Peptigrade

Nootropic & Neuroprotective

Semax

Heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro — synthetic analog of ACTH(4-7) with C-terminal Pro-Gly-Pro extension·Also known as: ACTH(4-7)-Pro-Gly-Pro, MEHFPGP, Семакс

FDARegulatory status

Not approved for human use in the United States. No IND on file; no Phase 2 or Phase 3 trial has ever been registered on ClinicalTrials.gov. Sold domestically only as a research chemical.

WADARegulatory status

Not explicitly listed on the 2026 WADA Prohibited List. However, as a non-approved (in the US/EU) peptide with CNS-active effects, it is reasonably captured by S0 — Non-Approved Substances — on the 2026 list in force January 1, 2026. Athletes under WADA jurisdiction should treat it as prohibited absent specific TUE guidance.

Regulatory note ·Semax is a registered pharmaceutical in the Russian Federation — it is listed on the Russian List of Vital & Essential Drugs (approved by the government of the Russian Federation on December 7, 2011 and reaffirmed in subsequent annual updates) as a nootropic indicated for acute ischemic stroke, transient ischemic attack, post-stroke rehabilitation, optic nerve disease, cognitive disorders, and select other CNS indications. Approval dates from the mid-1990s following Russian Phase 1 (1990–1994) and Phase 2 (1994–1996) programs at the Institute of Molecular Genetics, Russian Academy of Sciences. It has never been evaluated by FDA, EMA, Health Canada, MHRA, TGA, or PMDA. Almost the entire efficacy literature is in Russian-language journals with limited Western replication; this is the single largest caveat on the evidence base.

§ The quick take

TL;DR · Editor’s summary

Semax occupies an unusual epistemic position. It is a registered pharmaceutical in the Russian Federation — listed on the federal List of Vital & Essential Drugs since December 2011 — with an approval dossier covering acute ischemic stroke, transient ischemic attack, post-stroke rehabilitation, optic nerve disease, and cognitive disorders. Russian clinical practice dates to the mid-1990s. By Russian regulatory standards this is a meaningfully-studied drug. By the evidentiary standard Peptigrade applies to Western peptide claims, it is not.

The overwhelming majority of the efficacy literature is published in Russian-language neurology journals (Korsakov Zhurnal, Nevrologicheskii Vestnik) as open-label or small non-randomized series. No independent Western research group has replicated the acute-stroke or cognitive-recovery findings in a blinded, placebo-controlled Phase 2 or Phase 3 design. No IND exists at FDA. There is no registered Phase 2 or Phase 3 trial anywhere on ClinicalTrials.gov. The mechanistic work — BDNF/TrkB upregulation in rat hippocampus (Dolotov 2006), monoaminergic activation (Eremin 2005), MC4R receptor involvement, and Cu²⁺-mediated anti-amyloid effects in vitro (Medvedeva 2022) — is published in English-language journals but is almost entirely rodent or cell-culture work.

The top outcome-grade we assign is C (ischemic stroke), reflecting: a plausible mechanism, a real Russian registration, and real clinical use across decades, tempered by the absence of independent Western RCT replication and the well-documented methodological limitations of the available trials. Cognitive-enhancement claims in healthy adults are graded D — the two published human cognitive studies are small, acute-dose, and without sustained-use replication. Long-term human safety data is primarily Russian post-marketing surveillance with thin published detail. Athletes should treat Semax as WADA-prohibited under S0 absent TUE guidance.

§ Grade matrix

The grade
per outcome.

One peptide can earn very different grades for different uses. Here is every outcome we’ve graded for Semax, sorted by strength of evidence.

C

Acute ischemic stroke — adjunctive neuroprotection

Mixed

Registered indication in Russia since the mid-1990s. Gusev (1997, Korsakov Zhurnal) and Gusev (2018) reported clinical benefit at 12–18 mg/day intranasal in the acute phase; most subsequent Russian trials are small, open-label, or non-randomized. No independent Western RCT has been published. The registration-grade evidence in Russia does not meet Western Phase 3 RCT standards — hence C, not B.

18 studiesUpdated 2026-04-20
C

Transient ischemic attack & post-stroke cognitive recovery

Mixed

Russian-clinic data supports faster neurological recovery (Kostenko 2018; Stakhovskaya 2001). Outcome measures (NIHSS, Barthel, MMSE) are reported but without blinding or placebo control in most series. No Western replication.

