TL;DR
The ACTH fragment that still does the brain stuff without touching cortisol. Russian-approved for stroke.
What: Seven amino acids: Met-Glu-His-Phe-Pro-Gly-Pro. ACTH(4-7) with a Pro-Gly-Pro tail for stability. Developed at the Russian Academy of Sciences in the 1980s.
Does: Activates MC4R in hippocampus, cortex, and basal forebrain. Induces BDNF and NGF transcription. Blocks enkephalinase. Plasma half-life under five minutes; behavioral effects last a full day.
Evidence: Gusev and Skvortsova 1997 (PMID 11517472) hit neurological recovery endpoints in 30 acute stroke patients — basis for Russian registration. Dolotov 2006 (PMID 16635254) showed basal-forebrain BDNF elevation in three hours. Volkova 2006 (PMID 16996037) mapped the hippocampal BDNF/TrkB regulation.
Used by: Russian neurologists for acute stroke, TIA, and asthenia; pediatricians for attention disorders; Western community users intranasally for focus.
Verdict: Real stroke-adjunct signal from the Gusev team. Cognitive claims are mechanism-plausible, Russian-evidenced, and waiting on a Western Phase 3 replication.
What It Is
Semax is a synthetic heptapeptide with the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP). It is a modified analog of the ACTH(4-7) fragment of adrenocorticotropic hormone, to which a Pro-Gly-Pro tail has been added to improve metabolic stability. The molecule retains ACTH's neurotrophic and cognitive effects while losing ACTH's hormonal (cortisol-stimulating) activity — a cleaner pharmacological footprint that made it suitable for clinical development.
Development of Semax began in the 1980s at the Institute of Molecular Genetics of the Russian Academy of Sciences under the direction of Academician Nikolai Myasoedov and Professor Igor Ashmarin. The same laboratory system later produced Selank. Semax is registered and in clinical use in Russia for two distinct indications, each with its own formulation: a 0.1% intranasal solution for adjunctive treatment of acute ischemic stroke and transient ischemic attacks, and a 1.0% intranasal solution for cognitive/nootropic use in asthenic conditions. The stroke indication is supported by multiple Russian-language randomized trials, including studies by Gusev and Skvortsova demonstrating improved neurological recovery when Semax is added to standard acute stroke care.
In the Western optimization and nootropic community, Semax is best known as a fast-acting intranasal cognitive enhancer. Its mechanism — potent upregulation of BDNF and NGF via MC4R activation — is mechanistically credible for cognitive benefit, and its short plasma half-life coupled with long-duration CNS action (through gene-expression changes) gives it a characteristic "brief dose, extended effect" profile.
Semax is not FDA-approved. It is not currently a controlled substance in the US. It is not on the FDA Category 2 list. Community use is through imported Russian pharmacy product or gray-market research-chemical powder reconstituted for intranasal administration. Modified analogs — notably N-Acetyl Semax Amidate — are marketed as longer-duration versions in the same research-chemical supplier landscape.
Mechanism of Action
Semax's mechanism is centered on melanocortin-receptor-mediated regulation of neurotrophin expression, but it is genuinely pleiotropic across monoamines, enkephalins, and neuroinflammation.
- MC4R-mediated BDNF and NGF induction (primary) — Semax binds melanocortin-4 receptors (MC4R) in hippocampus, cortex, and basal forebrain. MC4R activation triggers cAMP/PKA and MAPK/ERK cascades that enhance transcription of BDNF, NGF, and GDNF genes. Intranasal Semax at 50–250 μg/kg elevated BDNF protein in rat basal forebrain within 3 hours (Dolotov et al., 2006; PMID 16635254).
- BDNF-TrkB signaling — Downstream of BDNF induction, TrkB receptor activation drives synaptic plasticity, long-term potentiation, and neurite outgrowth. The hippocampal BDNF/TrkB system is the proximal substrate for Semax's cognitive and learning effects (Volkova et al., Brain Res 2006; PMID 16996037).
- Monoamine modulation — Rapid activation of serotonergic and dopaminergic systems. Semax raises dopamine and serotonin metabolism in striatum, prefrontal cortex, and hippocampus — contributing to the "focused, motivated" phenotype users report.
- Enkephalin half-life extension — Like Selank, Semax inhibits peripheral and central enkephalin-degrading enzymes, prolonging endogenous enkephalin signaling (Kost et al., 2001). Contributes to mild anxiolytic and analgesic effects.
