Semax

What Semax is

Semax is a lab-made peptide that Russia approves as a medicine for stroke and a few other brain and nerve conditions. Russian doctors have tested it in patients. Most of the lab work used rats, mice or cells in a dish. No large randomized controlled trial has been run in the West, and the FDA has not approved it.

A peptide is a short chain of amino acids, the building blocks of protein. Semax has seven: Met-Glu-His-Phe-Pro-Gly-Pro, or MEHFPGP for short. It has two parts:

• The front. This is ACTH(4-7), a piece of the natural hormone ACTH (adrenocorticotropic hormone).
• The tail. Three more amino acids, Pro-Gly-Pro or PGP, are joined to the far end, called the C-terminal.

The PGP tail is what defines the design. Enzymes have a much harder time breaking the peptide down with the tail in place. The parent fragment, ACTH(4-10), lasts only seconds in blood plasma. The tail stretches that half-life to about 24 minutes, which is long enough to make a workable drug.

Semax dates from the late 1980s and the early 1990s. It was developed in Moscow, at the Russian Academy of Sciences’ Institute of Molecular Genetics. Ashmarin and colleagues described it in depth [1].

It comes as nose drops. From the nose, the peptide can travel to the brain and the rest of the central nervous system. This route also skips first-pass metabolism, the breakdown a swallowed drug goes through before it reaches the blood.

In Russia, Semax is a registered drug. It is also on the country’s list of Vital and Essential Medicines. Its approved uses include:

• ischemic stroke, the kind caused by blocked blood flow
• transient ischemic attack, or TIA
• thinking problems tied to cerebrovascular disease, which is disease of the brain’s blood vessels
• some optic nerve conditions

Things are different outside Russia and several nearby countries. The MHRA in the UK, the FDA in the US and the EMA in the EU have not approved it. No other major Western regulator has either.

That split matters for how the evidence should be read. Russian-language journals hold a large body of trial and lab data. A smaller share is in English and can be found through PubMed. Teams outside Russia have published little original data on it.

How much research there is

There are many Russian studies, some of them in patients, and almost nothing from Western labs.

Question	Answer
Is it approved?	Yes in Russia, for ischemic stroke, TIA, thinking problems from cerebrovascular disease, and optic nerve conditions. No at the FDA, MHRA or EMA
Peer-reviewed studies indexed in English	This guide cites 12+. The wider Russian-language record is estimated at several hundred papers
Tested in patients	Several Russian trials in stroke and cerebrovascular disease. There are no large Western randomized controlled trials
Tested in animals and cells	Steady reports of higher BDNF and NGF, protection of nerve cells, less inflammation, and changes in behavior, in rodents and in cells in a dish

How it might work

Semax does not work through one receptor or one pathway. Three kinds of effect in the central nervous system have been reported together:

• higher levels of neurotrophins, proteins that help nerve cells grow and survive
• changes in monoamines, a class of brain chemicals that includes dopamine
• anti-inflammatory signals

Most of this work used rodents or cells in a dish.

The ACTH piece and the PGP tail

Papers often call Semax an analog of ACTH(4-10), a seven-unit piece of ACTH. Semax keeps the first four units, ACTH(4-7), and swaps the last three for PGP. Scientists have known since the 1970s that ACTH(4-10) acts on nerves. In animals it affects behavior and thinking. On its own it is of little use as a drug. Enzymes cut it apart too fast.

Adding PGP solved that. PGP resists carboxypeptidases, enzymes that clip amino acids off the tail of a chain. With PGP on the end, the amino acids ahead of it are shielded too.

PGP does more than shield. Tests in cells and in animals confirmed that tissue releases the PGP fragment from Semax, and that PGP is active by itself. Several studies compared whole Semax with PGP alone. The two partly overlapped in their effects on gene activity and on measures of nerve cell protection [2]. Because of this, some Russian authors say that Semax, in some settings, is a “prodrug” for PGP. A prodrug is a compound that the body turns into the active one. That view is still debated.

Vyunova and colleagues added another idea. They proposed that transthyretin, a blood protein, may bind the peptide or carry it as part of its protective action. That would be one possible reason it ends up in the central nervous system after a dose through the nose [3].

BDNF and NGF

BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) are two neurotrophins. A rise in BDNF in certain brain regions is the molecular effect reported most often for Semax. NGF rises too, but less.

