A registered Russian stroke drug with thirty years of Russian-language trials that the FDA could not read, an animal record that is genuinely interesting, and a gray market that sells it for everything from ADHD to gastric protection.

Summary

  • Semax is a synthetic heptapeptide, Met-Glu-His-Phe-Pro-Gly-Pro: residues 4 to 7 of ACTH with a Pro-Gly-Pro tail added for stability. It is designed to keep ACTH's effects on the brain without its hormonal effects on the adrenal gland or pigmentation.1

  • It is a registered drug in Russia as 0.1 percent and 1 percent nasal drops, developed at the Institute of Molecular Genetics of the Russian Academy of Sciences. It is approved nowhere else.1

  • In rats, a single intranasal dose raised hippocampal BDNF protein 1.4-fold and its receptor's activation 1.6-fold, and improved learning. That is the mechanism the marketing rests on, and it is real in rats.2

  • The human stroke trials are published in Russian. The FDA excluded them from its 2026 evaluation because full references were not available in English, and found the English-language human literature insufficient for any of the three uses it reviewed.1

  • The one English-accessible open-label study in migraine and trigeminal neuralgia found semax resolved pain in 4 of 12 migraine patients and in a minority of those with trigeminal neuralgia.1

  • The FDA's adverse event database holds a 2025 report of eye pain and burning after use of semax nasal drops bought online, resulting in hospitalisation and symptoms persisting for at least a year.1

  • On 24 July 2026 the FDA's advisory committee voted 8 to 5, with one abstention, to recommend it for compounding for cerebral ischaemia, migraine and trigeminal neuralgia, against the FDA's recommendation. The FDA has not acted.3

  • A targeted PubMed search returns 206 records, most from Russian institutions and many available only as abstracts. There are no registered trials.

The Most Common Error About This Compound

Treating "approved in Russia" as if it settled the evidence question. It settles a regulatory one: a Russian authority registered a nasal drop for specific neurological uses on the basis of Russian trials. Those trials exist, and ONPEPS does not dismiss them; but they are mostly unblinded, published in Russian, and inaccessible to independent review, which is why the FDA set them aside rather than weighed them.1 A registration is a fact about Russia. It is not a substitute for a trial a reader can examine.

Identity

What Is Semax?

ACTH, the pituitary hormone that drives cortisol release, has a short internal fragment, residues 4 to 10, that acts on the brain independently of the adrenal gland and was studied for cognition in the 1970s. Semax takes residues 4 to 7 of that fragment and attaches Pro-Gly-Pro, a tripeptide that resists enzymatic breakdown, producing a molecule "suggested to be devoid of hormonal corticotropic and melanotropic properties while potentially retaining the neurobehavioral properties" of the parent.1 It was developed in Moscow and registered in Russia in the 1990s.

How Does It Reach the Brain?

Intranasally, and that is not incidental. In rats, the fraction of a semax dose reaching the brain and the brain-to-blood ratio were considerably higher after intranasal than after intravenous administration. In vitro it was rapidly hydrolysed in rat blood and brain to shorter peptides, the main metabolite being the Pro-Gly-Pro tail itself, which has activity of its own.14

Every human study of semax used the nasal route. The FDA found no pharmacokinetic or toxicity study of the subcutaneous route, which the nominations also proposed and which some vendors sell.1

Evidence Base

What Do the Animal Studies Show?

A consistent and well-documented effect on neurotrophic signalling. A single intranasal dose in rats increased hippocampal BDNF protein 1.4-fold, tyrosine phosphorylation of its receptor TrkB 1.6-fold, and the corresponding mRNAs three- and two-fold, alongside better performance in a conditioned avoidance task.2 Later work mapped NGF and BDNF expression across hippocampus, cortex and retina over time,5 and a 2020 transcriptome study in a rat model of ischaemia-reperfusion found semax modulated expression of hundreds of genes, including neurotransmitter and immune pathways.6

This is a better preclinical record than most compounds in the library have. It comes almost entirely from Russian groups, and it has not been reproduced outside Russia.

What Human Evidence Exists?

Three categories, and the FDA's handling of each is instructive.

Russian-language stroke trials. The FDA listed seven, from 1992 to 2018, and excluded them all: "because the full references were not available in English, these references were not considered as part of this evaluation."1 The most recent, in 110 patients after ischaemic stroke, reported that two ten-day courses of 6 mg daily raised plasma BDNF and improved motor performance and Barthel index scores; its English abstract does not describe randomisation or blinding.7

Healthy-volunteer studies in English. Kaplan's 1996 study of attention in 19 men, and two 2018 to 2020 functional MRI studies in 14 volunteers, one of which found a larger default mode network subcomponent after a single 1 percent nasal dose than after placebo.8 The FDA noted the two imaging studies appear to use the same subjects.1

One pain study. Koroleva's 1996 open-label study gave a single nasal dose to 37 adults with trigeminal neuralgia, dental plexalgia or migraine. Of 12 migraine patients, 4 reported cessation of pain within two hours and 8 reported it "less severe"; in typical trigeminal neuralgia there was no change in pain characteristics. The FDA's conclusion: semax "was not effective in resolving headache pain for the majority of subjects with migraine, and was not effective in resolving pain for the majority of subjects with trigeminal neuralgia."1

What Is It Sold For?

The FDA's list from the US market: "anxiety, depression, attention/memory improvement, ischemic events/stroke, nerve regeneration, diabetic neuropathy, ADHD, opioid withdrawal, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, dys-circulatory encephalopathy, optic nerve atrophy, pain, and gastric protection," as injectable and nasal products, alone and combined with selank.1 For most of those there is not even a Russian-language trial.

