Semax Research

Semax research sits within a long-running effort to understand short regulatory peptides derived from adrenocorticotropic hormone (ACTH). The molecule at its center is a small synthetic peptide built from the neuroactive core of ACTH. It is studied mainly for how it influences neurotrophic factor signaling, and for its behavior in models of brain injury. This article summarizes what published studies show about Semax, most of them preclinical. The focus is brain-derived neurotrophic factor (BDNF) and related neurotrophic signaling, findings from cerebral ischemia models, and the peptide's reported effect on enkephalin-degrading enzymes. All of this is set against the clinical registration context in Russia. Each finding below is identified as coming from a cell culture (in vitro), an animal model, or a human study. Nothing here should be read as an outcome an individual should expect. Semax is a research compound. It is not characterized here for human use.

What is Semax?

Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro. It is built on the ACTH(4-7) core, Met-Glu-His-Phe, extended at the C-terminus by three additional residues, Pro-Gly-Pro. The addition is intended to slow enzymatic breakdown and give the molecule a longer duration than the rapidly degraded parent fragment.

The peptide is a synthetic analog of the N-terminal (4-10) region of ACTH rather than a fragment of it. ACTH residues 8 to 10, Arg-Trp-Gly, are absent from Semax and are replaced by Pro-Gly-Pro. That region carries the neurotropic and behavioral activity historically associated with ACTH, but Semax lacks the corticotropic hormonal action of the full hormone. It is therefore studied as a neuroactive peptide rather than an endocrine one. It was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, and across the research literature it is typically applied intranasally.

BDNF and neurotrophic factor research

The most developed strand of Semax research concerns neurotrophic factors, the proteins that support neuronal survival, growth, and plasticity. The earliest cellular evidence is in vitro. Shadrina and colleagues reported in 2001 that Semax rapidly induced the messenger RNAs for both nerve growth factor (NGF) and BDNF in rat glial cell cultures.^[1] The authors suggested that its effects on neuronal survival might be mediated through the regulation of neurotrophin expression.

Work then moved into the intact brain. Dolotov and colleagues reported in 2006 that intranasal Semax raised BDNF protein in the rat basal forebrain within 3 hours, though not in the cerebellum. They also reported that cell membranes isolated from that same region carried specific, reversible binding sites for radiolabeled Semax in an in vitro binding assay. The reported dissociation constant was about 2.4 nM.^[2] In a companion study, the same group found that a single application in rats increased BDNF protein in the hippocampus. In that region, the same application also raised phosphorylation of trkB, the receptor through which BDNF signals.^[3]

A further in vivo study by Agapova and colleagues in 2007 measured neurotrophin gene expression across brain regions. It found that Semax produced rapid, gene- and region-specific changes. Expression of both NGF and BDNF rose in the hippocampus, and BDNF also rose in the brainstem and cerebellum, while NGF expression fell in the frontal cortex.^[4] Taken together, these are in vitro and animal findings that point to modulation of neurotrophic signaling rather than a single uniform increase.

Ischemia model findings

A second strand has examined Semax in animal models of cerebral ischemia, where restricted blood flow drives neuronal injury and neurotrophic and vascular signaling become central.

Dmitrieva and colleagues reported in 2008 on rats subjected to experimental cerebral ischemia. In that model, they found that Semax and its C-terminal fragment Pro-Gly-Pro altered the expression of several growth factor genes and their receptors in the affected brain tissue.^[5] Medvedeva and colleagues extended this to the vascular side of the response, reporting in 2013 on a rat model of focal cerebral ischemia. In it, Semax and Pro-Gly-Pro influenced the expression of vascular endothelial growth factor (VEGF) family genes and their receptors.^[6]

Both are animal findings that characterize how the peptide interacts with the molecular response to ischemic injury. Neither predicts an outcome in an organism beyond the model.

Enkephalin system research

A distinct line of work concerns the endogenous opioid system. Kost and colleagues reported in 2001 that Semax, along with the related peptide Selank, dose-dependently inhibited enkephalin-degrading enzymes from human serum in vitro.^[7] By slowing the enzymatic breakdown of enkephalins, the peptide is thought to prolong endogenous enkephalin signaling rather than acting directly on opioid receptors. Beyond the enzyme study, Semax and Selank were tested in the same experimental system in two further studies, both published in 2017. One exposed mouse embryonic stem cells and their derivatives to Semax, Selank, and other peptides in vitro, and measured proliferation, survival, and differentiation into neuronal precursors and neurons.^[19] The other tested Semax and Selank in rats with Parkinson's disease-like parkinsonism induced by 6-hydroxydopamine.^[20] It measured motor activity and anxiety-related behavior in an elevated plus maze, and passive defensive behavior.^[20] Results are reported for each compound in each paper.

