Selank vs Semax: two Russian peptides compared

Set Selank vs Semax side by side and the first thing that stands out is what the two share. Both are short synthetic peptides, each seven amino acids long ^[9], and a 2022 review of peptide medicines registered in Russia lists Semax as a nootropic drug and Selank as an anxiolytic ^[14]. Each is a natural regulatory fragment with the same three-residue tail, Pro-Gly-Pro, added at one end ^[8], ^[13]. The sections below cover what each peptide is made of, what the published studies propose about how each works, what the human studies measured, how the two differ, and where each stands with regulators.

Semax has the sequence Met-Glu-His-Phe-Pro-Gly-Pro ^[6]. The papers describe it as an analogue of the N-terminal fragment 4-10 of adrenocorticotropic hormone (ACTH) ^[6]; a 2023 review puts it more narrowly, saying that the N-terminus of Semax contains an ACTH(4-7) fragment and that the C-terminus is stabilised by the added Pro-Gly-Pro ^[13]. The 2022 review credits its synthesis to scientists at the Institute of Molecular Genetics of the Russian Academy of Sciences, working under the guidance of two academicians, I. P. Ashmarin and N. F. Myasoedov ^[14].

Selank has the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro ^[9]. It is a synthetic analogue of tuftsin, the short Thr-Lys-Pro-Arg fragment of the heavy chain of human immunoglobulin G ^[8]. According to a 2016 paper on its gene-expression effects, the molecule was elongated at the C terminus by three natural L-amino acids, Pro-Gly-Pro, to improve its metabolic stability and give a relatively longer duration ^[8]. A 2017 paper on the behaviour of rats given either peptide calls the parent molecule immunomodulatory ^[12].

Read side by side, the two sequences make the design plain. The last three residues are identical, Pro-Gly-Pro, and the first four differ: Met-Glu-His-Phe for Semax, from the hormone fragment, and Thr-Lys-Pro-Arg for Selank, from tuftsin ^[6], ^[8], ^[9]. The sources that explain the tail give the same reason for it in both cases, namely stability against breakdown ^[8], ^[13].

In a serum assay, the seven-residue forms of both peptides and their pentapeptide fragments inhibited enkephalin-degrading enzymes, while the tri-, tetra- and hexapeptide fragments did not ^[9]. The assay was in vitro.

One proposal for how Semax works is that it raises brain-derived neurotrophic factor (BDNF), a protein involved in the plasticity of synapses. In a 2006 study in rats, the authors first noted an earlier observation that Semax stimulated BDNF synthesis in astrocytes cultured from the rat basal forebrain, and then examined the living brain ^[6]. Membranes from the basal forebrain contained specific, reversible, calcium-dependent binding sites for radiolabelled Semax, with a dissociation constant (KD) of 2.4 ± 1.0 nM and a BMAX of 33.5 ± 7.9 fmol/mg protein ^[6]. After the peptide was applied to the rats, BDNF protein rose within 3 hours in the basal forebrain, but not in the cerebellum ^[6]. The authors concluded that the cognitive effects of Semax might be associated, at least in part, with higher BDNF in that region ^[6].

A second line of work asks what Semax does to gene activity when the brain is short of blood. In a 2014 genome-wide study, rats underwent permanent occlusion of the middle cerebral artery, a standard model of stroke, and the activity of genes in the affected cortex was compared with and without Semax at 3 and 24 hours ^[7]. Genes related to the immune system made up over 50% of the genes whose expression Semax altered, and chemokine and immunoglobulin genes formed the most notable groups ^[7]. Semax also altered the expression of 24 genes related to the vascular system at 3 hours and 12 at 24 hours, genes the authors link to the development and migration of endothelial tissue, vasculogenesis and related processes ^[7]. The authors concluded that the immune response is the process most markedly affected, and that this immunomodulating effect and the effect on the vascular system are likely to be key mechanisms of the peptide's neuroprotective action ^[7].

