Semax

01 · What it is

Semax’s evidence base divides along a geopolitical line that nobody has ever crossed. Western laboratories tested the parent peptide fragment in humans four times between 1976 and 1990, published the results, and moved on. A Russian institute modified the fragment, registered the modified version as a stroke drug, and has produced most of the world’s Semax research ever since. The two literatures do not cite each other’s conclusions, and no study has compared the two molecules head to head.

The first correction this guide has to make is structural, because the error is in the titles of the papers themselves. Semax is routinely described — including by its own developers ^7,18 — as an ACTH(4-10) analogue. It is not. Semax is Met-Glu-His-Phe-Pro-Gly-Pro: the first four residues of ACTH(4-10) followed by the tripeptide Pro-Gly-Pro. PubMed’s own indexing term for the compound is “ACTH(4-7)PGP”, and the more careful papers in the Russian literature use exactly that name ^13,22.

The difference is not pedantic. ACTH(4-10) is Met-Glu-His-Phe-Arg-Trp-Gly. Semax replaces Arg-Trp-Gly — including the tryptophan that is central to melanocortin receptor binding — with Pro-Gly-Pro, a sequence chosen to resist proteolysis. Semax is roughly half of the parent fragment with a protective tail on it, and the half that was removed is the half that binds the receptor family the parent belongs to.

The Western human evidence is for the parent, and it is old and unenthusiastic. ACTH(4-10) was tested for short-term memory ¹, for cognitive effects in the elderly ², for event-related potentials reflecting attention ³, and for the time course of effects on human attention ⁴ — four studies indexed as clinical trials, published between 1976 and 1990, after which the Western literature on this fragment as a cognitive agent effectively stops.

The Russian human evidence is for Semax and it is real, but it is one group and one language. Thirty patients in the acute period of hemispheric ischaemic stroke, with the most effective daily doses reported in that study as 12 mg for moderate strokes and 18 mg for severe ⁵. One hundred and eighty-seven patients with cerebrovascular insufficiency, assessed for tolerability and clinical efficacy ⁶. A later study of stroke patients examining plasma BDNF, motor performance and Barthel index across rehabilitation timing, with each group subdivided into semax-treated and untreated arms ¹⁵. All three are in Russian, in the same journal, with overlapping authorship.

The best-designed human studies are imaging studies in healthy volunteers, and they are placebo- controlled. Resting-state fMRI was performed three times — before, and 5 and 20 minutes after — intranasal 1% Semax in 14 subjects against placebo in 10, in a group of 24 healthy volunteers with a mean age around 44 ¹⁶. A larger connectomic study assessed whole-brain resting-state functional connectivity in 52 healthy participants for both Selank and Semax ¹⁷.

And one mechanistic finding complicates the whole account. Semax and Pro-Gly-Pro — the tripeptide tail alone — both activate transcription of neurotrophins and their receptor genes after cerebral ischaemia ⁹. If the tail does it, the ACTH-derived portion may not be where the activity lives.

02 · Evidence at a glance

Evidence grade

Early Clinical — multiple indexed human studies, none randomised and blinded in a treatment indication

Structure

Met-Glu-His-Phe-Pro-Gly-Pro — ACTH(4-7) plus Pro-Gly-Pro, not ACTH(4-10)

What was removed

Arg-Trp-Gly, including the tryptophan central to melanocortin receptor binding

Why PGP was added

Resistance to proteolysis

Origin

Institute of Molecular Genetics, Moscow

Indexed records (all names)

~520

Human studies of Semax

Stroke, 30 patients ⁵; cerebrovascular insufficiency, 187 patients ⁶; stroke rehabilitation ¹⁵ — all Russian-language

Human studies of the parent ACTH(4-10)

Four, Western, 1976–1990 ^1,2,3,4

Best-controlled human data

Placebo-controlled resting-state fMRI in healthy volunteers ¹⁶; connectomics in 52 participants ¹⁷

Randomised blinded efficacy trial

None identified

Complicating mechanistic finding

Pro-Gly-Pro alone activates the same neurotrophin transcription ⁹

Independent replication

One — a Chinese group in spinal cord injury ²⁴

Approval status

Not approved in the US or EU; registered in Russia, status not verified for this guide

03 · Mechanism of action

No identified receptor, and a reason to expect none

Semax has no established receptor. That is worth stating alongside the structural fact above, because the two are connected: melanocortin peptides act at MC1R–MC5R, and the residues Semax lacks — particularly tryptophan — are the ones that make ACTH fragments melanocortin ligands. A molecule built by deleting the receptor-binding portion of a receptor ligand should not be expected to act at that receptor, and no paper in this literature demonstrates that it does.

