Semax
ACTH(4-7)-PGP, Met-Glu-His-Phe-Pro-Gly-Pro, MEHFPGP, ACTH(4-10) analogue
Semax is a synthetic heptapeptide designed in the Soviet Union in the 1980s by taking the first four residues of the adrenocorticotropic hormone fragment ACTH(4-10) and attaching a Pro-Gly-Pro tail to slow enzymatic breakdown. It is registered as a nasal medicine in Russia for stroke and cognitive indications. It has never been through a large, independently run, placebo-controlled trial outside the former Soviet bloc, and there is no published controlled trial of it as a cognitive enhancer in healthy people.
Mechanism
Native ACTH(4-10) is Met-Glu-His-Phe-Arg-Trp-Gly. Semax keeps ACTH(4-7), which is Met-Glu-His-Phe, and replaces Arg-Trp-Gly with Pro-Gly-Pro. That substitution matters more than most summaries admit. His-Phe-Arg-Trp is the core pharmacophore through which melanocortins engage MC1R-MC5R; by discarding Arg-Trp, Semax loses the residues that drive receptor activation. This is why Semax produces neither the steroidogenic effect of ACTH at MC2R nor the pigmentary effect at MC1R, and it is why the widely repeated claim that Semax is an "MC4R agonist" overstates the evidence. Tritiated Semax does show saturable, specific binding to membranes prepared from rat basal forebrain, but the binding site has never been molecularly identified. Semax's direct receptor target remains, honestly, unknown.
What is reproducible downstream is transcriptional. Within roughly an hour of administration, rodent hippocampus and cortex show increased BDNF and NGF mRNA, increased TrkB message, and increased TrkB tyrosine phosphorylation, the canonical neurotrophin cascade feeding MAPK/ERK and PI3K/Akt. Genome-wide transcriptomic work in rat focal ischaemia complicates the neurotrophic story: the dominant signature there is immune and vascular, with Semax shifting inflammatory and angiogenesis-related gene sets in the ischaemic hemisphere rather than acting primarily as a neurotrophin inducer. Semax additionally alters dopaminergic and serotonergic turnover in rodents. A persistent confound runs through all of this: Semax is rapidly cleaved to Pro-Gly-Pro, which is itself biologically active, so effects attributed to the intact heptapeptide may partly belong to its metabolite.
What the research shows
The preclinical file is substantial and internally consistent. In rodent models of global and focal cerebral ischaemia, Semax reduces infarct volume, limits nitric oxide overproduction, and improves functional scores; in normal animals it raises BDNF/NGF transcription in hippocampus, frontal cortex and retina. The important caveat is provenance. Almost all of this work originates from a small cluster of Moscow institutes (principally the Institute of Molecular Genetics and the Institute of Molecular Biology of the Russian Academy of Sciences), often with the peptide's originators as co-authors. Independent Western replication of the core neuroprotection findings is essentially absent, and that is a structural weakness in the evidence base, not a minor one.
Human evidence is thin, old, and almost entirely Russian-language. The most cited clinical report is Gusev and colleagues' 1997 study in the acute period of hemispheric ischaemic stroke. Read closely, it is weaker than its reputation: 30 patients received Semax added to standard intensive therapy and were compared with a separately assembled control group of 80 patients given conventional therapy alone. There was no placebo, no described randomisation and no described blinding, and the two groups were of very unequal size. The report describes faster regression of general cerebral and focal (particularly motor) deficits, with daily doses of 12 mg in moderate strokes and 18 mg in severe strokes over courses of five and ten days. There are also small ophthalmology studies in optic nerve disease from 2000; the Polunin study allocated patients to intranasal drops, endonasal electrophoresis or a control condition, again as an add-on to standard neurotrophic and anti-inflammatory therapy, without a stated sample size. None of this work was independently replicated, and a search of ClinicalTrials.gov on 7 August 2026 returned no registered trial of Semax of any kind. Most importantly for how the compound is actually used: there is no published, adequately powered, double-blind trial of Semax as a nootropic in healthy adults. Every claim about focus, memory or productivity in a healthy user is an extrapolation from rodent transcriptomics and Russian stroke data.
Evidence assessment
Limited evidence
Human data exist but consist of small, non-randomised, Russian-language stroke and ophthalmology studies from a single research tradition, never independently replicated and never registered, with no controlled trial at all in the healthy-user population that drives its sale.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain Preclinical only
Tritiated Semax showed saturable specific binding to basal forebrain membranes and raised BDNF protein levels, though the binding site itself was not molecularly identified.