9 studiesUpdated 2026-04-20
D

Cognitive enhancement in healthy adults

Weak

Frequent off-label claim. Published evidence in healthy humans is limited to two small acute-dose studies (n=8 cognitive task performance; n=24 fMRI default-mode-network). No placebo-controlled replication, no sustained-use data. Mechanistic plausibility (BDNF/TrkB upregulation) is animal-derived.

5 studiesUpdated 2026-04-20
D

ADHD and attention disorders (pediatric & adult)

Weak

Used in Russian pediatric neurology for attention-deficit presentations. Evidence is limited to Russian-language case series and open-label reports. No blinded trial, no Western replication. Not sufficient for a Western evidence grade above D.

4 studiesUpdated 2026-04-20
D

Anxiety and stress-related disorders

Weak

Overlaps with Selank's positioning. Animal data shows anxiolytic signal via monoaminergic modulation (Eremin 2005). Human data is sparse and largely Russian-language. Selank is the more-studied anxiolytic peer.

4 studiesUpdated 2026-04-20
C

Optic nerve disease & ophthalmic neuroprotection

Mixed

Listed indication on the Russian formulary. Evidence is clinical-series-grade from Russian ophthalmology centers. Not independently replicated.

6 studiesUpdated 2026-04-20
D

Alzheimer's disease / amyloid aggregation

Weak

In-vitro evidence that Semax forms Cu²⁺ complexes and attenuates copper-induced Aβ₁₋₄₀ aggregation on artificial membranes (Medvedeva 2022, ACS Chem Neurosci). No animal-model amyloid pathology study in transgenic AD models published. No human trial.

3 studiesUpdated 2026-04-20

§ Why this grade

Sub-scores for this outcome.

Acute ischemic stroke (adjunctive neuroprotection)

Every grade rolls up six weighted sub-scores, each rated 1 to 5 with a written justification. Here is how the top-outcome grade was constructed.

Mechanism understood

3 / 5

BDNF/TrkB upregulation in hippocampus and basal forebrain (Dolotov 2006; Shadrina 2010), monoaminergic activation (Eremin 2005), and MC4R receptor activity are characterized at the pathway level in rodents and in vitro. No specific high-affinity mammalian receptor has been cloned. Human pharmacokinetics of intranasal administration are essentially absent from English-language peer-reviewed literature.

Human studies (count + quality)

2 / 5

Russian registration dossier exists and Russian clinical use dates to the mid-1990s (Gusev 1997; Gusev 2018; Kostenko 2018). Most published trials are small, open-label, or non-randomized, and the majority are in Russian-language journals not indexed in the same depth as English literature. No independent Western RCT.

Effect vs placebo

2 / 5

Russian clinical series report benefit on NIHSS, Barthel Index, and MMSE in acute stroke, but most are not blinded and several lack a true placebo arm. Independent placebo-controlled Western replication does not exist.

Long-term safety data

2 / 5

Russian post-marketing surveillance covers nearly three decades of clinical use and the safety signal is reportedly benign. Published English-language long-term safety data at the depth of FDA-reviewed drugs does not exist. Repeated-dose immunogenicity is uncharacterized.

Side effect profile

4 / 5

Russian clinical experience suggests a favorable tolerability profile at label doses with rare reports of local nasal irritation and transient mild hyperemia. No serious adverse event signal has been reported in the literature available to Peptigrade. The shallow depth of published Western safety data keeps this from a 5.

Regulatory status

2 / 5

Registered pharmaceutical in the Russian Federation — listed on the List of Vital & Essential Drugs (approved December 7, 2011; reaffirmed in subsequent updates) — with active approval for acute ischemic stroke, TIA, optic nerve disease, and cognitive disorders. Not approved by FDA, EMA, Health Canada, MHRA, TGA, or PMDA. No IND, no registered Phase 2/3 trial on ClinicalTrials.gov. WADA status not explicit; reasonably captured by S0.

§ What the science says

How Semax
works.

The scientific explanation of the molecule and its proposed mechanism, with a plain-English translation — written at an 8th-grade reading level — in the teal callouts below each section. Every claim is linked to a primary source below.