The same theme appears in people, though only at the level of a blood marker. In a 2018 study of patients after ischaemic stroke, plasma BDNF was measured in groups that did and did not receive Semax, and the authors reported that Semax increased plasma BDNF levels, which stayed high through the study period ^[3]. The study did not say it was blinded or randomised, and a rise in BDNF in the blood does not show what happened in the brain tissue ^[3]. It does fit the direction of the rat finding, and nothing more should be drawn from it.

Taken together, the Semax mechanism data are of three kinds: binding and a protein level in rat brain tissue ^[6], changes in gene expression in a rat stroke model ^[7], and a plasma marker in patients ^[3]. Each is an association between giving the peptide and a measurement. None is a demonstration that BDNF, or any one gene, is the route by which the peptide produces a clinical effect, and the authors of these papers frame them as proposals.

For Selank, the leading proposal is that it acts on the GABA system, the brain's main inhibitory signalling pathway, which is also the target of benzodiazepine tranquillisers. A 2016 paper starts from the clinical observation that Selank and classical benzodiazepines such as diazepam and phenazepam show a similar spectrum of physiological effects, and tests whether a similar mechanism lies behind it ^[8]. The authors measured the expression of 84 genes involved in neurotransmission in the frontal cortex of rats 1 and 3 hours after giving Selank or GABA (300 μg/kg) ^[8]. Expression of 45 genes changed significantly 1 hour after the compounds, and 22 genes changed at 3 hours ^[8].

The two profiles overlapped but did not match. Twenty-five of the 45 genes changed after either compound, four (Drd1a, Drd2, Ptgs2 and Slc6a13) changed only after Selank, and 16 changed only after GABA ^[8]. The authors found a positive correlation between the changes caused by the two compounds, and they described one possible molecular mechanism of Selank as allosteric modulation of the GABAergic system, while also stating that the match between the expression profiles was not perfect ^[8].

A second study looked at the receptor more directly. Using radioligand binding on membranes isolated from brain cells, the authors reported that Selank affected the binding of radiolabelled GABA as a positive allosteric modulator ^[10]. The combined action of Selank and some benzodiazepines was not cumulative and differed from either substance alone, and Selank was able to block the modulatory activity of diazepam and of olanzapine ^[10]. The authors judged that the binding sites of the peptide and of the benzodiazepine were apparently not the same but might partly overlap, and they concluded that one of Selank's anti-anxiety mechanisms can be associated with subtype-selective, concentration-dependent allosteric modulation of GABA receptors ^[10].

The gene-expression study reported changes in genes involved in neurotransmission, among them GABA receptor subunits, transporters, ion channels, and dopamine and serotonin receptors ^[8]. The 2017 rat study describes the parent molecule, tuftsin, as immunomodulatory ^[12].

The same caution applies as for Semax. The gene-expression work was done in rat frontal cortex, the binding work on isolated membranes, and the enkephalin assay in human serum in a test tube ^[8], ^[9], ^[10]. The authors of the receptor paper describe their conclusion as a hypothesis that their experiments support, not as a settled account of what the peptide does in a person ^[10].

The human evidence on these peptides is small and old by the standards of modern drug trials. The five human studies described here were published between 1997 and 2020, mostly in Russian journals, and range from 30 to 110 participants ^[1], ^[2], ^[3], ^[4], ^[11]. Two additional sources are reviews, one of the Semax clinical literature in stroke and one of peptide drug development in Russia ^[5], ^[14]. The figures below are therefore descriptions of what small studies reported and not estimates of what the peptides do.

Semax was studied mainly in ischaemic stroke. The 1997 study compared 30 patients given Semax with 80 controls on conventional therapy, and the authors reported that Semax had some influence on the rate of recovery of neurological function, especially motor function ^[4]. The 2018 study, 21 years later, measured plasma BDNF, motor performance and the Barthel index of daily function in 110 patients in early and late rehabilitation groups ^[3]. Both are described without any statement of blinding, and the 2018 abstract states no randomisation, which leaves room for differences between the groups that were present before treatment ^[3], ^[4].