Animal behavior is only partly consistent with an opioid-related action. Manchenko and colleagues reported in 2010 that intraperitoneal Semax produced an analgesic effect in rats in the Randall-Selitto paw-withdrawal test. The same study found that intranasal Semax, the route used in most Semax research, did not alter pain sensitivity at all. It nonetheless improved learning more than the intraperitoneal route. The authors took this dissociation as evidence that the nootropic and analgesic effects depend on different mechanisms and brain structures.^[8]

It is worth being precise about the evidence here. The enzyme inhibition is an in vitro biochemical finding, and the analgesia is an animal behavioral finding. The link between them, that inhibited enkephalin breakdown produces the observed analgesia, remains a proposed mechanism rather than a directly measured chain.

Human research

Semax is registered in Russia as a medicinal product, as nasal drops at two strengths.^[10] Neither Semax nor its acetate salt is a component of any FDA-approved drug,^[11] and FDA's page on bulk drug substances that may present significant safety risks in compounding lists Semax among substances previously in category 2 whose nominations were withdrawn, citing a potential risk of immunogenicity.^[17] Most of its human literature is Russian-language clinical work from the research network that developed the peptide, and the developers are named authors on several of the studies.

Stroke is the largest strand. Gusev and colleagues compared 30 patients in the acute period of hemispheric ischemic stroke who received Semax alongside standard intensive therapy with 80 patients of similar stroke severity given standard therapy alone.^[12] The abstract does not describe random allocation. The authors reported some acceleration in the regression of general cerebral and focal deficits, especially motor deficits, in the Semax group. Also in the acute period of ischemic stroke, a retrospective comparison reported a shift in immune markers toward anti-inflammatory signaling.^[9]

In 2018, Gusev and colleagues followed 110 patients through rehabilitation after ischemic stroke.^[13] Early and late rehabilitation groups were each split into patients who did and did not receive Semax, and the abstract does not say how patients were assigned. Plasma BDNF rose in the Semax subgroups and remained elevated over the study period, while in patients not given Semax it rose faster with early than with late rehabilitation. The authors reported faster improvement on the Barthel index of activities of daily living with Semax and with higher BDNF levels. It is the main human measurement of BDNF, the neurotrophic factor at the center of the preclinical work above, though it was made in blood plasma rather than in brain tissue. A 2005 study led by the same author covered 187 patients at different stages of cerebrovascular insufficiency and reported clinical improvement and good tolerability, without describing comparison groups or allocation in its abstract.^[14]

Two imaging studies in healthy volunteers measured brain activity rather than any clinical outcome. Lebedeva and colleagues gave intranasal Semax to 14 volunteers and placebo to 10, and reported a larger rostral, medial frontal component of the brain's default mode network on resting-state functional MRI.^[15] A 2020 study from the same group compared Semax, Selank, and placebo in 52 healthy participants and reported changes in functional connectivity between the right amygdala and the right temporal cortex.^[16] FDA has noted that the Semax-treated participants in the two studies may be the same people.^[11]

In a briefing document dated May 2026, prepared for its Pharmacy Compounding Advisory Committee, FDA reviewed the human evidence on Semax for three proposed uses (cerebral ischemia, migraine, and trigeminal neuralgia) and on safety, and recommended against adding Semax to the list of bulk drug substances that can be used in compounding.^[11] It did not evaluate the Russian-language studies of stroke and cerebrovascular disease described above, because full English versions were not available, so its conclusion that the evidence is insufficient to support Semax for cerebral ischemia rested on the one source it could assess, a meeting abstract that lacked relevant clinical endpoints. Other reports, some available only as meeting abstracts, cover pain, peptic ulcer, and depression and tics in children, and in several of them Semax was given alongside other treatment, which makes its own contribution hard to separate.^[11] FDA found no human pharmacokinetic study by any route, noted that most reports did not discuss adverse events, judged the clinical information insufficient to characterize Semax's safety, and raised concerns about a possible bleeding risk and about immunogenicity.^[11] On 24 July 2026, the committee voted 8 yes, 5 no and 1 abstention for both Semax free base and Semax acetate to be added to the 503A Bulks List; the recommendations are non-binding.^[18][21] No FDA decision had been published as of October 2026. None of this establishes an outcome for any individual.

Limitations

Several limitations shape how this literature should be read. A large share of the work originates from a small network of affiliated Russian institutes, and much of it is published in Russian-language journals. This limits independent replication.

The proposed mechanisms are multiple, spanning neurotrophic, enkephalinergic, and vascular signaling. The neurotrophic effects themselves are region-specific rather than uniform, so a single unifying account is not yet settled. On the human side, the studies are small, none of the abstracts cited here describes random allocation, and FDA's 2026 review found no human pharmacokinetic study, the kind of study that would measure Semax's half-life.^[11]

Conclusion

Semax is best understood as a metabolically stabilized ACTH(4-10) analog, an ACTH(4-7) core carrying a Pro-Gly-Pro extension. It is studied as a neuroactive peptide without the hormonal action of the parent hormone.

Its preclinical profile points to a multi-target picture. That picture includes modulation of NGF and BDNF signaling in cell and animal studies, along with altered growth factor and VEGF gene expression in animal ischemia models. It also includes inhibition of enkephalin-degrading enzymes in vitro alongside analgesic activity in animals. Human studies exist, most of them in patients with stroke or other cerebrovascular disease, but they are small and come largely from the developers' own network. In its 2026 review FDA recommended against adding Semax to the compounding list without having evaluated the Russian-language stroke studies, and its advisory committee then voted, without binding effect, to recommend adding it.^[11][18] The findings above describe what has been investigated, not what any individual should expect.