What it is

Semax is a synthetic heptapeptide (amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro, MEHFPGP, MW 813.92 Da, molecular formula C₃₇H₅₁N₉O₁₀S, CAS 80714-61-0, PubChem CID 9811102). Structurally it is the ACTH(4-7) fragment extended at the C-terminus with a Pro-Gly-Pro motif — the PGP extension confers proteolytic stability and prolongs biological activity relative to the parent ACTH fragment while eliminating classical corticotropic hormonal activity. It was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences under I.P. Ashmarin in the 1980s and entered Russian clinical practice after Phase 2 trials concluded in 1996. The name derives from 'семь аминокислот' (seven amino acids). Bioavailability is poor orally; the registered Russian formulation is intranasal drops (0.1% solution), with subcutaneous injection used in some research contexts. Binding to rat neuronal tissue has been characterized with a K_D of approximately 2.4 nM and is calcium-dependent; no specific high-affinity mammalian receptor has been cloned.

In plain English

Semax is a synthetic 7-amino-acid peptide developed in the 1980s at a Russian research institute. It was designed by taking a small piece of ACTH — a hormone your pituitary gland makes to trigger cortisol release — and modifying it. Scientists cut it down to a 4-amino-acid fragment (ACTH(4-7)) and added 3 more amino acids (Pro-Gly-Pro) at one end. That addition does two important things: it makes the peptide much harder for the body to break down, and it removes the cortisol-triggering effect entirely. The result is a peptide that may affect the brain without causing the stress hormone side effects of ACTH itself. It's taken as a nasal spray — a 0.1% solution of drops. You can't take it as a pill because it would be digested before it could work. Despite decades of study, no specific "receiver" on brain cells that Semax attaches to has ever been identified, even though its biological effects are well described in animal studies.

How it works

  1. 01

    BDNF and TrkB upregulation in hippocampus and basal forebrain

    Dolotov (2006, J Neurochem) showed that a single intranasal 50 µg/kg or 250 µg/kg dose of Semax increases BDNF protein levels in rat basal forebrain within 3 hours, without affecting cerebellar BDNF — indicating regional specificity. Shadrina (2010) and related work demonstrated that Semax upregulates both BDNF and its cognate receptor tropomyosin receptor kinase B (TrkB) in the hippocampus, and induces TrkB phosphorylation. The BDNF/TrkB axis is a well-validated mediator of synaptic plasticity, neurogenesis, and experience-dependent learning, which provides a coherent mechanistic basis for the cognitive and post-stroke recovery effects reported in Russian clinical literature.

    In plain English

    It raises a key brain-growth protein (BDNF) in the memory and learning regions

    A 2006 rat study showed that a single Semax dose raises BDNF (brain-derived neurotrophic factor) in specific brain regions — the memory and forebrain areas — within 3 hours. BDNF is like fertilizer for neurons: it promotes survival, growth of connections, and the ability to form new memories. The effect was specific — it didn't change BDNF levels in unrelated brain areas like the cerebellum. Later work confirmed Semax also activates the BDNF receptor (TrkB). This is the most credible biological explanation for why Semax might help stroke recovery and cognitive function.

  2. 02

    Monoaminergic (dopaminergic & serotonergic) activation

    Eremin (2005, Neurochem Res) demonstrated rapid activation of dopaminergic and serotonergic brain systems in rodents following Semax administration, with changes in regional monoamine turnover detectable within minutes. This provides a pharmacological basis for the acute mood, attention, and arousal effects reported in small human cognitive studies and underpins the off-label positioning of Semax as a nootropic.

    In plain English

    It activates dopamine and serotonin systems in the brain

    A 2005 rat study showed Semax rapidly activates dopamine and serotonin circuits in the brain, with measurable changes within minutes of dosing. Dopamine drives attention and motivation; serotonin affects mood and focus. This helps explain the reported effects on alertness and cognitive performance seen in small human studies.