- Anti-ischemic / neuroprotective (stroke) — In cerebral ischemia-reperfusion models, Semax reduces infarct size, preserves neurological function, and upregulates neurotrophin expression in salvageable penumbra tissue (Shadrina et al., multiple; Filippenkov et al., Genes 2020).
- Anti-inflammatory cytokine modulation — Reduces TNF-α, IL-1β, and IL-6 expression in stress and ischemia models; modulates microglial activation toward anti-inflammatory phenotype after neural injury.
- Antioxidant signaling — Upregulates endogenous antioxidant enzymes and reduces oxidative stress markers in ischemic and stress models.
- Attention, working memory, executive function — Behavioral studies and controlled attention tests in humans document improved vigilance, reaction time, working memory span, and executive control after single-dose and short-course Semax.
- Intranasal CNS delivery — Delivery via olfactory and trigeminal nerve pathways produces direct nose-to-brain transport, achieving higher CNS concentrations faster than systemic delivery would predict.
- Plasma-CNS disconnect — Plasma half-life is <5 minutes, but behavioral/cognitive effects persist 12–24+ hours because BDNF/NGF gene-expression changes outlast parent drug presence.
- No HPA axis stimulation — Despite ACTH-derived origin, Semax does not elevate cortisol. The modification that removes the ACTH(10-39) C-terminal hormonal segment preserves the neurotrophic effect while abolishing the corticotropic effect.
What the Research Shows
The Semax evidence base is split between an established Russian-language literature and a growing English-language mechanistic corpus.
- Acute hemispheric ischemic stroke (Gusev, Skvortsova et al., 1997; PMID 11517472) — Pivotal Russian trial. 30 patients in acute hemispheric ischemic stroke; Semax in combined intensive therapy accelerated recovery of damaged neurological functions in clinical and electrophysiological endpoints. Basis for Russian registration.
- Carotid ischemic stroke recovery (Skvortsova et al., 2002) — Effect of Semax on disability and handicap indexes in carotid ischemic stroke survivors.
- Basal forebrain BDNF binding and elevation (Dolotov et al., J Neurochem 2006; PMID 16635254) — Specific binding and elevation of BDNF protein in rat basal forebrain after intranasal Semax at 50–250 μg/kg within 3 hours.
- Hippocampal BDNF/TrkB regulation (Volkova et al., Brain Res 2006; PMID 16996037) — Semax regulates BDNF and trkB expression in the rat hippocampus.
- Neurotrophin gene expression (Agapova et al., Neurosci Lett 2007) — Regulation of BDNF, NGF, GDNF, and their receptor genes across multiple brain regions.
- Cerebral ischemia transcriptome (Filippenkov et al., Genes 2020) — ACTH(4-7)-PGP activates transcription of neurotrophins and their receptor genes after cerebral ischemia-reperfusion in rats.
- Enkephalinase inhibition (Kost et al., 2001; PMID 11443939) — Semax and Selank inhibit enkephalin-degrading enzymes from human serum.
- Learning and memory in aged rats (Storozheva et al., 2007) — Effects of Semax on different forms of learning and memory.
- Cognitive enhancement in asthenia — Russian clinical studies supporting the 1.0% nootropic formulation.
- Pediatric attention disorders — Russian clinical studies in children with attention and behavioral disorders.
- Optic nerve / retinal protection — Studies on Semax in optic neuropathy and glaucoma suggesting neuroprotective benefit.
- BDNF plasma response in stroke patients — Documented elevation of circulating BDNF after short-course Semax in stroke.
Honest Evidence Framing
Semax's strongest human evidence is for adjunctive use in acute ischemic stroke — a specific, clinically important indication with Russian Phase 3 support. For general cognitive enhancement, focus, and attention in healthy adults, evidence is largely Russian-language, open-label, and mechanism-grounded rather than placebo-controlled at a scale Western regulators would require. The mechanism is credible; expectations should be calibrated to "modest, real, measurable" rather than "transformative."
Human Data
Semax has a substantial Russian clinical dataset, particularly in acute ischemic stroke.
- Russian Phase 3 — ischemic stroke (Gusev 1997; PMID 11517472) — Multiple trials supporting Russian regulatory approval for acute ischemic stroke. Improved neurological recovery in adjunctive use.
- Transient ischemic attack — Semax included in Russian clinical protocols for TIA management.
- Cognitive enhancement in asthenia — Russian clinical studies supporting the 1.0% nootropic formulation.
- Pediatric ADHD / attention disorders — Russian clinical studies in children with attention and behavioral disorders.