What the field has instead is a set of downstream observations and one unusual framing: the “synacton” concept, which proposes that the clinically significant effects of the drug arise from the combined activity of the peptide and its degradation products rather than from a single species ¹². Related work has proposed a role for transthyretin in the peptide’s neuroprotection ¹¹.

A compound whose proposed mechanism is the collective action of itself and its fragments is a compound whose active species has not been identified.

Neurotrophins — and the tripeptide problem

The most-cited mechanistic account is that Semax raises brain-derived neurotrophic factor. Rapid induction of Bdnf, Ngf and TrkB expression has been reported in intact rat hippocampus after Semax, and after cerebral ischaemia both Semax and Pro-Gly-Pro activated transcription of neurotrophins and their receptor genes ⁹.

That second finding is the most important qualification in this guide’s mechanism section. Pro-Gly-Pro is a naturally occurring tripeptide, present in collagen breakdown products, and it is the tail added to make Semax protease-resistant. If PGP alone reproduces the neurotrophin effect, then attributing that effect to an ACTH-derived peptide is unsupported, and the compound’s identity as a melanocortin derivative becomes largely nominal.

Transcriptomics

The Moscow group’s principal output over the last decade is genome-wide expression analysis. Semax affected expression of immune and vascular system genes in rat brain focal ischaemia ¹⁰; it regulated immune response gene expression during ischaemic brain injury ¹³; ACTH-like peptides compensated the rat brain expression profile disrupted by ischaemia a day after experimental stroke ²¹; transcriptomic activity in rat brain cells was compared for ACTH(4-7)PGP and ACTH(6-9)PGP ²⁰; and genes associated with these peptides’ action were mapped across brain regions with differing degrees of ischaemic damage ²².

This is a substantial and technically competent body of work. It describes what changes downstream and does not identify what the peptide binds.

Monoamines and cholinergic neurons

Semax activated dopaminergic and serotoninergic brain systems in rodents ⁷, and affected rat basal forebrain cholinergic neurons ⁸. Systemic N-terminal ACTH fragments reduced inflammation- and stress-induced anhedonia in rats ¹⁴.

An independent mechanistic result

A 2025 study from a Chinese group reported that Semax targets the mu opioid receptor gene Oprm1, promoting deubiquitination and functional recovery after spinal cord injury in female mice, using RNA sequencing, network pharmacology and molecular docking to identify the target ²⁴.

The only substantial mechanistic work in this file from outside the originating programme, and it proposes a target — an opioid receptor gene — that the Russian literature does not discuss.

04 · Key research findings

Human stroke, in Russian. Semax was assessed in 30 patients in the acute period of hemispheric ischaemic stroke, in a clinical and electrophysiological study; the protocol used in that report found daily doses of 12 mg most effective for moderate strokes and 18 mg for severe ⁵. A separate study examined 187 patients across stages of cerebrovascular insufficiency for tolerability and clinical efficacy ⁶. A 2018 study evaluated Semax and rehabilitation timing against plasma BDNF, motor performance and Barthel index after ischaemic stroke, with each group subdivided into treated and untreated arms ¹⁵. A 2024 Russian review surveys the compound’s place in stroke therapy and rehabilitation ¹⁹.

Three human studies over twenty-one years, from overlapping author groups, in one journal, in Russian. None is described in its abstract as randomised or blinded. This guide has read none of them in full and relies on the indexed abstracts and PubMed’s clinical-trial tagging.

Human imaging, placebo-controlled. Resting-state fMRI in 24 healthy volunteers — 11 men, 13 women, mean age approximately 44 — scanned before and at 5 and 20 minutes after intranasal 1% Semax in 14 subjects or placebo in 10, reporting changes in default mode network measures ¹⁶. A functional connectomic study assessed whole-brain resting-state connectivity across predefined regions of interest in 52 healthy participants, for the anxiolytic Selank and the nootropic Semax ¹⁷.

