth hormone, so those results should never be presented as CJC-1295 results.
Double-blind randomized trial of 50 antiretroviral-treated HIV patients with abdominal fat accumulation given 2 mg daily tesamorelin (n=28) or placebo (n=22) for 6 months. Visceral fat fell by a net 42 cm2 (95% CI -71 to -14, P=0.005) and liver fat fell by a net 2.9 percentage points in lipid-to-water ratio (P=0.003). Fasting glucose rose 7 mg/dL at 2 weeks (P=0.03) but the difference was gone by 6 months. Limitation: small single-centre trial of tesamorelin, not CJC-1295, in a specific patient group.
Citation matches the real paper. Flagged for the page: the drug studied is tesamorelin, not CJC-1295.
Read the study →Pooled analysis of two multicentre, double-blind, placebo-controlled phase 3 trials in 806 antiretroviral-treated HIV patients randomized 2:1 to 2 mg daily tesamorelin (n=543) or placebo (n=263) for 26 weeks, with a 26-week safety extension. At week 26, visceral fat fell 24 +/- 41 cm2 versus a 2 +/- 35 cm2 rise on placebo (treatment effect -15.4 percent, P<0.001), triglycerides fell, and IGF-1 rose 108 +/- 112 ng/mL versus a 7 ng/mL fall. Subcutaneous fat was unchanged, meaning the effect was specific to visceral fat. Limitation: again tesamorelin, not CJC-1295, and confined to HIV-associated lipohypertrophy.
Citation matches the real paper. Flagged for the page: the drug studied is tesamorelin, not CJC-1295.
Read the study →412 HIV patients with abdominal fat accumulation were randomized to 2 mg daily subcutaneous tesamorelin or placebo for 26 weeks. Visceral adipose tissue on CT fell 15.2 percent on drug versus a 5.0 percent rise on placebo, triglycerides fell 50 mg/dL versus a 9 mg/dL rise, and IGF-1 rose 81.0 percent versus a 5.0 percent fall (all P<0.001), with no significant differences in glucose measures. Limitation: this is tesamorelin, a different GHRH analogue, in a specific patient population with antiretroviral-associated fat redistribution; it is not a CJC-1295 study and does not transfer to healthy adults.
Citation matches the real paper exactly. Flagged for the page: the drug studied is tesamorelin, not CJC-1295.
Read the study →Two randomized, placebo-controlled, double-blind ascending-dose trials over 28 and 49 days in healthy adults aged 21-61. A single subcutaneous injection produced dose-dependent increases in mean plasma GH of 2- to 10-fold lasting 6 days or more, and IGF-1 rises of 1.5- to 3-fold lasting 9-11 days, with an estimated half-life of 5.8-8.1 days. After repeated dosing, IGF-1 stayed above baseline for up to 28 days and no serious adverse reactions were reported. Limitation: small early-phase pharmacology study measuring hormone levels only, with no body composition, strength or clinical outcomes.
Citation matches the real paper exactly (Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA; JCEM 2006;91(3):799-805).
Read the study →Randomized, double-blind, placebo-controlled multicentre trial in 166 adults with adult-onset growth hormone deficiency, dosed for 12 months starting at 0.0125 mg/kg/day. Treated men and women showed significant decreases in total body and trunk fat and significant increases in lean body mass, plus significant improvements in total and LDL cholesterol. No significant treatment effect was seen on strength, endurance, quality of life or bone mineral density. Limitation: this is recombinant growth hormone in diagnosed deficiency, not a GHRH analogue and not healthy adults, so it sets an upper bound on what raising GH can do rather than showing what CJC-1295 does.
Citation matches the real paper. Flagged for the page: the drug studied is recombinant human growth hormone, not CJC-1295.
Read the study →Healthy men aged 20-40 had GH measured by 20-minute blood sampling over a 12-hour overnight window before and one week after a single 60 or 90 mcg/kg injection. Pulse frequency and pulse size were unchanged, but trough GH rose 7.5-fold (P<0.0001), mean GH rose 46 percent (P<0.01) and IGF-1 rose 45 percent (P<0.001). No difference was seen between the two doses. Limitation: very small single-arm before-and-after design in young healthy men, with no placebo group and no clinical endpoints.
Citation matches the real paper exactly (Ionescu M, Frohman LA; JCEM 2006;91(12):4792-7).
Read the study →IGF-1 LR3 is a modified version of insulin-like growth factor-1 designed to evade the binding proteins that normally control it, giving it a longer and stronger action. That same modification is why it is sold as a laboratory research chemical rather than a medicine. The research below is about natural IGF-1 biology, because there are no published human studies of IGF-1 LR3 itself.
Where the evidence stands. There is no human clinical evidence for IGF-1 LR3. Not one of the 16 references in this section studies the LR3 analogue; all concern native IGF-1 or the GH/IGF axis in general, and most are review articles rather than primary research. The two genuinely informative human studies are large observational cohorts, and both point the same uncomfortable direction: high IGF-1 levels are associated with higher insulin resistance and with higher risk of breast and prostate cancer and all-cause mortality. Several citations also carry the wrong journal, authors or country.
Review setting out how growth hormone and IGF-1 have opposing metabolic effects, with growth hormone raising blood glucose and promoting insulin resistance while IGF-1 lowers glucose and improves insulin sensitivity. This distinction matters for anyone considering these compounds, because raising one does not produce the same metabolic picture as raising the other. Limitation: a review article with no original data, and no coverage of the LR3 analogue.
Cited with co-authors Zadik and Klinger and volume 46(3). The real paper is Laron Z, Werner H, Endocr Rev 2025;46:877-890, article ID bnaf022. Co-authors and pages are wrong.
Read the study →Review of the interplay between growth hormone, IGF-1 and insulin, covering how the three hormones regulate each other and how that shapes clinical decisions in growth hormone excess and deficiency. Useful background for understanding why IGF-1 is used as the monitoring marker for growth hormone therapy. Limitation: a short review with no original data and no LR3 content.
Cited as volume 39(2), pages 180-198. The real paper is Nijenhuis-Noort EC, Berk KA, Neggers SJCMM et al., Endocrinol Metab 2024;39:83-89. Pages are wrong.
Read the study →Case-cohort study nested in EPIC-Heidelberg, with IGF-1 measured in 7,461 stored serum samples and a median 17.5 years of follow-up, covering 1,668 incident cancers, 1,428 cardiovascular events and 2,441 deaths. Higher IGF-1 was directly associated with breast cancer (HR 1.25, 95% CI 1.06-1.47) and prostate cancer (HR 1.31, 95% CI 1.09-1.57), and showed a U-shaped relationship with mortality, with both the lowest and highest IGF-1 groups facing higher hazards of cancer, cardiovascular and all-cause death. Limitation: observational, so it cannot prove that raising IGF-1 causes these outcomes, and it measures natural circulating IGF-1, not administered IGF-1 LR3.
Cited in the source as 'Cancers, 15(18), 4515' and described as a UK Biobank analysis with co-authors Murphy and Carreras-Torres. The real paper is Mukama T, Srour B, Johnson T, Katzke V, Kaaks R, JCEM 2023;108(10):e1092-e1105, and the cohort is EPIC-Heidelberg, not UK Biobank. Journal, volume, pages, co-authors and cohort are all wrong in the citation.
Read the study →Cross-sectional analysis of 3,354 adults aged 19-72 from the Danish Health2006 study, using HOMA-IR as the measure of insulin resistance. After adjustment for age, sex, physical activity and waist-to-height ratio, a U-shaped association emerged: both the lowest IGF-1 quintile (OR 1.65, 95% CI 1.16-2.34) and the highest quintile (OR 1.96, 95% CI 1.38-2.79) were associated with raised HOMA-IR compared with the middle quintile, and the finding held after excluding people with type 2 diabetes. Limitation: cross-sectional, so direction of causation is unknown, and it describes natural IGF-1 levels rather than the effect of injecting an IGF-1 analogue.
Cited as pages 766-773 in 'German adults'. The real paper is pages 768-773 and studies Danish adults (Friedrich N, Thuesen B, Jorgensen T et al., Diabetes Care 2012;35(4):768-73).
Read the study →Review of in vitro and in vivo studies testing ways of delivering IGF-1 to healing tendon, covering scaffolds, gene delivery and direct injection across rodent, rabbit and equine models. Reports generally improved cell proliferation, collagen synthesis and healing markers, but the delivery strategies and dosing vary widely between studies. Limitation: a review of preclinical work with no controlled human tendon trials, and no testing of IGF-1 LR3.
Real paper, but co-authors differ from the citation. Actual: Miescher I, Rieber J, Calcagni M et al., 'In Vitro and In Vivo Effects of IGF-1 Delivery Strategies on Tendon Healing: A Review', Int J Mol Sci 2023;24(3):2370. The citation omits that it is a review.
Read the study →Review in the '40 Years of IGF1' series covering IGF-1's actions on the skeleton, including its role in longitudinal bone growth, bone mineral density and the coupling of bone formation to resorption. Draws on genetic mouse models and human deficiency states. Limitation: a review of animal and clinical literature rather than a trial, and it addresses native IGF-1 rather than the LR3 analogue.
Cited as 'Yakar, S., & Leroith, D.' pages T61-T77. The real paper is Yakar S, Werner H, Rosen CJ, J Mol Endocrinol 2018;61(1):T115-T137. Second author and page range are wrong.
Read the study →Review of how insulin-like growth factors and their six binding proteins regulate cell proliferation, apoptosis and growth, and how disruption of that system contributes to carcinogenesis. It is the standard reference for why IGF-1 binding proteins matter, which is directly relevant because the LR3 modification exists specifically to escape those binding proteins. Limitation: a narrative review from 2000, not primary data, and it predates and does not test the LR3 analogue.
Citation matches the real paper (Grimberg A, Cohen P; J Cell Physiol 2000;183(1):1-9).
Read the study →Follistatin is the body's natural brake on myostatin, the protein that limits how much muscle you can build. Blocking myostatin produces some of the most dramatic muscle growth results in all of biology, including a fourfold increase in muscle mass in mice. The critical caveat is that essentially every one of those results came from gene therapy or genetic engineering, not from injecting follistatin peptide.
Where the evidence stands. This is the most scientifically sound of the five sections: 11 of 15 references verified cleanly with only minor errors. But the evidence does not support the product as sold. Every muscle-growth finding comes from delivering the follistatin gene by viral vector or from transgenic animals, not from injecting follistatin-344 peptide, and the only human trial in the list tested ACE-031, a different myostatin-blocking drug that was stopped early for safety. There are no human trials of injected follistatin-344.