- Optic nerve disorders — Russian ophthalmology case series for optic neuropathies.
- Post-surgical cognitive recovery — Small studies exploring use post-neurosurgery and post-anesthesia.
- Healthy adult nootropic studies — Smaller attention, working-memory, and reaction-time studies.
- BDNF plasma response in humans — Documented increase in circulating BDNF after short-course Semax in stroke patients.
Absent from the dataset: a modern FDA- or EMA-regulated Phase 3 trial. All rigorous clinical evidence is Russian. Western mechanistic and preclinical work is growing but has not yet produced registrational-grade clinical trials.
Dosing from the Literature
Russian-approved formulations (0.1% and 1.0% intranasal solutions) plus community practice provide the dosing framework.
| Protocol | Dose | Frequency | Notes |
|---|
| Ischemic stroke (Russian acute protocol) | Gusev protocol approx. 6 mg/day total (mg-range) | Acute care period, up to 10 days | High-dose acute neuroprotective; hospital-administered. |
| Nootropic / cognitive (Russian 1% label) | ~300–600 μg per dose | 2–3 drops per nostril, 2–3× daily | Standard cognitive-enhancement dose. |
| Community intranasal (research vial) | 300–600 μg | 1–3× daily, AM/midday | Typical dose for focus, attention, productivity. |
| High-dose cognitive | 600–1,000 μg | 1–2× daily | Used by some for more demanding cognitive tasks. |
| Acute "focus boost" | 300–500 μg | PRN, single dose | Onset 15–30 min; duration 4–8 hr subjective, 12–24+ hr downstream neurotrophic effect. |
| Cycle length | 2–4 weeks on | — | Followed by 1–2 weeks off. Continuous use reported safe but cycling is prudent. |
Dosing Disclaimer
Semax for stroke adjunct is given at much higher doses (mg-range) than nootropic use (μg-range) — these are different dosing paradigms entirely. Nootropic-dose Semax does not require ICU-grade monitoring; stroke-protocol Semax requires hospital administration. Do not conflate. Community nootropic doses >1 mg per dose have not shown additional benefit over 500–600 μg.
Reconstitution & Storage
Semax is supplied as either pre-mixed 0.1% or 1.0% intranasal solution (Russian pharmacy product) or as lyophilized powder (research-use vials, 5 mg or 10 mg).
| Form | Preparation | Concentration | 300 μg Dose | 600 μg Dose |
|---|
| 0.1% intranasal (stroke) | Pre-mixed | 1 mg/mL | 0.3 mL (6 drops) | 0.6 mL (12 drops) |
| 1.0% intranasal (nootropic) | Pre-mixed | 10 mg/mL | ~0.03 mL (1 drop) | ~0.06 mL (2 drops) |
| 5 mg powder | 1 mL BAC water | 5 mg/mL | 0.06 mL | 0.12 mL |
| 5 mg powder | 5 mL BAC water | 1 mg/mL (match 0.1%) | 0.3 mL | 0.6 mL |
| 10 mg powder | 1 mL BAC water | 10 mg/mL (match 1.0%) | 0.03 mL | 0.06 mL |
- Intranasal delivery — Dropper or metered spray. Tilt head back slightly, apply to inside of each nostril, sniff gently, hold 30 seconds, do not blow nose for 15 minutes.
- Storage — Unreconstituted: 2–8°C preferred. Reconstituted: 2–8°C, use within 21–28 days. Do not freeze reconstituted.
- Inspection — Clear, colorless solution. Discard if cloudy, discolored, or contaminated.
- Onset — 15–30 min subjective effect; peak 1–2 hr; cognitive effects persist 4–12 hr; gene-expression effects persist 24+ hr.
- Splitting between nostrils — Standard practice is to split dose evenly between left and right nostrils for balanced CNS exposure.
→ Use the Kalios Peptide Calculator for exact dosing volumes
Side Effects & Risks
Important
Semax has a clean Russian safety record, but BDNF/NGF upregulation is theoretical territory for anyone with a history of glioma or other neural-tissue tumors. Dosing after 4 PM can disrupt sleep. Worth discussing with your doctor before adding it to any existing cognitive or stroke regimen.
Semax has a strikingly clean safety profile across Russian clinical trials and post-marketing experience.
- Nasal irritation — Mild, transient. Most common complaint at higher concentrations.
- Headache (rare) — Occasional; usually self-limited.
- Mild insomnia — Primarily with late-day dosing. Avoid dosing after ~4 PM.
