What Has Published Research Reported About Semax?

What is Semax?

Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro. Dmitrieva and colleagues, from the Institute of Molecular Genetics of the Russian Academy of Sciences, describe it as an ACTH(4-7) fragment joined to the C-terminal tripeptide Pro-Gly-Pro, which the literature abbreviates PGP (source 6). Several titles instead call it an analogue of ACTH(4-10) (sources 2 and 4). The native heptapeptide ACTH(4-10) has the sequence Met-Glu-His-Phe-Arg-Trp-Gly and also sits at residues 46 to 52 of beta-lipotropin (source 11). Semax therefore keeps the first four residues of that fragment and replaces Arg-Trp-Gly with Pro-Gly-Pro. A 2018 review by Koroleva and Myasoedov compared the structures and effects of Semax and its fragments using published data from 1980 to 2016 (source 12).

From the sequences, the formulas and masses can be calculated. Semax is C37H51N9O10S, with a monoisotopic mass of 813.35 and an average mass of 813.93. ACTH(4-10) is C44H59N13O10S, with 961.42 and 962.10. These are calculated values, not figures reported in a cited paper, and they are the numbers a laboratory would compare against a mass spectrum. This Steadfast Research Group profile covers the biochemical, cell, rodent and analytical literature. Clinical use is outside its scope.

What did enzyme studies report about Semax?

In a 2001 paper in the Russian Journal of Bioorganic Chemistry, Kost and colleagues tested Semax and Selank against the enkephalin-degrading enzymes of human serum. They reported IC50 values of about 10 micromolar for Semax and 20 micromolar for Selank, described as more pronounced than puromycin (IC50 10 mM), bacitracin and some other peptidase inhibitors. Five-residue fragments of both heptapeptides also inhibited the enzymes, while the tri-, tetra- and hexapeptide fragments did not (source 1). This was an in vitro serum assay. The abstract refers only to enkephalin-degrading enzymes of human serum, so a specific enzyme should not be assumed. The same assay is discussed for the companion peptide in the Selank profile.

What did binding and neurotrophin protein studies report?

Dolotov and colleagues reported in 2006 that binding of tritium-labelled Semax was time dependent, specific and reversible, that specific binding required calcium ions, and that it had a mean dissociation constant of 2.4 nM and a Bmax of 33.5 fmol per mg protein. In the same paper, brain-derived neurotrophic factor (BDNF) protein rose in the rat basal forebrain 3 hours after Semax administration but not in the cerebellum (source 2). The paper did not identify the binding site, and the abstract does not say that the BDNF rise depends on it.

A second 2006 paper, in Amino Acids, traced how Semax is broken down in plasma membranes and in glial and neuronal cultures from rat basal forebrain, using a peptide labelled with isotopes at every residue. The abstract described the main breakdown steps as removal of the N-terminal Met-Glu and of the C-terminal Gly-Pro, giving pentapeptides, and reported different fragment patterns in glial and neuronal cells (source 3). The abstracts reviewed here did not state whether these pentapeptides are the same species as the inhibitory pentapeptide fragments in source 1, so that link is not drawn.

What did monoamine studies report?

Eremin and colleagues, in a 2005 paper in Neurochemical Research, measured monoamines in rodent striatum. They reported that tissue content of the serotonin metabolite 5-HIAA rose by about 25 percent 2 hours after Semax, and that extracellular 5-HIAA rose gradually to about 180 percent of its starting level over 1 to 4 hours. Semax alone did not change dopamine or its metabolites. When it was given 20 minutes before d-amphetamine, the authors reported a larger amphetamine-driven rise in extracellular dopamine and in locomotor activity, and they concluded that Semax modulated the striatal serotonergic system (source 4). The paper’s title describes activation of dopaminergic and serotoninergic systems, but the abstract-level results above show an effect on dopamine only in combination with d-amphetamine.

What did cell culture studies report?

In 2007, Storozhevykh and colleagues studied cultured cerebellar granule cells exposed to glutamate. They reported that Semax and its Pro-Gly-Pro fragment both delayed the onset of calcium dysregulation and the fall in mitochondrial membrane potential, and that neuronal survival was roughly 30 percent better on average with the peptides present. The authors proposed that the improved survival they saw in culture may come from better mitochondrial tolerance of calcium stress (source 5). This is a single culture system and an abstract-level result, so it says little about other cell types.

What did gene-expression studies in rat ischemia models report?

