Compound reference
Semax
Semax is a synthetic ACTH(4-7)-PGP heptapeptide, approved in Russia for ischemic stroke and used widely as a nootropic. It has a real mechanistic and clinical literature — but one that is overwhelmingly a single Russian research tradition, with little independent Western replication and no FDA approval.
- CAS
- 80714-61-0
- Formula
- C₃₇H₅₁N₉O₁₀S
- Molar mass
- ≈813.9 g/mol
- Sequence
- Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP) — ACTH(4-7) plus a Pro-Gly-Pro stabilizer
Regional/research peptide; not FDA-approved as a drug in the United States.
Mode of action
Semax is a synthetic heptapeptide, Met-Glu-His-Phe-Pro-Gly-Pro. Its front half is ACTH(4-7) — the melanocortin core of adrenocorticotropic hormone — and its back half is the tripeptide Pro-Gly-Pro (PGP), grafted on to slow enzymatic breakdown. That design gives Semax two defining traits: it is far more stable than the native ACTH fragment, and it keeps the neuroactive properties of the melanocortin core while lacking ACTH's hormonal (steroidogenic) action. It is given intranasally, which lets it reach the brain.
Mechanistically the best-characterized effect is on neurotrophins: Semax raises BDNF and NGF and increases TrkB receptor signaling in the hippocampus, a plausible substrate for both its cognitive and its neuroprotective claims. After experimental stroke, genome-wide studies show Semax shifting the brain transcriptome — upregulating immune, vascular, and neurotrophic genes while damping inflammatory and cell-death programs. It also modulates dopaminergic and serotonergic systems and inhibits the enzymes that degrade enkephalins, raising effective enkephalin levels. The mechanistic picture is coherent; the caveat is that most of it comes from one research lineage.
Main intended effect
Nootropic and neuroprotective — improving attention, learning, and memory, and protecting or aiding recovery of brain tissue after ischemic injury.
Areas of interest
The lead clinical indication is acute ischemic stroke, for which Semax is approved and used in Russia; related uses there include post-hypoxic encephalopathy, optic neuropathy, and cognitive or attention disorders. Outside Russia it circulates as a "nootropic" — a research peptide and nasal spray used off-label for focus and cognition.
Evidence for intended effects
Semax is unusual among research peptides in having genuine clinical use: it is a registered drug in Russia, and Russian trials support its stroke indication. A controlled study in acute hemispheric ischemic stroke reported faster regression of neurological deficits when Semax was added to standard care, and a later 110-patient study found that Semax raised plasma BDNF, with higher BDNF tracking better functional and motor recovery. Underneath sits a deep preclinical literature on BDNF/TrkB, ischemic transcriptomics, and monoamine effects.
The honest qualifier is provenance. That body of work is overwhelmingly Soviet and Russian, from a single connected research tradition, with limited independent replication in Western peer-reviewed literature and few modern double-blind, placebo-controlled trials by international standards. The key stroke studies were not randomized. And for the cognitive-enhancement use that drives its Western popularity, rigorous human evidence is thin — a forensic analysis of seized nootropic preparations noted that Semax had not completed clinical trials in the regulatory sense even as it was sold freely online.
| Strand | What exists | Tier |
|---|---|---|
| Ischemic stroke | Russian controlled + non-randomized clinical studies; approved in Russia | Regional clinical (limited replication) |
| Mechanism | BDNF/TrkB, ischemic transcriptomics, monoamine, enkephalinase | Strong preclinical (single tradition) |
| Cognitive enhancement | Animal nootropic data; no rigorous human RCTs | Weak human |
Studied amounts (literature dosing context)
In Russian stroke trials Semax was dosed intranasally and scaled to severity — for example 12 mg/day for moderate and 18 mg/day for severe stroke in one study, and two 6 mg/day courses of ten days each in another. Nootropic use is generally at substantially lower intranasal doses. These are regional-trial and off-label figures; there is no FDA-approved dose, and this page does not provide dosing guidance.
Safety and regulatory status
Within its Russian clinical use Semax is described as well tolerated, consistent with its lack of ACTH-like hormonal activity. That tolerability record, however, comes largely from the same regional literature and has not been characterized in large independent trials. Semax is not approved by the FDA or EMA and is not on a Western approval path. It is sold internationally as a gray-market research peptide — found in seized preparations and offered online as powder or nasal spray — so any such product is of unverified identity and purity. Semax is the close counterpart of Selank, the tuftsin-derived peptide from the same research program.
Sources
Semax, an ACTH(4-10) analogue with nootropic and neuroprotective properties
Narrative review in Neuroscience and Behavioral Physiology consolidating the preclinical and clinical literature on Semax, a synthetic heptapeptide analogue of ACTH(4-10), presenting its nootropic and neuroprotective properties to an English-language audience. The review covers Semax's modulation of dopaminergic and serotonergic systems, upregulation of BDNF and other neurotrophins, and protection against ischemic neuronal injury via attenuation of nitric oxide overproduction. Reported clinical applications include acute ischaemic stroke, post-hypoxic encephalopathy, optic neuropathy, and cognitive enhancement, primarily from Russian-language trials. The body of supporting evidence derives predominantly from Soviet and Russian research programs, with limited independent replication in Western peer-reviewed literature.
Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus
Preclinical study in rats (Brain Research 2006, PMID 16996037) showing that a single intranasal dose of Semax at 50 µg/kg body weight produced coordinated hippocampal neurotrophin responses: BDNF protein increased 1.4-fold, TrkB tyrosine phosphorylation increased 1.6-fold, BDNF exon III mRNA increased approximately 3-fold, and TrkB mRNA increased approximately 2-fold. Treated animals also showed an increase in the number of conditioned avoidance reactions, suggesting improved learning. The authors conclude that Semax modulates cognitive function by upregulating hippocampal BDNF/TrkB signaling, a pathway central to synaptic plasticity. These findings are from a single-dose rodent experiment and have not been replicated in human brain tissue.