• 2001, cell cultures. Shadrina and colleagues were the first to show it. In cultures of rat glial cells, the support cells of the brain, Semax quickly raised neurotrophin mRNA, the working copy of a gene [4].
• 2006, basal forebrain. Dolotov and colleagues gave rats Semax through the nose. It bound to specific sites in the basal forebrain, and BDNF protein went up in that same region. This tied binding at a receptor to the protein made later [5].
• 2006, hippocampus. A partner paper that year looked at the rat hippocampus. Semax changed the levels of both BDNF and TrkB, the receptor that BDNF signals through. So the peptide may tune the receptor side as well as the amount of BDNF [6].
• Timing. Agapova and colleagues tracked BDNF and NGF gene activity over time after a dose, in the frontal cortex and the hippocampus. The response depended on the region and on the time point [7].
• Three tissues. Shadrina and co-workers later set the retina, frontal cortex and hippocampus side by side. The neurotrophin responses were coordinated, but each tissue had its own pattern [8].

Dopamine

Semax is reported to affect monoamine signaling. Dopamine has drawn the most interest.

• Slominsky and colleagues (2017) used rats treated with 6-hydroxydopamine (6-OHDA), a chemical that produces a Parkinson’s-like state. Semax changed how the animals behaved, and so did the related peptide Selank. That points to a working link with brain circuits that depend on dopamine [9].
• Newer work looked at lab-made corticotropin fragments and the GABA receptor system. GABA is a signal that quiets nerve cells. The results suggest that Semax may also change this quieting signal, in part directly and in part with a delay. That would add to its monoamine effects on how excitable the brain is [10].
• In rats under chronic unpredictable stress, Semax had antidepressant-like and antistress effects. The behavior changes fit with action on both monoamines and the HPA axis, the body’s stress hormone system [11].

Inflammation in the brain

Cerebral ischemia means too little blood reaches the brain. In models of it, Semax is reported to change the activity of genes that run immune and inflammatory responses.

• Medvedeva and colleagues (2017) read the whole transcriptome, the full set of active genes, in rats with ischemic brain injury. Semax regulated immune response genes. Its effects on chemokine pathways and cytokine pathways were not the same [12].
• Earlier, the same group studied focal ischemia, where one area of the brain loses blood flow. They looked at genes of the VEGF (vascular endothelial growth factor) family and their receptors. The findings suggest Semax may pair anti-inflammatory signals with support for rebuilding blood vessels [13].
• Another line of work covers ischemia-reperfusion, when blood flow is cut and then returns. It proposes that Semax and PGP shift the inflammation genes and nerve signaling genes that respond. The pattern fits what is expected of the glyproline class of peptides [14].
• Sudarkina and colleagues confirmed the protective effect at the protein level. They profiled brain proteins in a rat ischemia-reperfusion model [15].

What the studies found

Animal and cell studies make up most of the evidence. The human data sit mostly in Russian-language papers. They come from small to medium trials run inside the Russian Federation.

Stroke trials in Russia

The clinical case for Semax in Russia rests on a series of trials in ischemic stroke, in its acute and subacute phases.

• 1997. Gusev, Skvortsova and colleagues published an early study of patients in the acute phase of a hemispheric ischemic stroke. It used clinical exams and electrical recordings of the brain. Treated patients recovered nerve function better than controls, and their electrical measures were better too [16].
• 2005. The same group tested Semax in patients who had chronic cerebrovascular insufficiency, a lasting shortage of blood flow to the brain. The aim was to keep the disease from getting worse or flaring up. They again reported a benefit on the main clinical measures they used [17].
• 2018. Gusev and colleagues came back to the question and compared how well Semax worked at different stages of ischemic stroke. They concluded it stayed useful from the acute phase through to rehabilitation [18].

Russian regulators approved Semax on the strength of these trials, and added it to the Vital and Essential Medicines list.

Western experts have not looked at them closely, for three reasons. Most of the papers are in journals printed in Russian, Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova among them. The size of the samples and the blinding methods vary from one trial to the next. And nobody outside the Russian Federation has run a large trial to confirm the results.