Randomized, double-blind, placebo-controlled ascending-dose trial of subcutaneous ACE-031 in ambulatory boys with Duchenne muscular dystrophy. Trends were seen toward increased lean body mass and bone mineral density, reduced fat mass, and maintenance of 6-minute walk distance versus decline on placebo, but none reached statistical significance. The study was stopped after the second dosing regimen because of nosebleeds and telangiectasias (visible dilated small blood vessels). Limitation: this tests ACE-031, an activin receptor decoy protein, not follistatin, and the early termination for vascular side effects is the single most important safety signal in this whole reference list.
Citation matches the real paper (Campbell C, McMillan HJ, Mah JK et al., Muscle Nerve 2017;55(4):458-464, published online December 2016). Flagged for the page: the drug is ACE-031, not follistatin.
Read the study →Study of follistatin in diabetic cardiomyopathy, reporting attenuated myocardial fibrosis via suppression of the TGF-beta/Smad3 pathway. Supports the broader picture that follistatin's anti-fibrotic activity extends beyond skeletal muscle into cardiac tissue. Limitation: an animal model of diabetic heart disease with no human data, and the finding is about preventing fibrosis rather than building muscle.
Citation matches the real paper (Wang Y, Yu K, Zhao C et al., Front Pharmacol 2021;12:683335).
Read the study →Delivering follistatin-288 by AAV6 vector markedly increased muscle mass and force-producing capacity in mice alongside increased protein synthesis and mTOR activation, and those effects were blunted by inhibiting mTOR or deleting S6K1/2. Crucially, the effect persisted regardless of whether myostatin was overexpressed or knocked out, showing follistatin works through Smad3 and mTOR independently of myostatin. Limitation: mouse gene-delivery study of the 288 isoform rather than injected follistatin-344 peptide.
Citation matches the real paper (Winbanks CE, Weeks KL, Thomson RE et al., J Cell Biol 2012;197(7):997-1008).
Read the study →An adeno-associated virus vector carrying the follistatin-344 gene (AAV1-FS344) was injected into the quadriceps of cynomolgus macaque monkeys. It produced pronounced and durable increases in muscle size and strength, and long-term transgene expression caused no abnormal changes in the morphology or function of key organs. This is the highest-order species in which follistatin has been tested. Limitation: this is a one-time gene therapy delivered by viral vector into a specific muscle, which is a fundamentally different intervention from injecting follistatin-344 peptide, and the sample was a small number of monkeys.
Citation matches the real paper (Kota J, Handy CR, Haidet AM et al., Sci Transl Med 2009;1(6):6ra15). Note a 2026 erratum has been issued against this paper.
Read the study →A single administration of myostatin-inhibitor genes, including follistatin, enhanced muscle mass and strength in normal and dystrophic mouse models for more than two years, and worked even when delivered to already-aged animals. This addressed a key limitation of earlier myostatin work, which had shown efficacy depending heavily on the age at which inhibition began. Limitation: mouse study using viral gene delivery, not peptide injection, and 'more than two years' is close to a full mouse lifespan rather than a long-term human timeframe.
Citation matches the real paper (Haidet AM, Rizo L, Handy C et al., PNAS 2008;105(11):4318-22).
Read the study →Myostatin-null mice carrying a follistatin transgene had roughly four times the muscle mass of wild-type mice, against the roughly two-fold increase seen from removing myostatin alone. This demonstrated that follistatin blocks additional muscle-limiting regulators beyond myostatin itself, and that the ceiling on muscle growth via TGF-beta signalling is far higher than previously thought. Limitation: a genetically engineered mouse, with the transgene present from conception; nothing here tests giving follistatin protein to a normal adult animal.
Citation matches the real paper (Lee SJ; PLoS One 2007;2(8):e789).
Read the study →Purified myostatin was shown to bind activin type II receptors, and that binding was inhibited by follistatin and, at higher concentrations, by the myostatin propeptide. Transgenic mice expressing high levels of follistatin, the propeptide or a dominant-negative receptor under a skeletal-muscle promoter all showed dramatic increases in muscle mass comparable to myostatin knockout mice. Limitation: transgenic overexpression from birth in mice, combined with biochemistry in purified systems; it establishes the mechanism, not a treatment.
Citation matches the real paper (Lee SJ, McPherron AC; PNAS 2001;98(16):9306-11).
Read the study →Review of the follistatin-like protein family, covering structure, the binding of activins and myostatin, and biomedical applications across muscle, fibrosis, reproduction and inflammation. It is the best single orientation piece in this reference list for understanding what follistatin actually is and does. Limitation: a review with no original data, and it does not evaluate follistatin-344 as an injectable product.
Citation matches the real paper (Parfenova OK, Kukes VG, Grishin DV; Biomedicines 2021;9(8):999). Note this same paper is cited twice in the section, as both reference 1 and reference 3.
Read the study →Dynatropin is sold as a growth hormone related peptide product. There is no published scientific research on Dynatropin itself. The reference list attached to it is made up entirely of studies on other, unrelated compounds, plus supplement retailer pages and a video that had not been recorded.
Where the evidence stands. No legitimate primary evidence exists for Dynatropin. Not one of the 14 references studies Dynatropin. Nine are studies of entirely different compounds (CJC-1295, MK-677, GHRP-2, L-arginine, an amino acid blend), four are commercial product and retailer pages for a different product called Secretropin, and one is a YouTube video listed as 'Pending', meaning it did not exist when the list was written. Of the nine research citations, six carry DOIs that resolve to completely unrelated papers and one appears to be entirely invented. Anything claimed for Dynatropin is borrowed from other molecules and should not be presented as evidence for this product.
Randomized, placebo-controlled, double-blind crossover study in 16 healthy adults (12 men, 4 women, mean age 32, mean BMI 26.4) given an oral amino acid blend or placebo after an overnight fast, with a one-week washout. At 120 minutes, GH had risen 682 percent (roughly eightfold) from baseline and was significantly higher than placebo (P=0.01), with a higher area under the curve (P=0.04). Limitation: a single-dose acute hormone spike in 16 people, with no body composition, strength or long-term data, and it tests an oral amino acid supplement rather than Dynatropin.
Cited in the source as 'Journal of the International Society of Sports Nutrition, 17, 43' with DOI 10.1186/s12970-020-00372-9, which does not resolve. The real paper is Tam CS, Johnson WD, Rood J, Heaton AL, Greenway FL, Am J Ther 2020;27(4):e333-e337. Journal, volume and pages are wrong.
Read the study →Two-year double-blind, randomized, placebo-controlled modified-crossover trial in 65 healthy adults aged 60-81 taking 25 mg oral MK-677 daily. Fat-free mass rose 1.1 kg (95% CI 0.7 to 1.5) versus a 0.5 kg fall on placebo (P<0.001) and body weight rose 2.7 kg versus 0.8 kg (P=0.003), with GH and IGF-1 restored to young-adult range. However, abdominal visceral fat and total fat mass did not change, fasting glucose rose 5 mg/dL (P=0.015), insulin sensitivity fell, and the lean mass gain produced no improvement in strength or function. Limitation: this is MK-677, an oral ghrelin mimetic, not Dynatropin, and the trade-off in glucose control is real.
Cited in the source as 'Journal of Clinical Endocrinology & Metabolism, 93(8), 2907-2914' with DOI 10.1210/jc.2007-2641, which does not resolve. The real paper is Nass R, Pezzoli SS, Oliveri MC et al., Ann Intern Med 2008;149(9):601-11. Journal, volume and pages in the citation are all wrong. Studies MK-677, not Dynatropin.
Read the study →Two randomized, placebo-controlled, double-blind ascending-dose trials in healthy adults aged 21-61. A single subcutaneous dose raised mean plasma GH 2- to 10-fold for 6 days or more and IGF-1 1.5- to 3-fold for 9-11 days, with a half-life of 5.8-8.1 days and no serious adverse reactions. Limitation: a hormone-level pharmacology study with no body composition or clinical outcomes, and it concerns CJC-1295, a completely different peptide from Dynatropin.
Citation is accurate, but the paper is about CJC-1295 and contains no reference to Dynatropin.
Read the study →Systematic review and meta-analysis of randomized clinical trials of L-arginine supplementation, alone and combined with growth hormone releasing hormone, on GH levels. Arginine alone produced a mean GH increase of 10.07 (95% CI 7.87 to 12.28), while arginine combined with GHRH produced 24.96 (95% CI 17.51 to 32.42), with no significant difference between patients and healthy individuals or between oral and injected arginine. Limitation: these are acute GH-stimulation-test measurements, not sustained treatment effects, and the review concerns arginine and GHRH, not Dynatropin.
Cited in the source as 'Nutrients, 14(21), 4643' with DOI 10.3390/nu14214643, which resolves to an unrelated paper about prenatal caffeine exposure. The real paper is Goli P, Yazdi M, Heidari-Beni M, Kelishadi R, Int J Endocrinol 2022;2022:8739289.
Read the study →Comparison of the pituitary response to GHRP-2 in 11 individuals with isolated GH deficiency caused by a homozygous GHRH receptor mutation versus 8 normal controls. GHRP-2 produced a 4.5-fold rise in serum GH in the deficient group (P=0.002), far below the 79-fold rise in controls (P=0.008), showing that GHRP-2 has a GHRH-independent action on pituitary somatotrophs. Limitation: a very small mechanistic study in a rare genetic population, testing GHRP-2 rather than Dynatropin.
Cited pages 3279-3286 and DOI 10.1210/jcem.86.7.7639, which resolves to an unrelated paper on antithyroid drugs. The real paper is Gondo RG, Aguiar-Oliveira MH, Hayashida CY et al., JCEM 2001;86(7):3279-83, DOI 10.1210/jcem.86.7.7694.
Read the study →Narrative review of the safety and efficacy of growth hormone secretagogues, covering the class as a whole. It is a review rather than primary research and reports no original data. Limitation: no new evidence, no Dynatropin content, and reviews of this kind cannot establish efficacy.
Cited in the source as '2017; 5(3), 241-252' with DOI 10.1016/j.sxmr.2017.03.003, which resolves to an unrelated paper about estrogen receptor modulators. The real paper is Sigalos JT, Pastuszak AW, Sex Med Rev 2018;6(1):45-53. Year, volume and pages are wrong.