These are the methodologically strongest human data in the file: placebo-controlled, objective imaging endpoints, healthy volunteers. They demonstrate that intranasal Semax changes measurable brain connectivity within minutes. They do not demonstrate that it does anything a person would notice.

The parent fragment in humans, and why it matters. ACTH(4-10) was tested for short-term memory ¹ and for cognitive effects in the elderly ² in 1976, and for attention using event-related potentials ³ and time-course methods ⁴ in 1987 and 1990.

Four human studies of the parent, from Western groups, followed by silence. That the fragment was investigated as a cognitive enhancer and abandoned is context the Semax literature does not engage with, and it is the single most useful piece of information a reader of this guide can carry.

Animal work. Monoamine system activation ⁷, effects on basal forebrain cholinergic neurons ⁸, neurotrophin transcription after ischaemia ⁹, immune and vascular gene expression in focal ischaemia ^10,13, anhedonia in rats ¹⁴, attenuation of behavioural and neurochemical alterations after early-life fluvoxamine exposure ¹⁸, transcriptomic profiles across ACTH-like peptides ^20,21,22, and correction of pathological impairments in an Alzheimer’s disease animal model ²³.

Consistent direction, large volume, and overwhelmingly one institute.

Independent animal work. Semax improved functional recovery after spinal cord injury in female mice, with a proposed Oprm1 target ²⁴.

Contemporary framing. Reviews list Semax among neuroactive peptides proposed to enhance BDNF signalling ²⁵, and among peptides discussed in gerontology ²⁵.

05 · Evidence overview

06 · Safety profile

Animal data. No formal toxicology programme is identified. The animal studies report efficacy and gene-expression endpoints ^{7–10,13,14,18,20,21–24}.

Human data. Semax has been given to at least 217 patients across the two larger Russian studies ^5,6 and to 14 healthy volunteers under placebo control ¹⁶, with a further 52 participants in the connectomic work ¹⁷. The cerebrovascular insufficiency study is described as assessing tolerability ⁶. No serious adverse events attributable to the compound appear in the abstracts reviewed here, and this guide has not read those papers in full.

What is genuinely unknown. What the compound binds — no receptor has been identified, and the proposed “synacton” account explicitly attributes activity to a mixture of the peptide and its fragments ¹². Whether the active species is Semax or Pro-Gly-Pro, given that the tripeptide alone reproduces the neurotrophin effect ⁹. Human pharmacokinetics by the intranasal route, absent entirely, despite intranasal being the studied and marketed route. Whether the acute connectivity changes seen at 5 and 20 minutes ¹⁶ persist, and whether they correspond to anything. Long-term exposure of any duration in a healthy person — every human treatment study was in patients with cerebrovascular disease. Repeat-dose toxicology, genotoxicity, reproductive toxicology and carcinogenicity: none identified. Endocrine effects, which deserve specific mention because the parent molecule is a fragment of a pituitary hormone and no study in this file measured cortisol or ACTH axis function after administration. And the identity and purity of any material sold outside the Russian pharmaceutical supply chain, on which nothing is published.

07 · US regulatory status

Current as of 6 September 2026. Semax is not approved as a drug in the United States or the European Union and is not a controlled substance in the United States.

The compound is described throughout the Russian literature as a registered drug used in the therapy of ischaemic stroke ^9,11, and a 2024 Russian review addresses its place in stroke therapy and rehabilitation ¹⁹. This guide does not state the terms of that registration, because doing so accurately would require Russian regulatory records that have not been consulted. That question is logged, and it is the same qualification applied to Thymalin and Vilon.

Under the World Anti-Doping Code, substances not approved for human therapeutic use by any governmental regulatory health authority fall within class S0 — a provision whose application to a substance approved in one country and not others is not something this guide will attempt to resolve. Competitors should consult the current Prohibited List directly rather than rely on secondary summaries, including this one.

08 · Limitations of the evidence

1. Semax is not ACTH(4-10), and much of its own literature says otherwise. It is ACTH(4-7) plus Pro-Gly-Pro ^13,22. Papers describing it as an ACTH(4-10) analogue ^7,18 are describing a molecule with three different residues at the C-terminus, including the loss of the tryptophan that makes ACTH fragments melanocortin ligands. Any inference from ACTH(4-10) pharmacology to Semax runs through that gap.

1. The human treatment evidence is Russian-language and this guide has not read it. Three studies ^5,6,15, one journal, overlapping authors, relied on here through indexed abstracts and PubMed’s clinical-trial tagging. The Early Clinical grade rests on that.