References

1. 1

   Shadrina MI, Dolotov OV, Grivennikov IA, Slominsky PA, Andreeva LA, Inozemtseva LS, et al. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neurosci Lett. 2001;308(2):115-118. PMID 11457573.
2. 2

   Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. J Neurochem. 2006;97(s1):82-86. PMID 16635254.
3. 3

   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. PMID 16996037.
4. 4

   Agapova TY, Agniullin YV, Shadrina MI, Shram SI, Slominsky PA, Lymborska SA, et al. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10. Neurosci Lett. 2007;417(2):201-205. PMID 17353092.
5. 5

   Dmitrieva VG, Dergunova LV, Povarova OV, Skvortsova VI, Limborskaya SA, Myasoedov NF. The effect of semax and the C-terminal peptide PGP on expression of growth factor genes and receptors in rats under conditions of experimental cerebral ischemia. Dokl Biochem Biophys. 2008;422:261-264. PMID 19024553.
6. 6

   Medvedeva EV, Dmitrieva VG, Povarova OV, Limborska SA, Skvortsova VI, Myasoedov NF, Dergunova LV. Effect of semax and its C-terminal fragment Pro-Gly-Pro on the expression of VEGF family genes and their receptors in experimental focal ischemia of the rat brain. J Mol Neurosci. 2013;49(2):328-333. PMID 22772900.
7. 7

   Kost NV, Sokolov OYu, Gabaeva MV, Grivennikov IA, Andreeva LA, Myasoedov NF, et al. Semax and selank inhibit the enkephalin-degrading enzymes from human serum. Bioorg Khim. 2001;27(3):180-183. PMID 11443939.
8. 8

   Manchenko DM, Glazova NYu, Levitskaya NG, Andreeva LA, Kamensky AA, Myasoedov NF. Nootropic and analgesic effects of Semax following different routes of administration. Ross Fiziol Zh Im I M Sechenova. 2010;96(10):1014-1023. PMID 21268834.
9. 9

   Miasoedova NF, Skvortsova VI, Nasonov EL, Zhuravleva EY, Grivennikov IA, Arsenieva EL, Sukhanov I. Investigation of mechanisms of the neuroprotective effect of Semax in the acute period of ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(5):15-19. PMID 10358912.
10. 10

    State Register of Medicines (GRLS), Ministry of Health of the Russian Federation, retrieved 2 October 2026. Semax nasal drops 0.1%, registration ЛП-№(009449)-(РГ-RU), 26 March 2025, and 1%, registration ЛП-№(010596)-(РГ-RU), 18 June 2025; holder JSC INPC Peptogen; both listed as valid. grls.rosminzdrav.ru
11. 11

    US Food and Drug Administration. FDA Briefing Document, Pharmacy Compounding Advisory Committee meeting, 23-24 July 2026: FDA evaluation of Semax-related bulk drug substances, Semax (free base) and Semax acetate, dated 11 May 2026. fda.gov/media/193348
12. 12

    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. PMID 11517472. In Russian.
13. 13

    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 Pt 2):61-68. PMID 29798983. doi:10.17116/jnevro20181183261-68. In Russian.
14. 14

    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. PMID 15792140. In Russian.
15. 15

    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;165(5):653-656. PMID 30225715. doi:10.1007/s10517-018-4234-3.
16. 16

    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;490(1):9-11. PMID 32342318. doi:10.1134/S001249662001007X.
17. 17

    US Food and Drug Administration. "Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks." Content current as of 22 April 2026, retrieved 3 October 2026; lists Semax (heptapeptide) under "Bulk drug substances nominated but withdrawn" (substances previously in category 2 whose nominations the nominators withdrew). fda.gov
18. 18

    Eglovitch JS. FDA advisory committee backs two more peptides, rejects one for compounding list. Regulatory Focus (Regulatory Affairs Professionals Society). 24 July 2026. raps.org
19. 19

    Kobylyanskii AG, Zolotarev YA, Andreeva LA, Grivennikov IA, Myasoedov NF. Studying the toxic effects of some biologically active peptides on the model of mouse embryonic stem cells. Bull Exp Biol Med. 2017;163(6):731-736. PMID 29063333. doi:10.1007/s10517-017-3891-y.
20. 20

    Slominsky PA, Shadrina MI, Kolomin TA, Stavrovskaya AV, Filatova EV, Andreeva LA, et al. Peptides semax and selank affect the behavior of rats with 6-OHDA induced PD-like parkinsonism. Dokl Biol Sci. 2017;474(1):106-109. PMID 28702721. doi:10.1134/S0012496617030048.
21. 21

    US Food and Drug Administration. July 23-24, 2026 Meeting of the Pharmacy Compounding Advisory Committee: Questions, listing separate votes on whether Semax (free base) and Semax acetate should be placed on the 503A bulks list. Retrieved 5 October 2026; the meeting page carried no minutes or vote tallies as of that date. fda.gov