Read the study →These are two different things that get talked about as if they were one. Melanotan I (afamelanotide) is an approved prescription medicine, sold as SCENESSE, a 16 mg implant used to increase pain-free light exposure in adults with erythropoietic protoporphyria, a rare light-sensitivity disease. Melanotan II is a different, unapproved research peptide with no marketing authorisation anywhere in the world, and it is the one sold online for tanning. Melanotan II is documented to cause nausea (severe in a meaningful minority of trial subjects), spontaneous erections and priapism, and darkening or changing moles; dermatology case series and a review record new dysplastic naevi and four reported melanomas arising in moles during or shortly after use. Product bought online is unregulated, so purity and dose are unknown. Nothing here should be read as a recommendation to use Melanotan II.
Where the evidence stands. Split evidence: Melanotan I (afamelanotide) has genuine placebo-controlled trials and FDA approval for a rare photosensitivity disease; Melanotan II is approved nowhere, its human data are three tiny 1990s and 2000s studies, and it carries documented harms including severe nausea, priapism and melanocytic changes with melanoma case reports.
Two multicentre, randomised, double-blind, placebo-controlled trials of 16 mg subcutaneous afamelanotide implants every 60 days in erythropoietic protoporphyria, with 74 patients in the EU study and 94 in the US study. In the US study median pain-free direct sunlight over 6 months was 69.4 hours on drug versus 40.8 hours on placebo (P=0.04); in the EU study 6.0 versus 0.8 hours (P=0.005), with fewer phototoxic reactions (77 versus 146, P=0.04). Adverse events were mostly mild. This is the evidence base for the drug's approval, and it applies to a rare inherited photosensitivity disorder, not to cosmetic tanning.
Cited details match exactly (N Engl J Med 2015;373(1):48-59).
Read the study →A double-blind, placebo-controlled crossover study in 10 men with erectile dysfunction and organic risk factors, using RigiScan monitoring over 6 hours. Melanotan II (0.025 mg/kg) produced subjectively reported erections after 12 of 19 injections versus 1 of 21 placebo doses, with mean tip rigidity above 80% lasting 45.3 minutes versus 1.9 minutes for placebo (P=0.047), and significantly higher reported sexual desire. Severe nausea followed 4 of the 19 active injections. Ten men is a very small sample and this is the sort of side-effect rate that matters for an unregulated product.
Journal, year, volume and pages are correct. Source paraphrased the title; the actual title is 'Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction.'
Read the study →A review of the University of Arizona group's own double-blind placebo-controlled crossover experience with Melanotan II in 20 men with psychogenic and organic erectile dysfunction. Erection occurred in 17 of 20 men without sexual stimulation, mean RigiScan tip rigidity above 80% lasted 41 minutes, and increased desire was reported after 13 of 19 active doses versus 4 of 21 placebo doses (P<0.01). At 0.025 mg/kg, 12.9% of subjects had severe nausea. It is a summary of the authors' own small studies rather than an independent trial, and total human exposure remains tiny.
Source cited Annals of the New York Academy of Sciences 909(1):129-142. Correct citation is Int J Impot Res. 2000;12(Suppl 4):S74-S79, title 'Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II.'
Read the study →A single-blind, alternating-day, placebo-controlled pilot phase I study of subcutaneous Melanotan II in three healthy male volunteers, dose-escalated from 0.01 to 0.03 mg/kg. Mild nausea occurred at most dose levels, 0.03 mg/kg caused Grade II somnolence and fatigue in one of two subjects, and a stretching and yawning complex preceded spontaneous erections lasting 1 to 5 hours. Two of three subjects showed increased facial, upper body and buttock pigmentation a week after dosing ended. Three subjects is the entire dataset, which is the point: this is the level of human evidence behind Melanotan II as a tanning agent.
Cited correctly (Life Sci 1996;58(20):1777-1784). This reference was filed under PT-141 in the source but studies Melanotan II.
Read the study →A retrospective observational analysis of 2,933 liver function tests, 1,186 protoporphyrin measurements and 1,659 afamelanotide implants across 70 patients with erythropoietic protoporphyria. Protoporphyrin rose significantly as time since the last implant increased (P<0.0001), while ALT and bilirubin fell as the number of implants in the preceding year rose (P=0.012 and P=0.0299). Retrospective and non-randomised, and differences between patients explained more of the variance than treatment did, so this is suggestive rather than proof of liver protection.
Source title was 'Afamelanotide is associated with dose-dependent effects on protoporphyrin IX and liver function tests in EPP'. Actual title: 'Afamelanotide Is Associated with Dose-Dependent Protective Effect from Liver Damage Related to Erythropoietic Protoporphyria.' Journal, year, volume and article number are correct.
Read the study →A three-year observational study of the entire Swiss erythropoietic protoporphyria cohort (n=39) treated with afamelanotide between 2016 and 2018. Median maximum phototoxic burn tolerance time rose from 10 minutes before treatment to 180 minutes on treatment, worst-reaction pain fell from a median 10/10 to 6/10, and treatment adherence was 97.4%. This is uncontrolled observational data with no placebo group, so expectation effects and behaviour change cannot be separated out.
Source gave the page as '15, 345'. Correct citation is Orphanet J Rare Dis. 2020;15(1):213. Full correct title: 'Increased phototoxic burn tolerance time and quality of life in patients with erythropoietic protoporphyria treated with afamelanotide - a three years observational study.'
Read the study →A dermatology review of the risks of unregulated alpha-MSH analogue use, covering both Melanotan I and Melanotan II sold outside medical supervision. It documents uncertainty over preparation, administration and dosage of illegally supplied product, and an increasing number of case reports of cutaneous complications, specifically melanocytic changes in existing moles and newly emerging dysplastic naevi. Four published case reports describe melanomas arising from existing moles during or shortly after melanotan use. The authors are explicit that causation is not proven and that multiple national health bodies have issued safety warnings.
Source cited BMJ Case Reports 2017, bcr2016218662. Correct citation is Habbema L, Halk AB, Neumann M, Bergman W. 'Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review.' Int J Dermatol. 2017;56(10):975-980.
Read the study →A single case report of a 16-year-old girl with FAMMM syndrome (a hereditary melanoma-prone mole syndrome) who presented with general skin tanning, multiple darkened melanocytic naevi and an enlarging naevus in the groin after self-injecting Melanotan II and using a UV tanning studio. Her GP referred her because some darkened naevi looked potentially malignant. A single case cannot establish causation, and the concurrent sunbed use is a confounder, but it illustrates the specific concern that drives the warnings on this peptide.
Source cited Case Reports in Dermatology 4(3):293-297. Correct citation is Sivyer GW. 'Changes of melanocytic lesions induced by Melanotan injections and sun bed use in a teenage patient with FAMMM syndrome.' Dermatol Pract Concept. 2012;2(3):203a10. The PMC id given in the source (PMC3663356) is correct for this paper.
Read the study →Gonadorelin is a lab-made copy of the body's own gonadotropin-releasing hormone, the ten-amino-acid signal the hypothalamus sends the pituitary to release LH and FSH. Because it is identical to the natural hormone, it is used two ways in medicine: as a diagnostic stimulus test (mostly for diagnosing precocious puberty in children) and, delivered continuously by a small pump in tiny pulses every 60 to 90 minutes, as a fertility treatment for people whose own GnRH signal has failed. The pulsatile delivery is the whole point; give it continuously and it shuts the axis down instead of switching it on.
Where the evidence stands. Well-established for two narrow clinical uses, diagnostic pituitary stimulation testing and pump-delivered pulsatile fertility treatment in hypogonadotropic hypogonadism, backed by meta-analyses covering over 1,400 patients; the trials are mostly small and observational, with very few randomised comparisons.
A completed multicentre, double-blind, randomised, placebo-controlled trial run by Ferring Pharmaceuticals testing three fixed doses of subcutaneous pulsatile gonadorelin acetate (10, 15 and 20 micrograms per pulse) delivered by OmniPod pump for ovulation induction in women with primary amenorrhoea from hypogonadotropic hypogonadism. Actual enrolment was 39 participants. This is one of the very few placebo-controlled randomised trials of gonadorelin, but no peer-reviewed publication of its results could be located, so only the registry record can be verified.
Registry record confirmed via the ClinicalTrials.gov API: title, sponsor, condition, interventions, enrolment and completed status all match the source's description. No published results paper found.
Read the study →A meta-analysis of eight articles from seven comparative studies covering 420 men with congenital hypogonadotropic hypogonadism, comparing pulsatile GnRH therapy against gonadotropin therapy for restoring fertility. Pulsatile GnRH produced larger testicular volume and spermatogenesis about 5.3 months earlier than gonadotropins (P=0.004), but rates of positive sperm detection, sperm concentration and pregnancy did not differ significantly. The authors state plainly that no high-quality randomised controlled trials exist in this area, which caps how much weight the comparison can carry.
Source cited 'Journal of Evidence-Based Medicine, 13(3), 191-200 (2020)'. Correct: Wei C, Long G, Zhang Y, et al. World J Mens Health. 2021;39(4):654-665 (epub July 2020). Title also differs from the source's shortened version.
Read the study →A comprehensive Endocrine Society review of congenital hypogonadotropic hypogonadism, the condition that defines gonadorelin's main therapeutic use. It sets out that the disorder arises from failure of normal episodic GnRH secretion, that mutations in more than 30 genes have been implicated, and that fertility can be induced with pulsatile GnRH or gonadotropin regimens in most patients. It also notes that roughly 10% to 20% of male patients spontaneously recover reproductive function, which is a real confounder when judging uncontrolled treatment series. This is a narrative expert review, not primary data.
Cited correctly (Endocr Rev. 2019;40(2):669-710).
Read the study →A systematic review and meta-analysis of 35 studies (3 randomised, 32 observational) covering 1,002 women with idiopathic or functional hypothalamic amenorrhoea treated with pulsatile GnRH. Pulsatile GnRH achieved high ovulation rates with a trend to high pregnancy and live-birth rates per ovulatory cycle, subcutaneous delivery matched intravenous, and ovarian hyperstimulation syndrome was rare and mild. The evidence base is dominated by observational studies with only three randomised trials, so the pooled rates should be read as descriptive rather than as controlled effect sizes.
Source cited volume 110(4):644-660. Correct: Fertil Steril. 2018;109(4):708-719.e8. Authors, year and journal are right. The PMC link given in the source (PMC8267282) points to a different paper (Hao 2021, listed separately here).
Read the study →A prospective, self-controlled, 7-day multicentre clinical study of pulsatile GnRH delivered by the Innopump hormone pump in 28 men with congenital hypogonadotropic hypogonadism across three Chinese hospitals. LH and FSH rose to 2.66 (SD 1.74) and 5.05 (SD 3.03) IU/L respectively, with only one upper respiratory infection and one episode of mild nausea, neither attributed to the therapy. Seven days with no control group is a device-reliability study, not an efficacy trial, and it says nothing about fertility outcomes.