Most mechanistic work on Semax used the permanent middle cerebral artery occlusion (pMCAO) model in rats and measured messenger RNA. In 2010, Dmitrieva and colleagues reported that Semax increased transcription of Bdnf, TrkC and TrkA 3 hours after occlusion and of Nt-3 and Ngf at 24 hours. Pro-Gly-Pro alone raised Bdnf and TrkC at 3 hours and Ngf, TrkB, TrkC and TrkA at 24 hours. The authors concluded that Semax selectively affected neurotrophin and receptor transcription in the ischemic cortex while the influence of Pro-Gly-Pro was mainly unspecific (source 6).

In 2014, Medvedeva and colleagues used a genome-wide analysis of rat cortex 3 and 24 hours after pMCAO, comparing Semax-exposed animals with ischemic control animals. They reported that Semax mostly raised the expression of immune-system genes, with immunoglobulin and chemokine genes the largest group. The authors tied the peptide’s effects to immunomodulatory action and to influence on the vascular system (source 7). A 2017 follow-up by Medvedeva and colleagues compared Semax with Pro-Gly-Pro and reported that Semax raised the immunoglobulin heavy chain gene and affected cytokine, stress-response and ribosomal protein genes. Immune response was the process most affected, antigen-presentation and interferon signaling were amplified, and Pro-Gly-Pro under ischemia dampened immune activity and reduced neurotransmission-related expression. The authors proposed neuroimmune crosstalk as the route (source 8).

A 2021 paper by Sudarkina and colleagues moved to protein level in a transient middle cerebral artery occlusion model. They reported that active CREB rose in subcortical structures including the ischemic focus at 24 hours, that MMP-9 and c-Fos fell in the adjacent frontoparietal cortex, and that active JNK fell in both tissues (source 9).

How have analytical laboratories identified Semax?

Semax appeared in a forensic setting in 2020. Vanhee, Francotte, Janvier and Deconinck reported in Drug Testing and Analysis that two unknown preparations seized at the end of 2017 and in 2018 contained the research peptides Selank and Semax, which to the authors’ knowledge had not completed any clinical trials. An online search excluding the dark web showed such peptides sold as lyophilized powder and in nasal sprays, and the authors argued that controlling laboratories need to be able to identify them correctly (source 10).

The workflow is the same one laboratories use for any research peptide. The calculated [M+H]+ near 814.36 and [M+2H]2+ near 407.68 in the table above are the values a Semax spectrum would be checked against, and an identity result should be paired with a purity figure from a separate method. The guides to reading a peptide COA, mass spectrometry verification and HPLC purity testing cover those checks, and red flags when buying research peptides discusses the seizure literature more broadly.

What terms recur in the Semax literature?

ACTH(4-10)

The heptapeptide Met-Glu-His-Phe-Arg-Trp-Gly, residues 4 to 10 of ACTH, from which Semax was derived (sources 2, 4 and 11).

PGP

The C-terminal tripeptide Pro-Gly-Pro, tested on its own as a comparator in sources 5, 6 and 8.

BDNF

Brain-derived neurotrophic factor, measured as protein in the basal forebrain and as mRNA in the cortex (sources 2 and 6).

Trk receptors

TrkA, TrkB and TrkC, the neurotrophin receptor genes measured in the 2010 ischemia study (source 6).

pMCAO

Permanent middle cerebral artery occlusion, the rat ischemia model in sources 6 and 7.

IC50 and KD

The inhibitor concentration giving half-maximal inhibition (about 10 micromolar in source 1) and the dissociation constant of labelled-ligand binding (2.4 nM in source 2).

What remains unresolved in the Semax literature?

Several limits apply. The enzyme assay used human serum, the binding and gene-expression work used rat tissue, and the culture result used one cell type, so the findings do not form a single mechanism. The expression papers measured mRNA, and only the 2006 and 2021 papers reached protein (sources 2 and 9). The 2005 monoamine paper reported an effect on dopamine only in combination with d-amphetamine (source 4). The binding site in source 2 was characterized by its constants but not identified in the abstract reviewed.

Independence is also limited. N. F. Myasoedov is listed among the authors of sources 2, 4, 5, 6, 8, 9 and 12, and sources 6, 8 and 9 share several authors, so the rat ischemia findings come largely from one research network, and the sources reviewed did not include a replication by an unrelated group. The sources reviewed for this profile were read at abstract level, and results such as the BDNF fold changes in the hippocampus and the melanocortin-receptor activity of Semax could not be confirmed from primary text and are not reported. This profile prints no animal or human amounts or schedules. How an evidence base can change after publication is covered in the dihexa profile, where the journal retracted two mechanism papers in 2025.