Thinking and behavior in animals

Three groups, led by Levitskaya, Kamensky and Dolotov, have studied Semax in rats and mice over a long research program. They reported that it:

• improved scores on learning and memory tasks, after one dose through the nose and after repeated doses
• had antistress effects under chronic unpredictable stress [11]
• corrected problems in the central nervous system of rodent pups that got too little oxygen before and after birth [19]

The studies mostly agree with each other. The usual cautions about rodent behavior work apply. Species differ. Results are sensitive to how a test is set up. And a fairly small circle of authors did the work. All of this limits how far the results can be carried over to human thinking.

BDNF in the lab

The rise in BDNF and NGF is also one of the stronger lab findings for Semax. Several independent experiments inside the Myasoedov and Grivennikov network reported neurotrophin gains after a dose:

• a quick rise in BDNF and NGF mRNA in cultured glial cells from rats [4]
• specific binding and more BDNF protein in the rat basal forebrain after nasal dosing [5]
• BDNF and TrkB moving together in the hippocampus [6]
• BDNF and NGF patterns mapped over time in three tissues: hippocampus, retina and frontal cortex [7], [8]

The same has been reported after cerebral ischemia. In the brain after ischemia, Semax and PGP raised the gene activity of neurotrophins and of their receptors [20].

Optic nerve

Some Russian clinics have tried Semax as an add-on for diseases of the optic nerve and retina. In 2022, Dragon and colleagues tested complex nerve stimulation programs, based on physical therapy, that included Semax. The patients had optic neuropathies with a range of causes. The treated groups had better functional results [21].

By Western standards of evidence-based medicine, this area is weak on method. The groups of patients are modest in size. Blinding is usually missing. Clinics measure outcomes in different ways. Still, it keeps showing up in Russian clinical papers, and it is one of the registered uses of the compound there.

Legal status in the US

• Not FDA approved. Semax has no marketing approval in the US. The same is true of the MHRA in the UK and the EMA in the EU.
• Approved in Russia. It is a registered drug there, with defined uses, a set form (nose drops), and a place on the country’s list of essential medicines.
• Research use. Elsewhere it can be had only as a research peptide, for in vitro and laboratory research. This guide is meant for education.

Limits of the research

1. Approved in one region. Semax is a registered drug in Russia and unapproved in the US, UK and EU. Anyone who sets Russian trial data next to Western-approved drugs should be open about that gap.
2. Little Western data. Russian clinical research is extensive, but Western teams have rarely repeated it. No large double-blind, placebo-controlled randomized trial has appeared in a high-impact English-language journal. Systematic reviews and meta-analyses are just as scarce.
3. Russian-language sources. Much of the research, above all the earlier trials and mechanism studies, is in Russian journals that PubMed and Scopus do not index reliably. Papers in English often cite those sources without giving the full methods. A careful reader needs to read Russian or lean on indexed reviews that summarize the work. Either way, it limits how sure anyone can be about a specific clinical claim.
4. A small circle of authors. Most of the mechanism and clinical work comes from a fairly small network of Russian groups. The names are Myasoedov, Grivennikov, Dolotov, Skvortsova and Gusev, plus their collaborators. That often happens when a compound is developed and mostly sold in one country. It does make checks by unconnected labs more important.

Russia treats Semax as a proven stroke medicine. Outside Russia, no large independent trial has confirmed that.

References

Selected peer-reviewed references. Ordered by relevance to this guide. Many foundational Semax studies appear in Russian-language journals; where possible, PubMed-indexed sources are cited.

