Article

Semax: the ACTH(4-7)-Pro-Gly-Pro peptide and its research record

Published 22 October 2026 · CognitivePepti Research Desk

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Prepared by: Research Desk. Sources are linked for verification.

Published 22 October 2026

At a glance

Type: synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP)
Design: the first four residues match positions 4 to 7 of adrenocorticotropic hormone (ACTH), joined to a Pro-Gly-Pro tripeptide; the literature calls it an "ACTH(4-10) analogue" or "ACTH(4-7)PGP"
Origin: developed in Moscow within a research programme on glyproline peptides
Research stage: most mechanistic work is in rats, mice and cultured cells; human data are limited to small Russian-language studies
Regulatory status: not an FDA-approved drug. An FDA briefing document prepared for the July 2026 Pharmacy Compounding Advisory Committee concluded that a balancing of the criteria "weighs against" placing Semax on the 503A Bulks List.

Design: an ACTH fragment with a stabilising tail

ACTH is a pituitary hormone. According to FDA's 2026 briefing document, its 4-10 fragment lacks the hormone's corticotropic and melanotropic activity but keeps neurobehavioural properties seen in animal studies. Semax keeps the ACTH(4-7) segment, Met-Glu-His-Phe, and replaces the rest with Pro-Gly-Pro.

In a 2005 review, Ashmarin et al. argued that peptides ending in this glyproline motif are far more stable in biological media than most regulatory peptides. They described Semax and Selank as "hybrid" peptides, in which a natural regulatory fragment is joined to a stabilising tail. Selank, the related tuftsin analogue, is covered in our Selank research overview.

A 2004 study from the same school measured how Semax breaks down in the presence of rat brain membranes. Using tritium-labelled peptide and HPLC, Dolotov et al. (2004) reported a half-life of more than one hour under those conditions. They proposed dipeptidyl aminopeptidases as the main enzymes, cleaving Semax step by step to the pentapeptide HFPGP and then to PGP.

Binding sites and neurotrophin studies

The best-known line of Semax research concerns brain-derived neurotrophic factor (BDNF), a protein involved in the growth and survival of nerve cells, and its receptor TrkB.

Specific binding. The 2004 study above, and a 2006 follow-up in the Journal of Neurochemistry (Dolotov et al., 2006), reported specific, reversible, calcium-dependent binding of labelled Semax to membranes from the rat basal forebrain. No receptor was identified.
BDNF protein. The same 2006 paper reported a rapid rise in BDNF protein in the rat basal forebrain after intranasal application, but not in the cerebellum.
Hippocampal BDNF and TrkB. In a separate 2006 study in Brain Research, Dolotov et al. reported about a 1.4-fold rise in hippocampal BDNF protein and a 1.6-fold rise in TrkB phosphorylation in rats, alongside more conditioned avoidance responses.
Earlier report. A 2003 brief communication described raised BDNF expression in several rat brain regions (Dolotov et al., 2003).

These are rodent measurements of molecular markers. They suggest why BDNF became the main hypothesis, but they do not establish a mechanism.

Monoamines

Eremin et al. (2005) examined dopamine and serotonin systems in rodents. Semax alone raised levels of the serotonin metabolite 5-HIAA in the striatum but did not change dopamine levels. Given before D-amphetamine, it markedly increased the amphetamine-induced rise in extracellular dopamine and locomotor activity. FDA's 2026 briefing document cites this finding as a concern, because increased striatal dopamine tone is a response typically linked to drugs of abuse.

Ischaemia models and newer targets

Several studies from Moscow groups have used the rat transient middle cerebral artery occlusion (tMCAO) model, an experimental model of ischaemia-reperfusion injury.

Filippenkov et al. (2020) used RNA sequencing and reported 394 genes expressed differently 24 hours after tMCAO in Semax-exposed rats compared with saline. The authors described suppression of inflammation-related genes and activation of neurotransmission-related genes.
Sudarkina et al. (2021) followed up at the protein level, reporting changes in MMP-9, c-Fos, JNK and active CREB in the same model.
Outside Russia, Liu et al. (2025), working in a mouse model of spinal cord injury, used network pharmacology and docking to propose the mu-opioid receptor as a Semax target. This is a single study and has not been replicated.
Sciacca et al. (2022), an Italian group, reported in cell-free and cell assays that Semax binds copper ions and interferes with copper-driven amyloid beta aggregation.

The human record

Published human data are sparse. One example is an open-label, non-randomised Russian study of 110 people after ischaemic stroke, which measured plasma BDNF and functional scores (Gusev et al., 2018). It had no placebo control.

FDA reached a similar view of the evidence. Its briefing document for Semax-related bulk drug substances states that there is insufficient evidence for the uses nominated (cerebral ischaemia, migraine and trigeminal neuralgia) and insufficient clinical information to characterise Semax's safety profile. It also notes that FDA found no human pharmacokinetic studies.

Regulatory status

July 2026 advisory committee. The meeting page for the 23–24 July 2026 Pharmacy Compounding Advisory Committee lists Semax (free base) and Semax acetate for discussion on 24 July as candidates for the 503A Bulks List.
FDA's briefing position. The briefing document concludes that a balancing of the criteria "weighs against" listing either form. It describes both forms as not well characterised, citing inconsistent naming and missing data on impurities, aggregates, endotoxin and microbial testing, and it raises a concern about immunogenicity. FDA states that it will not make a final determination until the advisory committee's input has been considered. This page does not report the committee's vote.
Safety-risk page. FDA's page on bulk drug substances that may present significant safety risks lists "Semax (heptapeptide)" among nominations that were withdrawn, noting a possible immunogenicity risk from aggregation and peptide-related impurities.
Outside the US. The briefing document notes that Semax is a registered drug in Russia and that there is no monograph for it in the European, Japanese or International Pharmacopoeia.

For a side-by-side comparison with Selank and DSIP, see the cognition peptide research guide.

Open research questions

Receptor. Specific binding sites were reported in 2004 and 2006, but no receptor has been identified.
Mechanism. Whether the BDNF, monoamine, gene-expression and opioid-receptor findings reflect one mechanism or several is unresolved.
Fragments. How much of the reported activity comes from Semax itself and how much from its breakdown products, HFPGP and PGP.
Replication. Most core findings come from the developing institutes; independent work is recent and limited.

Limitations of the evidence

Mechanistic data come mainly from rats and mice, with some cell and cell-free work.
Many studies measure expression of genes or proteins rather than functional outcomes.
Many early reports appeared in Russian-language journals or as brief communications.
The human record consists of small studies without placebo controls, and FDA found no human pharmacokinetic data.

Key terms

ACTH(4-10). A seven-residue fragment of adrenocorticotropic hormone.
Glyproline. A proline- and glycine-rich peptide motif such as Pro-Gly-Pro.
BDNF and TrkB. A neurotrophic protein and the receptor it signals through.
503A Bulks List. FDA's list of bulk drug substances that pharmacies may use in compounding under section 503A. Being on it is not FDA approval of a drug.

Where researchers source it

Purita is a store that lists Semax for laboratory research use only. Its product page labels the item for research use only and not for human or animal administration.

Purita product page

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