Source cited 'Subcutaneous pulsatile GnRH pump in FHA: long-term outcomes. Frontiers in Endocrinology, 12, 706838.' No such paper exists. The real Hao 2021 paper is: Hao M, Mao JF, Guan QB, et al. Ann Transl Med. 2021;9(12):962. It studies congenital hypogonadotropic hypogonadism in men over 7 days, not long-term outcomes in functional hypothalamic amenorrhoea.
Read the study →A retrospective review of GnRH stimulation tests in 188 consecutive children (169 girls) referred for early pubertal signs, comparing diagnostic accuracy at 15, 30, 60, 90 and 120 minutes. Central precocious puberty was diagnosed in 130 cases (69%); an LH level of 4.7 mU/mL or above at 30 and 60 minutes gave sensitivity and specificity above 99% (area under the ROC curve 1.0), with no gain from the later time points. Being retrospective and single-centre, the cut-off needs prospective confirmation before it changes practice everywhere.
Cited correctly (Medicina 2023;60(1):24, published 22 December 2023).
Read the study →PT-141 is a melanocortin receptor agonist that acts in the brain rather than on blood flow, which is why it affects sexual desire rather than just erection hardness. It is the one peptide in this group with full FDA approval: it is sold as Vyleesi for acquired, generalised hypoactive sexual desire disorder in premenopausal women, on the strength of two large phase 3 trials. The honest summary of those trials is that the effect is real and statistically solid, but modest in size, and nausea is common enough that most people in the long-term extension study stopped taking it.
Where the evidence stands. Strongest evidence in this group: FDA-approved for female HSDD on two phase 3 RCTs in 1,267 women, plus older randomised erectile-dysfunction studies in men; the female-desire benefit is small in absolute terms and nausea drives high discontinuation.
RECONNECT was two identical phase 3, randomised, double-blind, placebo-controlled trials of bremelanotide 1.75 mg injected as needed over 24 weeks in premenopausal women with hypoactive sexual desire disorder. Of 1,267 women randomised, 1,202 were in the efficacy analysis; desire scores rose 0.35 points more than placebo on the FSFI desire domain and distress fell 0.33 points more (both P<.001, integrated data). The gains are statistically robust but small on the scales used, and nausea, flushing and headache each affected 10% or more of women on drug. Both trials were funded by the manufacturers.
Cited details match the real paper exactly (Obstet Gynecol 2019;134(5):899-908).
Read the study →A double-blind, placebo-controlled evaluation of intranasal PT-141 in healthy men and in men with mild-to-moderate erectile dysfunction, with erections measured objectively by RigiScan. Doses above 7 mg produced a statistically significant erectile response versus placebo, with the first erection at roughly 30 minutes and a half-life of about 2 hours. Flushing and nausea were the commonest side effects and no maximum tolerated dose was reached. This is an early-phase pharmacology study with small numbers, not an efficacy trial.
Source cited this as Diamond et al. (2006), Urology 67(3):522-525, which does not exist. The PubMed link supplied resolves to the genuine paper: Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. Int J Impot Res. 2004;16(1):51-59. Corrected details used here.
Read the study →Subcutaneous PT-141 was given to healthy men (0.3 to 10 mg) and, in a crossover design, to men with erectile dysfunction who responded inadequately to 100 mg sildenafil. Erectile response measured by RigiScan was statistically significant above 1.0 mg in healthy men and at both 4 mg and 6 mg in the sildenafil non-responders. Sample sizes were small and the study was designed for safety and pharmacokinetics rather than for clinical efficacy endpoints.
Source reference 6 cited 'Diamond et al. (2004). The melanocortin receptor agonist PT-141 induces penile erection in men with erectile dysfunction. BJU International 93(4):522-526', which does not exist. This is the closest genuine paper from the same group and period: Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Int J Impot Res. 2004;16(2):135-142. Treat the mapping as an editorial correction, not a confirmation of the original citation.
Read the study →This 52-week open-label extension followed women who completed the RECONNECT core phase. Of 856 eligible women, 684 enrolled and only 272 finished; drug-related nausea affected 40.4%, flushing 20.6% and headache 12.0%. Desire scores in women who had been on bremelanotide throughout improved 1.25 to 1.30 points from baseline, with no new safety signals. The very high non-completion rate is the key limitation and the tolerability picture is worse than the 24-week data suggests.
Source cited this as Kingsberg, Shumel & Simon (2020), J Sex Med 17(6):1126-1137. No such paper exists. The PMC link given (PMC6819023) resolves to the real paper: Simon JA, Kingsberg SA, Portman D, et al. Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstet Gynecol. 2019;134(5):909-917. Corrected details used here.
Read the study →Thymosin Alpha-1 is a 28-amino-acid peptide made naturally by the thymus, the small gland behind the breastbone that trains the immune system's T cells. A synthetic copy is sold as the prescription drug Zadaxin (thymalfasin) and is marketed in roughly 35 countries, mainly for chronic hepatitis B and as a booster for vaccines, though it has never been approved by the FDA in the United States. It is by a wide margin the most heavily trialled peptide in this set, with tens of thousands of patients studied, but the largest and most rigorous trials have been notably less impressive than the early ones.
Where the evidence stands. The best-evidenced peptide here by far and an approved drug in about 35 countries, but not FDA approved in the US, and the two biggest modern trials in sepsis and hepatitis C both missed their primary endpoints.
TESTS was a double-blind, placebo-controlled phase 3 trial across 22 Chinese centres, randomising 1,106 adults with sepsis to Thymosin Alpha-1 or placebo by injection every 12 hours for seven days. Death from any cause within 28 days occurred in 23.4 percent of the drug group versus 24.1 percent on placebo, a hazard ratio of 0.99 (95 percent CI 0.77 to 1.27, P=0.93). No secondary or safety outcome differed either. Subgroup analyses hinted at benefit in patients over 60 and in those with diabetes, and possible harm under 60, but subgroup findings from a null trial are hypothesis-generating only, not proof.
NEGATIVE TRIAL. This is the definitive sepsis result and it supersedes the smaller, more encouraging ETASS trial by the same lead author.
Read the study →A prospective multicentre open-label randomised trial gave 690 patients with hepatitis B related compensated cirrhosis either Thymosin Alpha-1 plus the antiviral entecavir (n=351) or entecavir alone (n=339) for 52 weeks, following them a median of 38 months. The primary endpoint, a combination of liver decompensation, liver cancer or death, was no different between groups. Liver cancer occurred in 1.7 percent on combination therapy versus 2.1 percent on entecavir alone, a difference too small to be meaningful. Virological, serological and biochemical responses were also similar at week 104, and both regimens were well tolerated.
Null on the primary endpoint. Open-label design, which weakens it further, but it is the largest randomised hepatitis B cirrhosis dataset.
Read the study →ETASS randomised 361 patients with severe sepsis across six Chinese teaching hospitals to Thymosin Alpha-1 (n=181) or control (n=180). All-cause death within 28 days was 26.0 percent with the drug versus 35.0 percent in controls, a relative risk of 0.74 (95 percent CI 0.54 to 1.02). The result sat right on the edge of significance and moved depending on the statistical test used, P=0.062 unstratified but P=0.049 by log-rank. The trial was single-blind with no placebo, and the much larger double-blind TESTS trial later failed to reproduce the effect.
Widely cited as the flagship sepsis result, but it was not replicated by the 1,106-patient phase 3 trial in 2025.
Read the study →This multicentre randomised, placebo-controlled trial enrolled 552 people whose hepatitis C had already failed standard interferon plus ribavirin treatment, adding either Thymosin Alpha-1 (n=275) or placebo (n=277) to 48 weeks of retreatment. Sustained virological response, meaning the virus stayed undetectable, was 12.7 percent with the peptide versus 10.5 percent with placebo, not a significant difference (P=0.407). Among the subset who completed all 48 weeks the rate was higher with the peptide (41.0 percent versus 26.3 percent, P=0.048), but that is a post-hoc comparison in a self-selected group and cannot be treated as a real treatment effect. The authors concluded it plays no role in primary hepatitis C therapy.
NEGATIVE on the primary endpoint, despite hepatitis C being one of the drug's licensed indications in some countries.
Read the study →This large randomised study assigned 488 patients with metastatic melanoma to five arms combining the chemotherapy dacarbazine with interferon alfa and three different doses of Thymosin Alpha-1. The peptide arms met the prespecified tumour response bar, with 10 and 12 responses in two arms versus four in the control arm. Median overall survival was 9.4 months in peptide-treated patients versus 6.6 months in controls, a hazard ratio of 0.80, but this did not reach statistical significance (P=0.08), nor did progression-free survival (HR 0.80, P=0.06). The trial predates modern immune checkpoint drugs, which have since transformed melanoma treatment and make this regimen obsolete.
This trial is the basis of the drug's US FDA orphan drug designation for stage IIb to IV malignant melanoma, granted in 2006. Survival difference was positive in direction but not statistically significant.
Read the study →This systematic review pooled 11 randomised trials covering 1,927 sepsis patients, 967 given Thymosin Alpha-1 and 960 controls. Across all trials, 28-day death was reduced with an odds ratio of 0.73 (95 percent CI 0.59 to 0.90, P=0.003). But when the authors restricted the analysis to high-quality trials the effect disappeared (OR 0.82, 95 percent CI 0.65 to 1.03), and the same happened for multicentre trials only (OR 0.86, 95 percent CI 0.68 to 1.08). Trial sequential analysis concluded the total evidence base is still too small to settle the question.
A classic pattern: the apparent benefit is carried by smaller, lower-quality, single-centre studies.
Read the study →This systematic review pooled nine studies covering 5,352 hospitalised adults with COVID-19, of whom 1,152 received Thymosin Alpha-1. Overall there was no significant effect on death (relative risk 1.03, 95 percent CI 0.60 to 1.75, P=0.92), with very high heterogeneity between studies (I-squared 90 percent) meaning the individual results disagreed sharply. Subgroups did show apparent benefit in patients over 60 (RR 0.68) and in severe or critical cases (RR 0.66). The authors' own conclusion was that the data do not support using it in hospitalised COVID-19 patients, and almost all the included studies were retrospective rather than randomised.
A separate 2023 meta-analysis of eight studies reported a mortality benefit (RR 0.59), so the COVID literature genuinely contradicts itself. Both are built on retrospective data.