1. No randomised, blinded efficacy trial was identified for Semax in any indication. The only placebo control in the human file is in an imaging study of healthy volunteers ¹⁶.

1. The imaging studies show an effect on connectivity, not a benefit. Changes in default mode network measures 5 and 20 minutes after intranasal dosing ¹⁶ are a pharmacodynamic demonstration. No study links them to a clinical outcome.

1. Pro-Gly-Pro may be doing the work. Semax and PGP both activated neurotrophin and receptor gene transcription after cerebral ischaemia ⁹. No study has separated their contributions in a behavioural or clinical endpoint.

1. No receptor has been identified in thirty years, and the leading account from the originating group attributes activity to a mixture of the parent and its metabolites ¹².

1. Research concentration is extreme. The great majority of the file carries Myasoedov, Andreeva, Limborska or Dergunova as an author ^{7,8,9,10,11,12,13,14,16,17,18,20,21,22}. One substantial independent study exists, in a different indication, from a different country ²⁴.

1. The Western abandonment of the parent fragment is unexplained in this literature. Four human trials between 1976 and 1990 ^1,2,3,4 and then nothing. Whether that reflects negative results, a shift in research fashion, or commercial factors is not established by anything cited here, and this guide does not assert an explanation — only that the discontinuity exists and is never addressed by the Semax literature.

1. Endocrine safety is unexamined for a fragment of a pituitary hormone. No study in this file reports HPA axis measures after administration.

1. Nothing is known about non-pharmaceutical material. No published analysis has examined the identity or purity of any product sold as Semax outside the Russian supply chain.

09 · References

1. Dornbush RL, Nikolovski O. ACTH 4-10 and short-term memory. Pharmacol Biochem Behav. 1976;5(Suppl 1):69–72.

   PMID 189333 ↗

2. Ferris SH, Sathananthan G, Gershon S, Clark C, Moshinsky J. Cognitive effects of ACTH 4-10 in the elderly. Pharmacol Biochem Behav. 1976;5(Suppl 1):73–78.

   PMID 189334 ↗

3. Born J, Fehm-Wolfsdorf G, Voigt KH, Fehm HL. Influences of ACTH 4-10 on event-related potentials reflecting attention in man. Physiol Behav. 1987;39(1):83–87.

   PMID 3031714 ↗

4. Born J, Unseld U, Pietrowsky R, Bickel U, Voigt K, Fehm HL. Time course of ACTH 4-10 effects on human attention. Neuroendocrinology. 1990 Aug;52(2):169–174.

   PMID 2177158 ↗

5. Gusev EI, Skvortsova VI, Miasoedov NF, Nezavibat’ko VN, Zhuravleva EIu, Vanichkin AV. [Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study)]. Zh Nevrol Psikhiatr Im S S Korsakova. 1997;97(6):26–34. Clinical trial. Russian.

   PMID 11517472 ↗

6. Gusev EI, Skvortsova VI, Chukanova EI. [Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency]. Zh Nevrol Psikhiatr Im S S Korsakova. 2005;105(2):35–40. Russian.

   PMID 15792140 ↗

7. Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochem Res. 2005 Dec;30(12):1493–1500.

   PMID 16362768 ↗

8. Grivennikov IA, Dolotov OV, Zolotarev YA, Andreeva LA, Myasoedov NF, Leacher L, Black IB, Dreyfus CF. Effects of behaviorally active ACTH (4-10) analogue — Semax on rat basal forebrain cholinergic neurons. Restor Neurol Neurosci. 2008;26(1):35–43.

   PMID 18431004 ↗

9. Dmitrieva VG, Povarova OV, Skvortsova VI, Limborska SA, Myasoedov NF, Dergunova LV. Semax and Pro-Gly-Pro activate the transcription of neurotrophins and their receptor genes after cerebral ischemia. Cell Mol Neurobiol. 2010 Jan;30(1):71–79.

   PMID 19633950 ↗

10. Medvedeva EV, Dmitrieva VG, Povarova OV, Limborska SA, Skvortsova VI, Myasoedov NF, Dergunova LV. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics. 2014 Mar 24;15:228.