The heptapeptide SEMAX stimulates BDNF expression in different areas of the rat brain in vivo Preclinical only
A single administration of Semax increased BDNF expression across several rat brain regions.
Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents Preclinical only
Semax altered dopaminergic and serotonergic turnover in rodent brain, indicating monoaminergic effects additional to any neurotrophic action.
The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis Preclinical only
The dominant transcriptional response to Semax after focal ischaemia involved immune and vascular gene sets rather than a primarily neurotrophic signature.
Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study) Limited evidence
Adding Semax was reported to increase the rate of regression of general cerebral and focal, especially motor, deficits. The unequal, separately assembled control group and the absence of any described randomisation or blinding mean the effect estimate cannot be relied on, and the study has never been independently replicated or registered.
Evaluation of therapeutic effect of new Russian drug semax in optic nerve disease Limited evidence
Reported improvement in visual acuity, visual field, electrical sensitivity and conductivity of the optic nerve, and colour vision when Semax was added to standard therapy.
Kinetics of Semax penetration into the brain and blood of rats after its intranasal administration Preclinical only
Semax reached brain tissue rapidly after intranasal dosing while being cleared from blood within minutes, with the Pro-Gly-Pro fragment predominating among detectable species.
N-terminal degradation of ACTH(4-10) and its synthetic analog semax by the rat blood enzymes Preclinical only
Semax is degraded from the N-terminus by blood aminopeptidases, establishing the very short plasma survival of the intact heptapeptide.
Safety
Adverse effects reported in Russian clinical use are minor and mostly local: nasal irritation and transient headache with the intranasal formulation. There is no reported cardiovascular or endocrine signal, which is mechanistically coherent given the loss of melanocortin receptor activity. But the safety record rests on exactly the same small, non-independent literature as the efficacy record. There is no long-term controlled safety study, no formal toxicology package published to modern regulatory standards in English, and no data at all on chronic use by healthy adults, which is the dominant real-world use. Material sold online as "research grade" is not manufactured under pharmaceutical GMP, and identity, purity and endotoxin content are not independently verified.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation from the MHRA. Semax is not a controlled drug, but as an unlicensed medicinal product it may not lawfully be sold, supplied or advertised for human use under the Human Medicines Regulations 2012. Personal import and online sale operate outside that framework. |
| United States | Not FDA-approved for any indication, and no US marketing application has ever been completed. Semax has been nominated as a bulk drug substance for pharmacy compounding under section 503A of the Federal Food, Drug and Cosmetic Act; FDA has treated a number of research peptides in that nomination process as raising significant safety concerns, which means a compounding pharmacy may not lawfully use them while the review is unresolved. This monograph was unable to verify Semax's exact current placement on FDA's 503A bulks lists from primary FDA sources at the time of writing, and readers who need the authoritative position should consult FDA's published lists directly. In practice Semax circulates in the US as an unapproved substance sold under a "research use only" label. |
| WADA (sport) | Not named on the WADA Prohibited List and not clearly captured by any current category. Athletes should note that WADA's S0 (non-approved substances) provision covers pharmacological substances with no current regulatory approval for human therapeutic use in the relevant jurisdiction, which is a plausible route to prohibition for compounds of this kind. |
Questions
It is registered as a medicine in the Russian Federation, where it is supplied as a nasal formulation for cerebrovascular and cognitive indications and, at a lower strength, in ophthalmology. It has no marketing authorisation in the United States, the United Kingdom or the European Union, and no regulator outside the post-Soviet region has assessed it.
Nobody has measured it properly. The BDNF and TrkB findings come from rat hippocampus, cortex and retina. There is no published human study measuring central BDNF after Semax administration, and peripheral blood BDNF is a poor proxy for brain levels in any case.
Not in any straightforward sense. Semax lacks the Arg-Trp residues that form the core His-Phe-Arg-Trp pharmacophore for melanocortin receptors, which is precisely why it has none of ACTH's hormonal activity. Specific binding has been demonstrated in rat basal forebrain membranes, but the receptor has never been identified.
Weaker than it is usually presented. The most-cited report gave Semax to 30 stroke patients and compared them with a separately assembled group of 80 patients on conventional therapy: no placebo, no described randomisation, no described blinding, and very unequal groups. That design cannot separate a drug effect from differences between the two populations.
No published controlled trial has tested that. The human literature concerns stroke patients and optic nerve disease, in small Russian-language studies from the 1990s and 2000s. Claims about focus or memory in healthy users are extrapolation, not evidence.