Read the study →This systematic review pooled seven randomised trials totalling 1,144 patients with hepatitis B related cirrhosis, comparing the antiviral entecavir plus Thymosin Alpha-1 against entecavir alone. Combination therapy produced a higher complete response rate overall (relative risk 1.18, 95 percent CI 1.07 to 1.30), and at 24 weeks clearly better viral clearance (RR 1.91) and loss of the HBeAg viral protein (RR 2.05). Crucially, by 48 and 52 weeks those advantages had disappeared, with no significant difference between groups. So the peptide appears to speed up the early response rather than change the final outcome.
Several included trials were Chinese-language and of modest quality, so the pooled estimate should be treated cautiously.
Read the study →A pilot clinical trial in haemodialysis patients, a group whose weakened immune systems respond poorly to vaccines, compared the adjuvanted H1N1 pandemic flu vaccine alone against the same vaccine plus Thymosin Alpha-1 at 3.2 mg or 6.4 mg. In the 94-patient intention-to-treat population, both peptide groups had better antibody titres and geometric mean ratios at day 21 than vaccine alone, and only the peptide groups fully met the European regulator's three licensing criteria for seroconversion and seroprotection. No adverse events were attributed to the peptide. It was explicitly a pilot, with no placebo arm and a small sample, and the authors called for larger studies.
Vaccine adjuvant use in immunosuppressed patients is one of the drug's licensed indications in several countries. The supporting trial evidence is nonetheless small.
Read the study →A retrospective analysis followed 468 patients who had surgery for a single hepatitis B related liver tumour, comparing those given Thymosin Alpha-1 afterwards with those who were not, over a median 60 months. Using propensity score matching to balance the groups on measurable characteristics, patients on the peptide had significantly better recurrence-free survival (P=0.006) and overall survival (P less than 0.001). In multivariable analysis the peptide was an independent predictor of both overall survival (hazard ratio 0.31) and recurrence-free survival (HR 0.38). This was not a randomised trial, so unmeasured differences between the groups could still explain the result.
Observational with propensity matching, not randomised. A large multicentre randomised trial in resected liver cancer (NCT02281266) was announced in 2015 but no results publication was located.
Read the study →Researchers retrospectively reviewed 76 severe COVID-19 patients across two Wuhan hospitals in early 2020 and compared those who happened to receive Thymosin Alpha-1 against those who did not. Mortality was 11.1 percent in the treated group versus 30.0 percent untreated (P=0.044), and treated patients showed recovery of depleted T cell counts and reduced markers of T cell exhaustion. This is the single most quoted COVID result for the peptide, but it is small, retrospective and not randomised, so who got the drug was decided by clinicians rather than by chance and the groups may simply have differed.
Included to show what the widely-circulated COVID claim actually rests on. Retrospective, n=76, and not confirmed by later pooled analysis.
Read the study →Larazotide is an 8-amino-acid oral peptide designed to hold shut the tight junctions, the sealing bands between the cells lining the gut, so that fragments of gluten cannot leak through into the tissue underneath and set off an immune attack. It was developed for coeliac disease in people who still get symptoms despite a strict gluten-free diet, and it is the only coeliac drug ever to reach a phase 3 trial. That phase 3 trial was stopped early in June 2022 because an interim look at the data showed it was not going to work.
Where the evidence stands. Reached phase 3, then failed: the trial was terminated early for futility in 2022 and the results have never been published in a peer-reviewed journal.
CeDLara was a phase 3 randomised, double-blind, placebo-controlled trial of larazotide for persistent symptoms in coeliac patients already on a gluten-free diet, with a target of 525 patients. On 21 June 2022 the sponsor 9 Meters Biopharma announced that a planned interim analysis, done after roughly half the target enrolment had completed the 12-week double-blind phase, showed that a prohibitively large number of extra patients would be needed to reach a meaningful result. The trial was terminated with 307 patients actually enrolled. This is a clear failure, not a pause, and development of larazotide for coeliac disease effectively ended with it.
FAILED PHASE 3. Verified from the ClinicalTrials.gov record (NCT03569007), which lists the trial as TERMINATED with 307 actual participants and the reason 'Trial terminated by Sponsor', corroborated by the sponsor's 21 June 2022 announcement. No peer-reviewed results paper exists, so the numbers behind the failure have never been published. Treat any positive larazotide claim as predating this.
Read the study →This multicentre, randomised, double-blind, placebo-controlled phase 2b trial gave 342 adults with coeliac disease, all on a gluten-free diet for at least a year, larazotide at 0.5, 1 or 2 mg three times daily for 12 weeks, with placebo run-in and run-out phases. The primary endpoint, average symptom score on the Celiac Disease Gastrointestinal Symptom Rating Scale, was met at the 0.5 mg dose (P=0.022), which also cut symptomatic days by 26 percent and increased improved-symptom days by 31 percent. Critically, the 1 mg and 2 mg doses were no different from placebo on any endpoint, meaning there was no dose-response, which is a strong warning that the single positive result may be chance. Safety was comparable with placebo.
This is the trial usually cited as proof larazotide works. The absence of any dose-response, with the two higher doses inert, was the red flag that the failed phase 3 later confirmed.
Read the study →In this exploratory double-blind randomised placebo-controlled trial, 184 coeliac patients on a gluten-free diet were given larazotide at 1, 4 or 8 mg three times daily, or placebo, plus a deliberate daily challenge of 2.7 grams of gluten for 6 weeks. The main measure, the lactulose-to-mannitol ratio used to gauge gut leakiness, showed no significant difference between larazotide and placebo, so the drug did not demonstrably do the thing it was designed to do. Secondary results were better: the 1 mg dose reduced gluten-induced symptoms (P=0.002), and antibody rises against tissue transglutaminase were far smaller on larazotide (roughly 4 to 8 fold versus 19 fold on placebo). Side effect rates matched placebo.
Primary endpoint NOT met. The positive findings here are secondary and exploratory.
Read the study →This dose-ranging, placebo-controlled trial randomised 86 diet-controlled coeliac patients to larazotide at 0.25, 1, 4 or 8 mg three times daily or placebo, with or without a 2.4 gram daily gluten challenge for 14 days. The primary efficacy outcome was again the urinary lactulose to mannitol ratio measuring gut permeability. The measurements proved highly variable in an outpatient setting, and the permeability increase caused by the gluten challenge was not even significantly greater than in the gluten-free control group, meaning the trial could not test its own hypothesis. The permeability endpoint was therefore uninformative rather than merely negative.
Primary endpoint NOT met, and the assay itself was too noisy to be trusted. This recurring measurement problem dogged the whole programme.
Read the study →This inpatient double-blind randomised placebo-controlled proof-of-concept study gave single 12 mg doses of AT-1001, the original name for larazotide, to coeliac patients undergoing an acute gluten challenge. Under controlled inpatient conditions the placebo group showed a 70 percent rise in intestinal permeability after gluten, while the AT-1001 group showed none. Interferon gamma rose in 4 of 7 placebo patients (57 percent) versus 4 of 14 on the drug (29 percent), and gut symptoms were more frequent on placebo (P=0.018). This was a tiny study of 21 patients using single doses, so it establishes a plausible mechanism and nothing more.
The founding study for the whole programme. Its clean inpatient result was never reproduced in the larger outpatient trials.
Read the study →Thirty-two male Sprague-Dawley rats were split into control, larazotide alone, acute pancreatitis, and pancreatitis plus larazotide groups, with the drug given orally for 7 days before pancreatitis was induced. Compared with untreated pancreatitis, larazotide significantly reduced intestinal damage scores, zonulin immunoreactivity and gut permeability, and cut bacterial translocation, meaning gut bacteria escaping into liver, mesentery or spleen, from 100 percent of animals to 50 percent (all P less than 0.01). This supports the tight-junction mechanism outside coeliac disease. It is a small rodent study with pretreatment before the injury, a setup that rarely matches how patients present.
Included to show the mechanism is real in animals even though the coeliac clinical programme failed. Preclinical only.
Read the study →LL-37 is the only cathelicidin made by humans, a 37-amino-acid fragment cut from a larger precursor protein called hCAP18. It is part of the innate immune system, the fast, non-specific first line of defence, and it does two jobs at once: it punches holes in bacterial membranes, and it signals to immune cells to coordinate inflammation and wound repair. The laboratory and animal evidence for both roles is large and well established. The human treatment evidence is much thinner, and the one properly powered trial of LL-37 as a drug did not work.
Where the evidence stands. Deep mechanistic and preclinical evidence, but the only adequately powered human trial, a 148-patient phase 2b in leg ulcers, failed on its primary analysis.
A randomised double-blind placebo-controlled trial in Jakarta applied LL-37 cream or placebo cream twice weekly for 4 weeks to diabetic foot ulcers with mild infection. The granulation index, a measure of healthy new tissue filling the wound, improved significantly more with LL-37 at every timepoint from day 7 to day 28 (P values 0.031 to 0.009). However the peptide did not reduce the inflammatory signals IL-1 alpha or TNF alpha, and did not significantly reduce bacterial colonisation, which undercuts the antimicrobial rationale for using it. The trial was small, registered as NCT04098562 with an estimated enrolment of 40, and single-centre.
Exact randomised sample size is not given in the abstract and the full text is paywalled. The n=40 figure is the registered estimated enrolment on ClinicalTrials.gov.
Read the study →HEAL LL-37 was a phase 2b double-blind, randomised, placebo-controlled multicentre trial in 148 patients with hard-to-heal venous leg ulcers, testing topical LL-37 at 0.5 or 1.6 mg/mL alongside standard compression therapy. Patients averaged 67.6 years old with ulcers lasting a median 20.3 months and a mean wound area of 11.6 square centimetres. Across the full study population there was no significant improvement in healing versus placebo on any measure. A post-hoc subgroup analysis found benefit in patients with wounds of at least 10 square centimetres, but post-hoc subgroups from a failed trial are a hypothesis, not a finding. The drug was safe and well tolerated at both doses.
NEGATIVE TRIAL. This is the single most important human result for LL-37 and it is a failure. It directly contradicts the encouraging first-in-man study below.
Read the study →This first-in-human trial enrolled 34 patients with hard-to-heal venous leg ulcers, running a 3-week open-label placebo lead-in followed by 4 weeks of double-blind twice-weekly topical LL-37 at 0.5, 1.6 or 3.2 mg/mL, or placebo. The healing rate constant was roughly six times higher than placebo at 0.5 mg/mL (P=0.003) and three times higher at 1.6 mg/mL (P=0.088), with mean ulcer area falling 68 percent and 50 percent respectively. Oddly, the highest dose of 3.2 mg/mL performed no better than placebo, an inverted dose response that is a warning sign rather than a reassurance. With 34 patients split across four arms, the group sizes were tiny.