    PMID 24661604 ↗

11. Vyunova TV, Medvedeva EV, Andreeva LA, Dergunova LV, Limborska SA, Myasoedov NF. [Possible role of transthyretin in the biological mechanism of the regulatory peptide neuroprotection]. Mol Gen Mikrobiol Virusol. 2016;34(3):104–109. Review. Russian.

    PMID 30383932 ↗

12. Vyunova TV, Andreeva LA, Shevchenko KV, Myasoedov NF. Synacton and individual activity of synthetic and natural corticotropins. J Mol Recognit. 2017 May;30(5).

    PMID 27921334 ↗

13. Medvedeva EV, Dmitrieva VG, Limborska SA, Myasoedov NF, Dergunova LV. Semax, an analog of ACTH(4-7), regulates expression of immune response genes during ischemic brain injury in rats. Mol Genet Genomics. 2017 Jun;292(3):635–653.

    PMID 28255762 ↗

14. Markov DD, Yatsenko KA, Inozemtseva LS, Grivennikov IA, Myasoedov NF, Dolotov OV. Systemic N-terminal fragments of adrenocorticotropin reduce inflammation- and stress-induced anhedonia in rats. Psychoneuroendocrinology. 2017 Aug;82:173–186.

    PMID 28551512 ↗

15. 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. Clinical trial. Russian.

    PMID 29798983 ↗

16. Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, Myasoedov NF. Effects of Semax on the default mode network of the brain. Bull Exp Biol Med. 2018 Sep;165(5):653–656.

    PMID 30225715 ↗

17. Panikratova YR, Lebedeva IS, Sokolov OY, Rumshiskaya AD, Kupriyanov DA, Kost NV, Myasoedov NF. Functional connectomic approach to studying Selank and Semax effects. Dokl Biol Sci. 2020 Jan;490(1):9–11.

    PMID 32342318 ↗

18. Glazova NY, Manchenko DM, Volodina MA, Merchieva SA, Andreeva LA, Kudrin VS, Myasoedov NF, Levitskaya NG. Semax, synthetic ACTH(4-10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats. Neuropeptides. 2021 Apr;86:102114.

    PMID 33418449 ↗

19. Spirin NN, Fedorov VN, Vdovichenko VP. [Place of oligopeptide H-Met-Glu-His-Phe-Pro-Gly-Pro-OH in the therapy and rehabilitation of patients with ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 2024;124(8. Vyp. 2):56–63. Review. Russian.

    PMID 39166935 ↗

20. Filippenkov IB, Glazova NY, Sebentsova EA, Stavchansky VV, Andreeva LA, Myasoedov NF, Levitskaya NG, Limborska SA, Dergunova LV. Changes of transcriptomic activity in rat brain cells under the influence of synthetic adrenocorticotropic hormone-like peptides. Biochemistry (Mosc). 2024 Sep;89(9):1643–1656.

    PMID 39418522 ↗

21. Filippenkov IB, Shpetko YY, Stavchansky VV, Denisova AE, Gubsky LV, Andreeva LA, Myasoedov NF, Limborska SA, Dergunova LV. ACTH-like peptides compensate rat brain gene expression profile disrupted by ischemia a day after experimental stroke. Biomedicines. 2024 Dec 13;12(12):2830.

    PMID 39767736 ↗

22. Filippenkov IB, Shpetko YY, Ales DA, Stavchansky VV, Denisova AE, Yuzhakov VV, Fomina NK, Gubsky LV, Andreeva LA, Myasoedov NF, Limborska SA, Dergunova LV. Genes that associated with action of ACTH-like peptides with neuroprotective potential in rat brain regions with different degrees of ischemic damage. Int J Mol Sci. 2025 Jun 28;26(13):6256.

    PMID 40650034 ↗

23. Radchenko AI, Kuzubova EV, Apostol AA, et al. The potential of the peptide drug Semax and its derivative for correcting pathological impairments in the animal model of Alzheimer’s disease. Acta Naturae. 2025 Oct–Dec;17(4):110–120.

    PMID 41479572 ↗

24. Liu R, Chen Y, Huang H, et al. Semax peptide targets the mu opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice. Br J Pharmacol. 2025 Nov;182(22):5489–5516.

    PMID 40692165 ↗

25. Mavrych V, Shypilova I, Bolgova O. Therapeutic peptides in gerontology: mechanisms and applications for healthy aging. Front Aging. 2026 Apr 7;7:1790247.

    PMID 42021992 ↗