Safety

What Is Known?

The Russian registration implies a safety review ONPEPS cannot examine. In the English-accessible studies, most did not discuss adverse events; the pain study reported none after a single dose.1 There are no human pharmacokinetic data by any route.

Two specific items came out of the FDA's review. One reference described possible anti-thrombotic properties, which "raises concern about the risk of bleeding, particularly in certain populations at risk for bleeding or if combined with other medications that increase bleeding risk."1 And the adverse event database contained one report, from May 2025: eye pain and burning after using semax 0.1 percent nasal drops purchased online, "resulting in hospitalization and persistence of symptoms for at least a year."1 One report is not a rate. It is the only human safety signal on file, and it concerns the product as actually bought.

What Is Unknown

Everything for the subcutaneous route, for chronic use, and for combination with selank, which the market sells as a pair. Whether the effect on BDNF signalling, sustained, has consequences nobody has looked for. And whether the Russian trial record would survive the scrutiny it has never had.

Regulatory Status

Where Is It Approved?

Russia, as nasal drops.1 Nowhere else, and not in the European, Japanese or international pharmacopoeias. It is not named on the WADA Prohibited List; because it holds a governmental approval, the S0 catch-all does not obviously apply, and ONPEPS cannot state a definitive status.

What Happened in July 2026?

In September 2023 the FDA placed semax in Category 2 of its interim compounding policy, and as of April 2026 it appears among substances nominated but withdrawn.9

On 24 July 2026 the Pharmacy Compounding Advisory Committee considered semax free base and acetate for the 503A bulks list for cerebral ischaemia, migraine and trigeminal neuralgia, proposed as nasal spray or subcutaneous injection at 7.5 mg/mL or 1 mg/mL. The FDA proposed against inclusion: neither form was well characterised, no information existed on how a nasal spray device would be selected or qualified, safety was insufficiently characterised with the bleeding and immunogenicity concerns added, and effectiveness was unsupported for all three uses.1 The committee voted 8 to 5, with one abstention, to recommend inclusion.3

The recommendation is advisory. As of this page's verification date the FDA has not added semax to the bulks list, and no pharmacy in the United States has a lawful basis on which to compound it. The FDA's review records that a compounding pharmacy and its owner were sentenced for unlawful distribution of compounded drugs including semax.1

Related ONPEPS Coverage

What Would Change This Page

English-language publication of the Russian stroke trials with their methods, which would let them be weighed rather than set aside. A blinded, placebo-controlled study by any route, anywhere, which would be the first a reader could examine. The FDA's decision on the July 2026 recommendation.

References

  1. US Food and Drug Administration. Semax-related bulk drug substances (semax (free base) and semax acetate): FDA presentation to the Pharmacy Compounding Advisory Committee, 24 July 2026. Docket FDA-2025-N-6895. Primary source for the pharmacology, the excluded Russian trials, the pain study, the FAERS report, the bleeding concern and the FDA's recommendation. fda.gov

  2. Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54-60. Paywalled. pubmed.ncbi.nlm.nih.gov/16996037

  3. ONPEPS. FDA peptide news July 2026: the only source you need. Records the 8 to 5 vote with one abstention on semax. onpeps.com

  4. Stavchansky VV, Yuzhakov VV, Botsina AY, Skvortsova VI, Bondurko LN, Tsyganova MG, et al. The effect of Semax and its C-end peptide PGP on the morphology and proliferative activity of rat brain cells during experimental ischemia: a pilot study. J Mol Neurosci. 2011;45(2):177-185. Paywalled. pubmed.ncbi.nlm.nih.gov/20617398

  5. Shadrina M, Kolomin T, Agapova T, Agniullin Y, Shram S, Slominsky P, et al. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. J Mol Neurosci. 2010;41(1):30-35. Paywalled. pubmed.ncbi.nlm.nih.gov/19662538

  6. Filippenkov IB, Stavchansky VV, Denisova AE, Yuzhakov VV, Sevan'kaeva LE, Sudarkina OY, et al. Novel insights into the protective properties of ACTH(4-7)PGP (Semax) peptide at the transcriptome level following cerebral ischaemia-reperfusion in rats. Genes (Basel). 2020;11(6):681. Open access. pubmed.ncbi.nlm.nih.gov/32580520

  7. Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN. The efficacy of semax in the treatment of patients at different stages of ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3 Vyp 2):61-68. In Russian; English abstract. pubmed.ncbi.nlm.nih.gov/29798983

  8. Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, et al. Effects of Semax on the default mode network of the brain. Bull Exp Biol Med. 2018;165(5):653-656. Paywalled. pubmed.ncbi.nlm.nih.gov/30225715

  9. US Food and Drug Administration. Category 2 of the Bulk Substances Nominated Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act. Entry for semax (heptapeptide). Content current as of 22 April 2026. fda.gov

Not Medical Advice

Semax is a registered medicine in Russia and an unapproved substance everywhere else. Nothing here substitutes for its Russian label or for a prescriber. Given the bleeding concern the FDA raised, anyone on anticoagulants or antiplatelet drugs should raise it with a clinician before use. Consult a qualified healthcare provider before acting on anything here.

Evidence counts on the library index retrieved 23 July 2026. Literature and regulatory sources verified 16 September 2026. The FDA had not acted on the July 2026 advisory recommendation as of that date. Re-verify against docket FDA-2025-N-6895 before relying on any regulatory statement here.