Frequently quoted as proof LL-37 heals wounds. The larger phase 2b trial by the same group did not replicate it.
Read the study →Using a more sensitive screening medium, researchers identified an ultrashort 8-residue fragment of LL-37 and used it to design a shortened analogue called LL-37mini. The analogue was potent against methicillin-resistant Staphylococcus aureus, E. coli and Pseudomonas aeruginosa without being toxic to mammalian cells, blocked bacterial attachment and biofilm formation, broke up already-formed biofilms in the dish, and killed MRSA in mouse wound biofilms. Bacteria failed to develop resistance across repeated passages, consistent with it attacking the membrane directly. This is early preclinical work on a modified peptide, not on LL-37 itself, and has not been tested in humans.
Tests LL-37mini, an engineered shortened derivative, not native LL-37.
Read the study →Researchers found that two thirds of patients with moderate-to-severe plaque psoriasis carry T cells specifically targeting LL-37, treating the peptide as a self-antigen the immune system attacks. These LL-37-specific T cells produce inflammatory signals including interferon gamma and Th17 cytokines, infiltrate psoriatic skin lesions, and their presence in blood tracks with how active the disease is. This identifies LL-37 as a driver of autoimmune skin inflammation, not simply a protective molecule. It is a genuine safety consideration for anyone proposing to raise LL-37 levels, and it is laboratory immunology rather than a treatment study.
Included deliberately as a counterweight. LL-37 is elevated in psoriasis and rosacea, so more is not automatically better.
Read the study →This Science paper showed that when human macrophages, the immune cells that swallow bacteria, detect a microbe via Toll-like receptors, they turn up the vitamin D receptor and the enzyme that activates vitamin D. That cascade induces LL-37, which then kills Mycobacterium tuberculosis living inside the cell. The authors also found that blood serum from African-American donors, a group with higher tuberculosis susceptibility, had low vitamin D and was poor at supporting this LL-37 induction. This is the foundational mechanism paper linking vitamin D status to innate immunity, but it is laboratory work in cells, not evidence that giving LL-37 or vitamin D treats infection in people.
One of the most cited papers in the field. It explains why LL-37 matters biologically, and is routinely misquoted as clinical proof that supplementing LL-37 fights infection.
Read the study →KPV is the last three amino acids of alpha-melanocyte-stimulating hormone, kept for the anti-inflammatory part of that hormone's activity while dropping the pigment-darkening part. In laboratory work it dampens NF-kB signalling and the cytokines that drive gut, skin, lung and brain inflammation. Every study below is in animals or cells.
Where the evidence stands. Consistent anti-inflammatory signal across mouse colitis, peritonitis and brain-injury models and across human cell lines, but there is not one published human clinical trial of KPV in this reference list. The evidence base is entirely preclinical.
A double-network hydrogel designed to bind and release KPV was tested in an inflamed colon model, showing restoration of the gut mucosal barrier. It is a delivery-plus-efficacy study rather than a test of KPV alone. Limitation: animal model, and the printed citation in the source document was materially wrong (see note), which is itself a reason to treat the surrounding reference list carefully.
CORRECTION: printed as 'A KPV-binding double-network hydrogel restores gut barrier function and suppresses colitis in vivo', Acta Biomaterialia 140, 390-403. Actual: Zhao Y, Xue P, Lin G, et al. 'A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon.' Acta Biomater 2022;143:233-252. Title, volume and pages were all wrong as printed.
Read the study →KPV was loaded into hyaluronic-acid-coated polymer nanoparticles (about 272 nm) so it would survive the gut and reach colon epithelial cells and macrophages, then delivered orally inside a chitosan/alginate hydrogel to mice with ulcerative colitis. The targeted system accelerated mucosal healing and cut TNF-alpha substantially more than plain KPV nanoparticles, with no sign of toxicity to intestinal cells. Limitation: mouse model, and the benefit depended on the engineered delivery vehicle rather than free KPV.
Citation as printed matches: Mol Ther 25(7), 1628-1640, DOI 10.1016/j.ymthe.2016.11.020.
Read the study →Mice underwent controlled cortical impact to simulate traumatic brain injury, then received a single intraperitoneal dose of 1 mg/kg alpha-MSH(11-13) (KPV) 30 minutes later. Treated animals had a considerably smaller secondary lesion volume, reduced microglial activation by branch counting, and less neuronal apoptosis on cleaved caspase-3 and NeuN staining, although TNF-alpha and IL-1beta levels were not reduced. Limitation: mouse model with a single acute dose; the cytokine markers did not move, so the mechanism is not fully explained.
Citation as printed matches: PLoS One 8(8), e71056, DOI 10.1371/journal.pone.0071056.
Read the study →KdPT, a closely related tripeptide derived from the same alpha-MSH C-terminus, was tested in two independent mouse colitis models (dextran sodium sulfate and IL-10 knockout) plus colonic epithelial cell assays. Treated animals showed markedly reduced inflammation, and in cells KdPT increased proliferation, sped wound closure, improved transepithelial electrical resistance after interferon-gamma/TNF-alpha challenge, and preserved tight-junction proteins, with no effect on melanin production. Limitation: this tested KdPT, an analogue, not KPV itself, and the models are rodent.
Citation as printed matches: Am J Pathol 179(3), 1230-1242. Important caveat: the peptide studied is KdPT, not KPV, and should not be presented as KPV data.
Read the study →In a mouse model of crystal-induced peritonitis, systemic KPV significantly reduced white blood cell accumulation in the peritoneal cavity, and the effect persisted in mice with a non-functional MC1 receptor and was not blocked by an MC3/4 receptor antagonist. Unlike the full alpha-MSH peptide, KPV did not raise cAMP or inhibit macrophage cytokine release in vitro, suggesting it works by interfering with IL-1beta signalling rather than through melanocortin receptors. Limitation: rodent model, and it establishes mechanism rather than clinical benefit.
Citation as printed matches: JPET 306(2), 631-637, DOI 10.1124/jpet.103.051623.
Read the study →Researchers tested KPV permeation across dermatomed human skin using passive diffusion, microneedles, iontophoresis, and the two combined. Passive diffusion delivered KPV below the detection limit of 0.01 microgram/mL; microneedles raised it to 4.4 microgram/cm2/h, and iontophoresis plus microneedles increased the permeation rate 35-fold over microneedles alone. Limitation: ex vivo human skin in a diffusion cell, not living patients, and it measures delivery rather than any clinical effect.
Minor correction: pages are 1814-1820, not 1814-1823 as printed. J Pharm Sci 2017;106(7):1814-1820.
Read the study →In immortalised human bronchial epithelial cells (16HBE14o-) stimulated with TNF-alpha or respiratory syncytial virus, KPV produced a dose-dependent drop in NF-kB activity, matrix metalloproteinase-9 activity, and IL-8 and eotaxin secretion. Mechanistically, KPV entered the nucleus, stabilised IkB-alpha and blocked nuclear translocation of p65RelA by competing at its importin-alpha3 binding site. Limitation: entirely in vitro in an immortalised cell line, with no animal or human confirmation of airway benefit.
Citation as printed matches: Int J Physiol Pathophysiol Pharmacol 4(2), 59-73.
Read the study →Human keratinocytes (HaCaT and normal primary cells) were exposed to alpha-MSH, KPV, KP-D-V and ACTH peptides. None of the peptides raised cyclic AMP, but KPV produced rapid, acute rises in intracellular calcium across a very wide concentration range, indicating the anti-inflammatory tripeptides do not act through the classical MC1-receptor/cAMP route in skin. Limitation: cell-culture only, and this is a mechanistic result that complicates rather than supports simple receptor-based claims for topical KPV.
Minor correction: actual title spells out 'adrenocorticotropic hormone' rather than 'ACTH', and pages are 1010-1019. J Invest Dermatol 2004;122(4):1010-9. Otherwise as printed.
Read the study →BPC-157 is a lab-made chain of 15 amino acids copied from a fragment of a protein found in human stomach juice. It has been studied for tissue repair: tendon and muscle healing, gut lining integrity, blood vessel growth and nerve recovery. Almost everything known about it comes from rats and cell cultures; the human evidence is a single small retrospective case series, so its effects in people are genuinely unproven.
Where the evidence stands. Very large rodent and cell-culture literature, but no published randomised human trials.
A 2025 systematic review pooled every published study on BPC-157 in musculoskeletal injury up to June 2024. Of 36 studies, 35 were preclinical (animal or laboratory) and just one was clinical: a retrospective chart review in which 7 of 12 patients with chronic knee pain reported symptom relief. The authors note there is no controlled human safety or efficacy data, that BPC-157 is not FDA-approved and is banned in professional sport.
Citation printed without journal name; confirmed as HSS Journal 2025;21(4):485-495, PMID 40756949.
Read the study →A short review pulling together the central nervous system work on BPC-157 in rodents: traumatic brain injury, spinal cord compression, stroke-like ischaemia and drug-induced brain damage. The authors describe consistent protective effects across these models. As with most of this literature, the work comes from one research group and has not been reproduced in humans.
Exact match: Vukojevic J et al., Neural Regen Res 2022;17(3):482-487, PMID 34380875.
Read the study →A narrative review collecting the animal wound-healing work on BPC-157, covering surgical incisions, deep burns, diabetic ulcers and chemical burns in rodents, and describing effects on clot formation and resolution, blood vessel growth and blood flow after ischaemia. It is a summary of the authors' own laboratory output rather than independent replication, and contains no human wound data.
Narrative review, not primary research. First author is Seiwerth S (Sikiric P is senior author), so the printed 'Sikiric, P., et al.' is loose but the paper is correct: Front Pharmacol 2021;12:627533, PMID 34267654.
Read the study →Rats had their spinal cord compressed at the L2-L3 level, then received a single injection of BPC-157 ten minutes later. Treated rats showed steadily improving tail motor function, no self-mutilation of the paralysed limb, and resolved spasticity by day 15, with less nerve fibre loss and swelling under the microscope. This is an acute rodent injury model with immediate dosing, which is a long way from a person with an established spinal injury.
Printed as Perovic et al. (2021), Neuroscience Letters 742, 135518 - no such paper exists. The real study is Perovic D et al. (2019), J Orthop Surg Res 14:199, PMID 31266512.