- Over-activation — At higher doses or in sensitive users, can produce stimulant-like over-arousal. Dose reduce.
- No documented sedation — Unlike benzodiazepines or sedative nootropics.
- No documented dependence / withdrawal — Clean in both registries.
- No HPA-axis stimulation — Despite ACTH origin. Does NOT elevate cortisol.
- No documented tolerance — Chronic use does not clearly diminish response at standard doses.
- Drug interactions — Limited documented interactions. Synergistic with caffeine/modafinil for focus effect (additive, not potentiation).
- Pregnancy / lactation — Not studied; avoid.
- Pediatric use — Russian literature includes pediatric dosing under clinician supervision.
- WADA status — Not specifically listed as a banned substance. Athletes should confirm with their federation; umbrella categories can be interpreted broadly.
- Purity concerns — Gray-market research powder varies. Third-party HPLC COAs are the floor. Russian pharmacy import (if accessible) is the quality gold standard.
- Cancer considerations — BDNF/NGF elevation is a theoretical consideration for users with a history of neural-tissue tumors (glioma, schwannoma). Not specifically studied; reasonable caution.
Bloodwork & Monitoring
Semax is a low-monitoring-burden compound. Routine neurology/psychiatric monitoring is adequate for most users.
- Baseline CMP and CBC — Standard.
- TSH, free T4 — Baseline for cognitive-performance work to rule out hypothyroidism.
- Structured cognitive tests — Cambridge Brain Sciences, CANTAB equivalents, or simple n-back and reaction-time tests to track response objectively.
- Attention scales — Adult ADHD rating scale, if relevant.
- Sleep tracking — Wearable or sleep diary to detect any stimulant-like sleep perturbation.
- Blood pressure — Not known to affect BP at nootropic doses; baseline is prudent.
- Subjective tracking — Productivity journaling, focus-session performance, or task-completion rates provide real-world outcomes.
Commonly Stacked With
The canonical Russian peptide stack. Semax in the AM for cognitive/focus effect; Selank in the PM for stress-resilience/anxiolytic effect. Complementary BDNF-elevating mechanisms with different emotional/cognitive emphasis.
Modafinil / Armodafinil
Stimulant-like focus enhancement from a different mechanism (histaminergic, dopaminergic, orexinergic). Non-peptide; prescription in the US. Additive focus effect for demanding cognitive tasks. Monitor BP and sleep.
Dihexa
Orally bioavailable angiotensin IV analog with strong BDNF-elevation mechanism and longer duration. Paired with Semax in community cognitive-stack protocols. Evidence base is mostly preclinical.
Caffeine + L-theanine
Classical focus adjunct. L-theanine smooths caffeine's anxiogenic edge; caffeine provides stimulant baseline. Semax layers on top without overlapping mechanism.
Omega-3 (EPA/DHA)
2–3 g/day; supports BDNF signaling and neuroinflammation resolution. Complementary to Semax's neurotrophic pathway.
Creatine monohydrate
3–5 g/day. Emerging evidence for cognitive benefit under sleep-debt conditions; complementary to Semax's attention effect during demanding cognitive work.
→ Check compound compatibility in the Stack Builder
Regulatory Status
Current Status — April 2026
Semax is approved by the Russian Federation Ministry of Health for acute ischemic stroke and transient ischemic attack (0.1% intranasal formulation) and for adjunctive nootropic/cognitive use in asthenic conditions (1.0% intranasal formulation).
Semax is not approved by the FDA, EMA, or any other major Western regulator. It is not a controlled substance in the United States. It is not currently on the FDA Category 2 Bulk Drug Substances list. Gray-market access is through research-chemical suppliers or international pharmacy import.
Semax is not specifically listed on the WADA Prohibited List. Competitive athletes should confirm with their federation given broad umbrella categories.
Because Semax is neither an approved drug in the US nor a scheduled substance, its legal status sits in a similar gray space as Selank — not prohibited but not a legitimate FDA-regulated prescription. Use implies informed consent to imported or research-chemical product quality.
Cost & Access
Semax is not approved for human use in the United States. It is available through research suppliers for laboratory research purposes only in the U.S. market.
Semax is approved as a prescription pharmaceutical in Russia (developed by the Russian Academy of Medical Sciences) for the treatment of stroke recovery, cognitive impairment, and asthenic conditions, typically as a 0.1% or 1.0% intranasal spray. It is not available through Western prescription channels.