The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis
Genome-wide transcriptional study (BMC Genomics 2014, PMID 24661604) examining Semax effects on gene expression in a rat model of permanent middle cerebral artery occlusion (pMCAO) at 3 and 24 hours post-stroke. More than 50% of Semax-induced transcriptional changes involved immune system genes, including upregulation of immunoglobulin and chemokine genes. Vascular-related genes were also affected: 24 genes at 3 hours and 12 genes at 24 hours, encompassing endothelial development, smooth muscle cell migration, hematopoiesis, and vasculogenesis. The authors propose that Semax's neuroprotective action operates primarily through immunomodulation and vascular system regulation during ischemia rather than direct neuronal targets. These transcriptomic findings are from a permanent occlusion rat model and may not fully translate to human ischaemic stroke.
Semax and Selank inhibit the enkephalin-degrading enzymes from human serum
In vitro biochemical study (Bioorganicheskaia Khimiia 2001, PMID 11443939) testing Semax and Selank as inhibitors of enkephalin-degrading enzymes (enkephalinases) in human serum. Both heptapeptides dose-dependently inhibited enkephalin degradation: Semax displayed an IC50 of approximately 10 µM and Selank an IC50 of approximately 20 µM, each more potent than the reference inhibitors puromycin (IC50 10 mM) and bacitracin. Pentapeptide fragments of each compound retained inhibitory activity, while tri-, tetra-, and hexapeptide fragments did not, indicating a length-dependent structural requirement. The authors propose that inhibition of endogenous enkephalin degradation, thereby prolonging opioid-peptide signaling, represents one mechanistic component of the anxiolytic and stress-protective effects of both peptides. This is an in vitro human serum assay; extrapolation to in vivo CNS enzyme inhibition requires further study.
Nootropic activity of the ACTH4-10 analog semax (MEHFPGP) in rats
Early preclinical report (Zhurnal Vysshei Nervnoi Deyatelnosti imeni I.P. Pavlov 1996, PMID 9054168) characterising nootropic activity of the synthetic ACTH(4-10) analogue Semax (Met-Glu-His-Phe-Pro-Gly-Pro) in rat behavioural models of learning and memory. The study evaluated cognitive-enhancing effects using standard rodent paradigms sensitive to nootropic compounds. Semax demonstrated facilitation of learning-related performance, establishing early in vivo evidence for the peptide's nootropic profile. As a Russian-language journal report from 1996, the full methodological details including doses, route of administration, and effect sizes are not available in the English abstract; findings are therefore described qualitatively. Results are from animal behavioural experiments and have not been validated in controlled human cognitive studies.
Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study)
Controlled clinical and electrophysiological study published in Zh Nevrol Psikhiatr evaluating Semax added to standard intensive therapy in the acute period of hemispheric ischemic stroke. Thirty patients received Semax at 12 mg (moderate severity) or 18 mg (severe stroke) over 5–10-day courses, compared with 80 conventionally treated controls of comparable stroke severity. Semax was associated with accelerated regression of general cerebral and focal motor deficits. Electrophysiological monitoring via EEG mapping and somatosensory evoked potentials tracked changes in brain functional state during treatment. The authors conclude that Semax has a clinically meaningful adjunctive role in acute ischemic stroke management, with dosing guided by stroke severity.
The efficacy of Semax in the treatment of patients at different stages of ischemic stroke
Clinical trial (Gusev, Martynov and colleagues) published in Zh Nevrol Psikhiatr, enrolling 110 post-ischemic stroke patients (43 men, 67 women; mean age 58.0±9.7 years). Semax was administered as two 6,000 mcg/day courses for 10 days each with a 20-day interval; patients were followed for 5 months. Semax significantly elevated plasma BDNF levels, which remained elevated throughout the observation period; higher BDNF correlated positively with Barthel Index improvement (functional independence) and with motor recovery on the MRC scale. Early rehabilitation (mean ~89 days post-stroke) potentiated BDNF-associated functional gains compared with late rehabilitation (~214 days). The study was non-randomized, limiting causal inference, but supports BDNF elevation as a mechanistic link between Semax and accelerated post-stroke recovery.
The occurrence of putative cognitive enhancing research peptides in seized pharmaceutical preparations
Forensic and analytical study (Vanhee, Francotte, Janvier, and Deconinck, Drug Testing and Analysis 2020) reporting detection of the cognitive-enhancing research peptides Semax and Selank in pharmaceutical preparations seized by controlling agencies. The authors note that, despite being marketed and used as nootropics, these peptides had not completed any clinical trials in the Western regulatory sense, and an accompanying online survey found them freely available as lyophilized powder for injection or in nasal sprays. They developed a liquid chromatography–tandem mass spectrometry method to identify such peptides and framed the seizures as an incentive for regulators to prepare for further encounters. Illustrates the gray-market reality and unverified provenance of Semax and Selank products sold outside their countries of regional approval.
Evaluation of Research Grade Peptides Marketed Directly to Consumers Reveals Extensive Variability in Purity and Measured Abundance
Analysis (Mendias and Awan, preprint, 2026) of 6,441 gray-market peptide samples across fourteen compounds — including ipamorelin, BPC-157, CJC-1295, GHK-Cu, PT-141, retatrutide, semaglutide, sermorelin, TB-500, tesamorelin, and tirzepatide. Applying two quality-acceptance frameworks, between 41.6% and 71.1% of samples failed to meet basic quality criteria, and about 15% showed measurable endotoxin contamination. The study quantifies how often directly-marketed "research grade" peptides miss purity and content benchmarks — a central safety concern for any non-pharmaceutical source.