Read the study →This review examined BPC-157 across tendon, ligament and skeletal muscle injury and noted that every study located had reported positive and rapid healing effects. The authors are explicit that the overwhelming majority of that work was done in small rodents, that the mechanism is not properly understood, and that human efficacy remains unconfirmed. A literature in which no study ever reports a negative result is itself a reason for caution.
Printed as Gwyer et al. (2021), 'Healing potential of BPC-157 in musculoskeletal disorders: A review', Int J Mol Sci 22(13), 7003 - wrong title, journal and year. The real paper is Gwyer D, Wragg NM, Wilson SL (2019), Cell Tissue Res 377:153-159, PMID 30915550.
Read the study →A review arguing that BPC-157, given into the gut, produces effects in the brain via the brain-gut axis, including nerve regeneration, protection after traumatic brain injury and recovery from spinal compression in animals. It also reports effects on serotonin and dopamine signalling in rodents. The paper references early safety work in inflammatory bowel disease and multiple sclerosis, but presents no controlled human efficacy results.
Exact match: Curr Neuropharmacol 2016;14(8):857-865, PMID 27138887.
Read the study →Researchers took tendon tissue and tendon fibroblasts from rats and exposed them to BPC-157 in the dish. Cells grew out of the tendon explants faster, survived better when deliberately stressed with hydrogen peroxide, and migrated more, apparently through the FAK-paxillin signalling pathway. Cell proliferation itself was not increased. This is laboratory work on isolated cells, not an injury study in a living animal or a person.
Exact match: Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH. PMID 21030672.
Read the study →Thymosin beta-4 is a small protein made naturally by nearly every cell in the body. Its main job is binding actin, the internal scaffolding cells use to change shape and move, which puts it at the centre of wound healing, blood vessel growth and tissue repair. There is a deep animal and cell-biology literature behind it, but the only well-designed human trials are in eye-surface disease - not in muscle, tendon or joint repair, which is what it is usually sold for.
Where the evidence stands. Deep animal and cell-biology evidence; the only good human trials are in eye-surface disease.
Researchers first compared blood proteins in 6 patients having their first heart attack against 6 matched healthy people, then validated the finding in 156 heart attack patients versus 232 healthy controls. Thymosin beta-4 was markedly higher in patients (median 1093 vs 421 ng/mL) and tracked closely with troponin, the standard heart damage marker. Crucially this shows the body releases more thymosin beta-4 after cardiac injury - it is a marker study, not evidence that injecting the peptide treats anything.
Exact match: Lu Z et al., JAHA 2025;14(4):e038177, PMID 39950438.
Read the study →A review of proteomic and tissue-staining studies mapping where thymosin beta-4 and its relative beta-10 appear across human organs, from fetal development through adult life, using saliva, gingival fluid and stained tissue sections. It establishes that these peptides are genuinely widespread and developmentally regulated in humans, and discusses links to cancer biology. It describes natural biology, not the effect of taking the peptide as a drug.
Exact match: Faa G et al., Cells 2024;13(13):1115, PMID 38994967.
Read the study →Rats had a McFarlane skin flap raised - a standard surgical model where the far end of the flap normally dies from poor blood supply - and were given thymosin beta-4 daily for seven days. More of the flap survived in treated animals, with lower levels of the cell-death marker caspase-3 and higher beta-catenin and c-Myc, indicating the Wnt/beta-catenin growth pathway was switched on. The study is small (15 rats) and short.
Exact match: Tao X, Pan X, Xue M, Zhao G, Rui Y. Arch Med Sci 2024;20(2):708-712, PMID 38757041.
Read the study →Mice had a heart attack induced surgically and were then treated with thymosin beta-4. Left ventricular function - how well the main pumping chamber works - was better in treated mice, and the benefit tracked with increased levels of a protein called chitinase 3-like-1. It is a mouse study in a small, non-open-access journal, and notably a separate large-animal study in pigs found no benefit from systemic thymosin beta-4 around cardiac ischaemia, so the cardiac picture is not consistent.
Exact match confirmed via Crossref: Stark C, Helenius M, Taimen P et al., Transl Med Commun 2016;1:8.
Read the study →Rats received a controlled impact brain injury, then thymosin beta-4 or saline starting six hours later - a delay chosen to mimic real-world treatment timing. Treated rats had better movement and spatial learning recovery, smaller areas of dead brain tissue and more new nerve cell growth, with the higher dose working better. It remains a rodent model of a single, standardised injury; nothing comparable has been run in people.
Printed title is shortened; full title is 'Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours after traumatic brain injury in rats.' J Neurosurg 2012;116(5):1081-1092, PMID 22324420.
Read the study →A review of thymosin beta-4's effects on the cornea, describing promotion of cell migration and wound closure, dampening of inflammation and suppression of cell death, mainly from the authors' own animal and cell studies. The eye is where thymosin beta-4 has since gone furthest clinically, with subsequent randomised trials in dry eye and neurotrophic keratopathy. This 2007 paper is a narrative review, not a trial.
Exact match: Sosne G, Qiu P, Kurpakus-Wheater M. Clin Ophthalmol 2007;1(3):201-207, PMID 19668473. Indexed as a review article.
Read the study →Full-thickness skin wounds in rats were treated with thymosin beta-4 either on the wound or by injection. New skin regrew 42% faster than saline controls at day 4 and up to 61% faster at day 7, wounds contracted at least 11% more, and there was more collagen and more new blood vessels. In a separate dish assay, skin cells migrated two to three times more with as little as 10 picograms of peptide. This is a healthy rat wound model, not an injured human.
Exact match: Malinda KM et al., J Invest Dermatol 1999;113(3):364-368, PMID 10469335.
Read the study →Scientists grew miniature brain tissues (organoids) from stem cells carrying a familial Alzheimer's mutation. These organoids produced fewer mature neurons, aged faster and made more amyloid, and the gene for thymosin beta-4 was switched down - a pattern also seen in neurons from actual Alzheimer's patients. Adding thymosin beta-4 back reversed the developmental deficits and reduced amyloid, and the effect repeated in Alzheimer's model mice. This is lab-grown tissue and mice, not treated patients.
Exact match: Zeng PM et al., Stem Cell Reports 2025;20(9):102601, PMID 40816274.
Read the study →ARA-290 is an 11-amino-acid fragment engineered from erythropoietin. It was deliberately designed to keep EPO's tissue-repair and anti-inflammatory signalling, through what its developers call the innate repair receptor, while losing EPO's blood-building effect and the clotting risks that come with it. Human testing has been narrow and specific: small phase 2 trials in people with nerve-fibre damage from sarcoidosis or type 2 diabetes, measuring corneal nerve fibre regrowth and symptom scores. Results have been encouraging on nerve-fibre measures and inconsistent on pain, and the peptide has never been approved for anything.
Where the evidence stands. Genuinely human-tested but early: three small phase 2 randomised trials totalling around 130 patients, showing measurable nerve-fibre regrowth and symptom improvement but no significant pain benefit in the largest one; no phase 3 data and no approval anywhere.
A phase 2b, 28-day randomised trial of cibinetide at 1, 4 or 8 mg/day versus placebo in 64 people with sarcoidosis-associated small nerve fibre loss and neuropathic pain, with corneal nerve fibre area as the primary endpoint. The 4 mg dose gave a placebo-corrected increase of 697 square micrometres (95% CI 159 to 1,236; P=0.012) and increased regenerating intraepidermal GAP-43-positive fibres (P=0.035), with nerve-area change correlating with 6-minute walk distance. Pain improved in every group including placebo, and the placebo-corrected pain reduction in the moderate-to-severe subgroup did not reach significance (P=0.157), so the structural nerve finding is much stronger than the symptom finding.
Source cited 'van Velzen, M., et al. (2014) ... IOVS 55(10):6212-6219'. Correct: Culver DA, Dahan A, Bajorunas D, et al. 'Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.' Invest Ophthalmol Vis Sci. 2017;58(6):BIO52-BIO60. Van Velzen is a co-author, not first author, and the year, volume and pages differ.
Read the study →A phase 2 randomised placebo-controlled trial in which people with type 2 diabetes and painful neuropathy self-injected 4 mg ARA 290 or placebo daily for 28 days and were followed a further 28 days. Of 49 enrolled, 48 were analysed and 42 (21 per group) had complete HbA1c series; the ARA 290 group showed improved HbA1c and lipid profiles over the 56-day window and significantly better PainDetect neuropathic symptom scores, with corneal nerve fibre density increasing in those who started most impaired. No safety issues were identified, but with roughly 21 patients per group across multiple endpoints this is hypothesis-generating rather than conclusive.
Cited correctly (Mol Med. 2014;20(1):658-666). PubMed indexes the print date as March 2015; the volume and pages given in the source are right.
Read the study →A double-blind, placebo-controlled exploratory trial in 22 patients with sarcoidosis and small fibre neuropathy, given intravenous ARA 290 2 mg three times weekly (n=12) or placebo (n=10) for four weeks. At week 4 the small fibre neuropathy screening list score improved significantly more on ARA 290 (change of -11.5 versus -2.9, P<0.05), along with the pain and physical functioning dimensions of the SF-36. Crucially, the Brief Pain Inventory and fatigue scores improved equally in both groups, so the pain benefit was not separable from placebo, and 22 patients is a pilot.
Source cited Pain 153(7):1546-1553 (2012). Correct: Heij L, Niesters M, Swartjes M, et al. 'Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study.' Mol Med. 2012;18(1):1430-1436.
Read the study →A dose-response study in rats with spared nerve injury, given ARA 290 or vehicle on days 1, 3, 6, 8 and 10 and followed for 20 weeks. ARA 290 significantly reduced mechanical and cold allodynia out to 20 weeks across doses from 3 to 60 micrograms/kg, and rats given 30 micrograms/kg showed no increase in spinal microglial reactivity at either 2 or 20 weeks, while vehicle-treated animals did. Astrocyte reactivity was unchanged. This is rodent data on an induced nerve injury and does not translate directly to human neuropathy.
Cited correctly (Mol Pain. 2014;10:13). Source wrote the pages as '10(1), 1-12'; the article number is 13.
Read the study →B7-33 is a stripped-down single-chain version of the human hormone relaxin, built to keep relaxin's anti-scarring effect while dropping the blood-pressure-lowering and tumour-promoting signalling that limited the full hormone. It works by biasing the relaxin receptor RXFP1 towards one signalling pathway (ERK) rather than another (cAMP). Everything known about it comes from mice, rats and cell culture: there has never been a human trial of B7-33, and no dose, safety profile or side-effect rate in people has ever been established.