U.S. compounding pharmacies cannot legally compound Semax under current FDA bulk-substance rules. Online research-chemical channels supply Semax at variable purity; independent third-party HPLC + mass-spec verification is the practical floor for due diligence.
Semax is not specifically named in HHS Secretary Robert F. Kennedy Jr.'s February 2026 Category 2 reclassification announcement, which applies to a defined set of peptide bulk substances. Semax's regulatory pathway for U.S. approval would require a sponsor-led IND/NDA program; no such program is publicly active as of April 2026.
Estimated pricing as of April 2026. Actual costs vary by provider, location, and prescription status. Kalios does not sell compounds.
Related Compounds
The Russian-developed nootropic cluster plus the neurotrophic peptides that share Semax's BDNF mechanism.
N-acetylated semax variant with extended half-life and cleaner intranasal bioavailability.
N-acetylated selank analogue with longer duration and smoother anxiolytic profile.
Adamantane-class actoprotector. Russian dopaminergic / adaptogenic nootropic.
Porcine brain-derived peptide mixture. Neurotrophic formulation used clinically in stroke and dementia.
Cerebrolysin-derived synthetic peptide engineered to retain the neurotrophic core activity.
Key References
- Ashmarin IP, Nezavibatko VN, Levitskaya NG, Koshelev VB, Kamensky AA. Design and investigation of an ACTH(4-10) analog lacking D-amino acids and hydrophobic radicals. Neurosci Res Commun. 1995;17:31-39.
- Gusev EI, Skvortsova VI, Miasoedov NF, Nezavibatko VN, Zhuravleva EIu, Vanichkin AV. [Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study)]. Zh Nevrol Psikhiatr Im S S Korsakova. 1997;97(6):26-34. PMID: 11517472.
- Skvortsova VI, Platonova IA, Tvorogova TV, Miasoedov NF. Effect of semax on disability and handicap indexes in patients survived carotid ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 2002;102(Suppl 5):36-39.
- Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. J Neurochem. 2006;97 Suppl 1:82-86. PMID: 16635254.
- Volkova MV, Shadrina MI, Kolomin TA, Dolotov OV, Grivennikov IA, Shaburova EV, Solntseva OS, Myasoedov NF, Limborska SA, Slominsky PA. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54-60. PMID: 16996037.
- Agapova TY, Agniullin YV, Shadrina MI, Shram SI, Slominsky PA, Lymborska SA, Myasoedov NF. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH(4-10). Neurosci Lett. 2007;417(2):201-205.
- Shadrina M, Kolomin T, Agapova T, et al. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. J Mol Neurosci. 2010;41(1):30-35.
- Stavchansky VV, Tvorogova TV, Botsina AY, Skvortsova VI, Limborska SA, Myasoedov NF, Dergunova LV. The effect of Semax and its C-end peptide PGP on expression of neurotrophins and their receptors in rat brain during incomplete global ischemia. Mol Biol (Mosk). 2011;45(6):1026-1035.
- Filippenkov IB, Stavchansky VV, Denisova AE, et al. Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats. Genes (Basel). 2020;11(6):681.
- Kost NV, Sokolov OY, Gabaeva MV, Grivennikov IA, Andreeva LA, Myasoedov NF, Zozulya AA. [Semax and selank inhibit the enkephalin-degrading enzymes from human serum]. Bioorg Khim. 2001;27(3):180-183. PMID: 11443939.
- Storozheva ZI, Proshin AT, Sherstnev VV, Stolyarov ID, Boĭko AN. Effects of Semax on different forms of learning and memory in adult and aged rats. Bull Exp Biol Med. 2007;143(4):482-485.
- Myasoedov NF, Skvortsova VI, Nasonov EL, et al. [Study of the mechanisms of neuroprotective action of semax in ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(5):15-19.
- Glazova NY, Sebentsova EA, Manchenko DM, et al. Prolonged beneficial effect of neonatal treatment with Semax on the grooming behavior of elderly rats. Bull Exp Biol Med. 2013;155(6):731-733.
- Potaman VN, Antonova LV, Dubynin VA, et al. Entry of the synthetic ACTH(4-10) analogue into the rat brain following intravenous injection. Neurosci Lett. 1991;130(1):11-13.
- Kolomin T, Shadrina M, Slominsky P, Limborska S, Myasoedov N. A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neuroscience and Medicine. 2013;4:223-252.
- Russian Federation State Register of Medicines. Semax — 0.1% and 1.0% intranasal solutions. Approved Russian Ministry of Health.
Last updated: April 2026 | Profile authored by Kalios Peptides research team