Selank was studied in anxiety disorders. Zozulia and colleagues compared it with the benzodiazepine medazepam in patients with generalised anxiety disorder and neurasthenia and reported similar anxiolytic effects ^[1]. Medvedev and colleagues compared phenazepam alone with phenazepam plus Selank and reported that the combination reached an effect earlier on one scale and reduced side-effects of the tranquilliser ^[2]. PubMed indexes both as randomised trials, but the abstracts do not say whether either trial was blinded ^[1], ^[2].

A 2024 review of clinical studies of Semax in ischaemic stroke concluded, from the studies its authors gathered, that the peptide was clinically effective in the acute and recovery periods of stroke and in both atherothrombotic and cardioembolic subtypes ^[5].

Only one human study gave both peptides. In the 2020 resting-state fMRI study, 52 healthy participants were scanned three times, before and 5 and 20 minutes after Semax, Selank or placebo ^[11]. The authors mapped how strongly each of four regions, the amygdala and the dorsolateral prefrontal cortex in each hemisphere, was connected to the rest of the brain ^[11]. They reported group and condition differences in connectivity between the right amygdala and a region spanning the fusiform, inferior and middle temporal and parahippocampal gyri of the right hemisphere, and described both general and specific effects of the two peptides on the link between the right amygdala and the right temporal cortex ^[11]. This is a brain-imaging finding in healthy people. It does not say that either peptide changes anxiety or cognition, and it was not a trial in patients.

Two further comparisons are not in people. In rats with parkinsonism-like damage from the toxin 6-OHDA, neither peptide affected motor activity or passive defensive behaviour, while Selank decreased the animals' anxiety in an elevated cross-shaped maze ^[12]. In the human serum assay, both peptides inhibited enkephalin-degrading enzymes, Semax at an IC50 of 10 µM and Selank at 20 µM ^[9]. No source in this guide reports a head-to-head trial of the two peptides in patients.

The comparison is clearest by origin, target and evidence base. Semax comes from a hormone fragment, has been studied chiefly in stroke and cognition, and has the more extensive rat work on BDNF and gene expression ^[3], ^[4], ^[6], ^[7], ^[13]. Selank comes from tuftsin, has been studied chiefly in generalised anxiety and neurasthenia, and has the rat and in vitro work on GABA binding and gene expression ^[1], ^[2], ^[8], ^[10]. A 2022 review lists Semax as a registered nootropic drug and Selank as a registered anxiolytic in Russia ^[14].

Several questions remain open, and the limits set out in the human-studies section apply to each. The mechanism data come mostly from rats and from test-tube work, in which a change in a gene or a protein was measured and its cause was not shown ^[6], ^[7], ^[8], ^[10]. The Semax findings come from stroke and the Selank findings from anxiety, so a difference between the two in the literature may reflect what each was tested in, not what each does.

A 2022 review of Russian peptide medicines lists Semax as a nootropic drug and Selank as an anxiolytic among 14 peptide-based products it records as registered in the Russian Federation ^[14], a registration that applies in that country. The review's authors state that the neuroprotective effects of Semax have been established in vitro and in animal models of cerebral ischaemia, as well as under clinical conditions ^[14]; that is their summary, to be read with the study-level limits above.

The United States Food and Drug Administration (FDA) page on certain bulk drug substances for use in compounding lists "Selank acetate (TP-7)" and "Semax (heptapeptide)" among substances previously in category 2 of its interim policies that were withdrawn by the nominators ^[15]. For Selank, the FDA says it lacks important information regarding any safety issues raised by selank acetate administered to humans, and that compounded drugs containing it may pose a risk of immunogenicity for certain routes of administration because of potential aggregation and peptide-related impurities ^[15]. For Semax, it says it has no, or limited, safety-related information for proposed routes of administration, and therefore lacks sufficient information to know whether the drug would cause harm if administered to humans ^[15]. The page is described as current as of 22 April 2026, and a withdrawn nomination is not an approval of any kind ^[15].

No source in this guide records a marketing authorisation for either peptide from the MHRA, the EMA, the FDA or Colombia's INVIMA, and the FDA says it lacks information on their safety in humans ^[15].