Where the evidence stands. Preclinical only. Consistent anti-fibrotic and cardioprotective effects in mouse and rat models plus solid receptor pharmacology, but zero human data of any kind, so no human dose, safety profile or efficacy claim is supported.
An authoritative review of relaxin's anti-fibrotic biology across the cardiovascular system, kidney, lung, liver, skin and tendons. Its central point is selectivity: relaxin inhibits fibroblast proliferation, differentiation and matrix production driven by pro-fibrotic cytokines but not in unstimulated cells, while also increasing matrix breakdown via matrix metalloproteinases. It also flags that relaxin's anti-fibrotic effect is influenced by sex. This is background on the parent hormone, not evidence for B7-33 specifically, and it is a narrative review rather than pooled data.
Cited correctly (Br J Pharmacol. 2017;174(10):962-976).
Read the study →A comprehensive Physiological Reviews article covering the relaxin family peptides and their receptors, including RXFP1, the receptor B7-33 was designed to target selectively. It is the field's standard reference for receptor pharmacology, tissue distribution and downstream signalling. It provides the mechanistic grounding for biased agonism at RXFP1 but contains no data on B7-33 itself, which was created three years later.
Cited correctly (Physiol Rev. 2013;93(1):405-480).
Read the study →Male 129sv mice with isoprenaline-induced cardiomyopathy were treated from day 7 to day 14 post-injury with relaxin, B7-33 or the ACE inhibitor perindopril. B7-33 and relaxin equally reduced left ventricular fibrosis and normalised inflammation, cardiomyocyte hypertrophy, blood vessel density and aortic contractility, while perindopril lowered blood pressure and inflammation but did not reduce fibrosis or hypertrophy over the same window. The comparison is a 7-day treatment window in mice; it does not establish that B7-33 outperforms an ACE inhibitor in humans or over longer treatment.
Cited correctly (Biomed Pharmacother. 2023;160:114370).
Read the study →A rodent unilateral ureteral obstruction study plus NRK52E cell experiments testing how relaxin reduces kidney fibrosis. Relaxin downregulated Wnt/beta-catenin signalling and reduced epithelial-to-mesenchymal transition in tubular epithelial cells, protecting transporter expression and reducing renal interstitial fibrosis after obstruction, with the same mechanism confirmed in cell culture. This is relaxin, not B7-33, and it is an acute surgical obstruction model rather than a model of chronic human kidney disease.
Cited correctly (Ren Fail. 2022;44(1):513-524).
Read the study →Adult male CD1 mice underwent 30 minutes of coronary artery ligation followed by reperfusion, with cardiac function measured by echocardiography and infarct size by staining. B7-33 reduced infarct size from 45.32% to 21.99% (P=0.02) and preserved fractional shortening (29% versus 23%, P=0.02) at 24 hours, with the functional gap widening by 7 days (29% versus 20%). Effects were traced to reduced cardiomyocyte death and endoplasmic reticulum stress. This is an acute mouse ischaemia-reperfusion model with treatment given around the time of injury, which is a long way from the clinical situation.
Cited correctly (J Am Heart Assoc. 2020;9(8):e015748).
Read the study →This is the original design and synthesis paper for B7-33, a B-chain-only analogue of human gene-2 relaxin. It demonstrated that B7-33 binds RXFP1 and preferentially activates ERK phosphorylation over cAMP in cells naturally expressing the receptor, making it the first functionally selective RXFP1 agonist, and that it prevented or reversed fibrosis and organ dysfunction in three rodent models of heart and lung disease with potency similar to full relaxin. Importantly, unlike relaxin it did not promote prostate tumour growth in vivo. All findings are in cells and rodents.
Source cited 'Hossain, M. A., Man, B. C., Zhao, C., Wade, J. D., & Samuel, C. S. (2016). The relaxin analog B7-33 ameliorates end-stage organ fibrosis. Scientific Reports, 6, 35638.' That citation is wrong: Sci Rep. 2016;6:35638 is an unrelated urethroplasty stem-cell paper. The genuine Hossain 2016 B7-33 paper is: 'A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1.' Chem Sci. 2016;7(6):3805-3819.
Read the study →PNC-27 is an experimental laboratory peptide built from a fragment of the p53 protein joined to a membrane-penetrating sequence. In cell-culture work it attaches to HDM-2 protein sitting in the outer membrane of certain cancer cells and appears to punch pores in that membrane. All of the research below is laboratory or animal work; there is no human clinical trial, and PNC-27 is not an approved or established treatment for anything.
Where the evidence stands. Strictly early laboratory research. Every efficacy finding comes from cultured cells or freshly isolated tumour cells in a dish, from a single research group with patents on the compound. The only human data in this reference list is a published case report of a patient who suffered a massive gastrointestinal haemorrhage after taking it. PNC-27 has never been shown to treat cancer in people, and it is marketed online in ways the medical literature has explicitly flagged as a concern.
A published case report describes a 46-year-old woman with end-stage metastatic cervical cancer who presented with haematemesis after experimental PNC-27 therapy. Endoscopy found a 2 cm pigmented gastric ulcer, treated with epinephrine and endoclips, but bleeding continued, she required repeated transfusions, and she died after transition to comfort care. The authors note there is no published human efficacy or safety data for PNC-27 and that it is marketed online as a non-toxic cancer cure. Limitations: a single case in a gravely ill patient with many other exposures, so causation cannot be established, but it is the only human report that exists.
CORRECTION: printed pages 'S1880' are the abstract number, not the page. Actual: Am J Gastroenterol 2017;112(Suppl 1):S1035-S1036, conference abstract 1880. This is a conference abstract rather than a full peer-reviewed paper.
Read the study →PNC-27 was tested against three cervical cancer cell lines (HTB-35, SW756, HeLa) and one untransformed cervical epithelial line, showing low IC50 values against the cancer lines and no effect on the normal cells. Adding lithium acetoacetate, a ketone body, lowered the IC50 values further across all three cancer lines. Limitation: cell culture only, published in a low-visibility open-access journal, by the same group that developed the peptide.
Article confirmed on the publisher site: Med Res Arch 2025;13(5), article 6471. Printed title capitalisation differs slightly from the published version.
Read the study →Using immuno-scanning electron microscopy with 6 nm gold-labelled anti-PNC-27 antibody and 15 nm gold-labelled anti-HDM-2 antibody, the researchers saw both particle sizes in roughly 1:1 ratio arranged in layered ring-shaped structures at pores near treated cancer cell surfaces. No pores appeared in PNC-27-treated untransformed control fibroblasts. Limitation: structural imaging plus computational modelling in cell culture; it describes a mechanism, not a therapeutic effect.
Citation as printed matches: Biomedicines 2022;10(5):945, DOI 10.3390/biomedicines10050945. Authors declare they are inventors on PNC-27 patents.
Read the study →Three human acute myeloid leukaemia cell lines (U937, OCI-AML3, HL60) were shown by flow cytometry to carry high levels of HDM-2 on their cell-surface membranes. PNC-27 bound that membrane HDM-2 and triggered necrosis with LDH release within four hours, while normal haematopoietic cells were spared. Limitation: cell lines in culture only, no animal or human treatment data.
CORRECTION: printed title says '...and hemolysis of red blood cells'. Actual title: 'Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells.' Anticancer Res 2020;40(9):4857-4867. Pages printed as 4857-4869 are also slightly wrong.
Read the study →Primary cultures were grown from tumour cells taken directly from patients newly diagnosed with ovarian cystadenocarcinoma (one mucinous, one high-grade papillary serous). PNC-27 inhibited growth dose-dependently and was cytotoxic on MTT and LDH assays, including against long-established chemotherapy-resistant ovarian lines, while the control peptide PNC-29 had no effect. Limitation: only two patients' tumours, tested outside the body in culture; this is not a treatment trial and no patient received the peptide.
CORRECTION: printed title says 'human primary epithelial ovarian cancer'. Actual title: 'Ex vivo Efficacy of Anti-Cancer Drug PNC-27 in the Treatment of Patient-Derived Epithelial Ovarian Cancer.' Ann Clin Lab Sci 2015;45(6):650-658. Journal, year and pages as printed are correct.
Read the study →K562 leukaemia cells, which have both copies of p53 deleted, were shown to strongly express HDM-2 in their membranes. PNC-27 co-localised with it and produced close to 100% cell killing with LDH release, while the control peptide PNC-29 and murine leukocyte controls were unaffected, indicating the mechanism does not require a working p53 pathway. Limitation: a single cell line in culture, no in vivo component.
CORRECTION: printed title is heavily abbreviated. Actual title: 'The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue human leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells.' Ann Clin Lab Sci 2014;44(3):241-248.
Read the study →The foundational mechanistic paper. Researchers found substantial HDM-2 protein in the membranes of a range of cancer cell lines but not in several untransformed cell lines, showed PNC-27 co-localising with membrane-bound HDM-2, and then made normal MCF-10-2A cells vulnerable to the peptide by transfecting them with membrane-targeted HDM-2. Limitation: entirely cell culture, with no animal survival or human data, and every result comes from the group holding the patents.
CORRECTION: printed as PNAS 107(44), 19120-19125. Actual: PNAS 2010 Feb 2;107(5):1918-1923, DOI 10.1073/pnas.0909364107. Title and authors match exactly; volume, issue and page numbers as printed were wrong.
Read the study →Nothing matches that. Try a shorter word, or tap Everything above.
Peptides are usually sold in stacks, and the stack is usually justified by saying each one works on a different stage of healing. That reasoning is sound. What does not currently exist is a published study testing any of these combinations against the peptides used on their own.
So every study on this page tested one compound at a time. When a source document attaches a reference list to a combination protocol, it is in practice listing the single agent research for each ingredient. That is worth knowing rather than glossing over, and it cuts both ways: no evidence a stack beats its parts is not evidence it does not.
The starting point was a peptide reference book of roughly 320 citations. We did not simply reproduce it. Every study on this page was looked up individually and checked that the paper exists and that the title, authors, journal and year match what was claimed.
172 references did not survive that check and are not on this page. Some pointed at a real paper but the wrong one. Some had a link belonging to a different study entirely. Some could not be found at all. A few were product marketing pages or self published books dressed up in a numbered reference list.
We are telling you this because it is the whole point. Anyone can paste a long bibliography under a peptide and call it evidence. The number that matters is how much of it holds up when you actually open it.
Compiled August 2026. Study selection favours human trials where they exist; where a peptide has none, that is stated on its card rather than hidden. Information only, not medical advice. Anything you take should be decided with us, on a protocol, not off a web page.