1. Ashmarin IP. Anticipated and unexpected physiological effects of oligopeptides (glyprolines, ACTH analogs, tuftsin, thyroliberin). Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova. 2001;87(11):1471–1476. PMID: 11816278
2. Medvedeva EV, Dmitrieva VG, Povarova OV, Limborskaia SA, Skvortsova VI, Miasoedov NF, Dergunova LV. Effect of tripeptide Pro-Gly-Pro on rat brain transcriptome in focal ischemia. Molekuliarnaia Biologiia. 2014;48(2):277–287. PMID: 25850296
3. Vyunova TV, Medvedeva EV, Andreeva LA, Dergunova LV, Limborska SA, Myasoedov NF. Possible role of transthyretin in the biological mechanism of regulatory peptide neuroprotection. Molekuliarnaia Genetika, Mikrobiologiia i Virusologiia. 2016;34(3):104–109. PMID: 30383932
4. Shadrina MI, Dolotov OV, Grivennikov IA, Slominsky PA, Andreeva LA, Inozemtseva LS, Limborska SA, Myasoedov NF. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neuroscience Letters. 2001;308(2):115–118. PMID: 11457573
5. Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, Kamensky AA, Grivennikov IA, Engele J, Myasoedov NF. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. Journal of Neurochemistry. 2006;97 Suppl 1:82–86. PMID: 16635254
6. Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, Dubynina EV, Novosadova EV, Andreeva LA, Alfeeva LY, Kamensky AA, Grivennikov IA, Myasoedov NF, Engele J. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research. 2006;1117(1):54–60. PMID: 16996037
7. Agapova TY, Agniullin YV, Shadrina MI, Shram SI, Slominsky PA, Lymborska SA, Myasoedov NF. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10. Neuroscience Letters. 2007;417(2):201–205. PMID: 17353092
8. Shadrina M, Kolomin T, Agapova T, Agniullin Y, Shram S, Slominsky P, Lymborska S, Myasoedov N. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. Journal of Molecular Neuroscience. 2010;41(1):30–35. PMID: 19662538
9. Slominsky PA, Shadrina MI, Kolomin TA, Stavrovskaya AV, Filatova EV, Andreeva LA, Illarioshkin SN, Myasoedov NF. Peptides Semax and Selank affect the behavior of rats with 6-OHDA-induced PD-like parkinsonism. Doklady Biological Sciences. 2017;474(1):106–109. PMID: 28702721
10. Vyunova TV, Andreeva LA, Shevchenko KV, Glazova NY, Sebentsova EA, Levitskaya NG, Myasoedov NF. Synthetic corticotropins and the GABA-receptor system: Direct and delayed effects. Chemical Biology & Drug Design. 2023;101(6):1393–1405. PMID: 36828803
11. Inozemtseva LS, Yatsenko KA, Glazova NY, Kamensky AA, Myasoedov NF, Levitskaya NG, Grivennikov IA, Dolotov OV. Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. European Journal of Pharmacology. 2024;984:177068. PMID: 39442746
12. 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. Molecular Genetics and Genomics. 2017;292(3):635–653. PMID: 28255762
13. 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. Journal of Molecular Neuroscience. 2013;49(2):328–333. PMID: 22772900
14. Stavchansky VV, Filippenkov IB, Remizova JA, et al. Insight into glyproline peptides’ activity through the modulation of the inflammatory and neurosignaling genetic response following cerebral ischemia-reperfusion. Genes. 2022;13(12):2380. PMID: 36553646
15. Sudarkina OY, Filippenkov IB, Stavchansky VV, et al. Brain protein expression profile confirms the protective effect of the ACTH(4-7)PGP peptide (Semax) in a rat model of cerebral ischemia-reperfusion. International Journal of Molecular Sciences. 2021;22(12):6179. PMID: 34201112
16. Gusev EI, Skvortsova VI, Miasoedov NF, Nezavibat’ko VN, Zhuravleva EIu, Vanichkin AV. Effectiveness of Semax in the acute period of hemispheric ischaemic stroke (clinical and electrophysiological study). Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 1997;97(6):26–34. PMID: 11517472
17. Gusev EI, Skvortsova VI, Chukanova EI. Semax in prevention of disease progression and development of exacerbations in patients with cerebrovascular insufficiency. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2005;105(2):35–40. PMID: 15792140
18. Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN. The efficacy of Semax in the treatment of patients at different stages of ischaemic stroke. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2018;118(3.2):61–68. PMID: 29798983
19. Maslova MV, Maklakova AS, Sokolova NA, Ashmarin IP, Goncharenko EN, Krushinskaya YV. The effects of ante- and postnatal hypoxia on the central nervous system and their correction with peptide hormones. Neuroscience and Behavioral Physiology. 2003;33(6):607–611. PMID: 14552554
20. 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. Cellular and Molecular Neurobiology. 2010;30(1):71–79. PMID: 19633950
21. Dragon AK, Korchazhkina NB, Sheludchenko VM, Yusef Y, Kosova JV, Makarova MA, Elfimov MA. Results of the application of complex physiotherapeutic neurostimulation in optical neuropathies of various genesis. Voprosy Kurortologii, Fizioterapii i Lechebnoi Fizicheskoi Kultury. 2022;99(4.2):72–77. PMID: 36083821