  3. 03

    Melanocortin receptor activity without hormonal ACTH effect

    Semax retains ACTH(4-7)-derived affinity for melanocortin receptors — particularly MC4R, which is implicated in cognition, energy homeostasis, and CNS neuroprotection — but the Pro-Gly-Pro C-terminal extension eliminates the corticotropic (HPA-axis-activating) effect of native ACTH. This receptor profile is partial — no systematic receptor-binding screen at human melanocortin subtypes has been published — but it explains the absence of ACTH-like cortisol elevation in clinical use.

    In plain English

    It acts on a brain receptor linked to cognition — without triggering cortisol

    Semax retains some ability to attach to melanocortin receptors in the brain — particularly MC4R, which is linked to cognition and energy regulation. Normal ACTH also activates these receptors but at the same time triggers cortisol release from the adrenal glands. The extra amino acids added to Semax (Pro-Gly-Pro) remove the cortisol-triggering part. So Semax may keep the cognitive-receptor activity without the stress-hormone side effects. This picture is incomplete — a full receptor-binding map in humans has not been published.

  4. 04

    Enkephalin-degrading enzyme inhibition

    Semax and related ACTH-derived peptides inhibit enkephalin-degrading enzymes (reported IC₅₀ ≈ 10 µM in vitro). The resulting potentiation of endogenous enkephalin tone has been proposed as a contributor to mood, pain, and stress-related effects, though the clinical relevance of this mechanism at intranasal doses achieving much lower CNS concentrations is unclear.

    In plain English

    It may prolong your brain's natural mood-and-pain chemicals

    Semax can block enzymes that break down enkephalins — natural brain chemicals that affect mood, pain, and stress. By slowing their breakdown, Semax may let those chemicals act longer. How much this matters at the low concentrations that actually reach the brain after a nasal spray is unclear — the lab test used higher concentrations than a typical dose would achieve.

  5. 05

    Anti-aggregation activity at Aβ₁₋₄₀ in copper-loaded membranes

    Medvedeva (2022, ACS Chem Neurosci) showed that Semax forms stable complexes with Cu²⁺ ions and attenuates copper-induced amyloid-β (Aβ₁₋₄₀) aggregation and the associated membrane disruption in artificial lipid bilayers. This is an in-vitro finding in a chemically simplified system; it has not been extended to animal models of Alzheimer's pathology or to humans, and should be read as a biochemical hypothesis-generating observation rather than evidence for an AD indication.

    In plain English

    In a lab dish, it reduces copper-triggered protein clumping linked to Alzheimer's

    A 2022 study showed Semax binds copper ions and prevents them from triggering clumping of amyloid-beta — the protein linked to Alzheimer's — on artificial membranes in a lab dish. This is preliminary. It has not been tested in any animal Alzheimer's model or in people. Treat it as an interesting hypothesis, not as evidence that Semax treats Alzheimer's.

  6. 06

    Intracellular calcium dynamics

    Recent work (2025, Bull Exp Biol Med) reports that Semax modulates intracellular Ca²⁺ dynamics in rat brain neurons, suggesting an additional signaling axis beyond BDNF/TrkB and monoaminergic modulation. The downstream significance for neuroprotection and cognition is not yet characterized.

    In plain English

    A 2025 study found it also changes calcium signals in brain cells

    A 2025 study reported that Semax changes how calcium moves inside rat brain neurons. Calcium signaling is a key way neurons communicate and adapt. What this means for neuroprotection or cognition in humans isn't known yet — this is a recent, early finding.

  7. 07

    What is NOT known about the mechanism

    No specific, high-affinity mammalian receptor for Semax has been cloned. Human pharmacokinetics of intranasal Semax are essentially absent from English-language peer-reviewed literature; plasma half-life, CNS penetration, and dose-linearity are inferred from rodent work. Whether the BDNF, monoaminergic, melanocortin, and enkephalinase-inhibition mechanisms act in concert or dominate at clinically relevant doses is not resolved.

    In plain English

    What we still don't know

    No specific receptor that Semax attaches to has ever been found. We don't know how much of a nasal-spray dose actually reaches the human brain, how long it stays, or whether repeated doses accumulate. The BDNF, dopamine/serotonin, melanocortin, and enkephalin mechanisms are all measured downstream — not at the receptor attachment point. Which of these actually drives the clinical effects, and at what doses, is unresolved.

§ Investigated uses

What it’s
been studied for.

Investigated does not mean proven. This list shows every use that appears in the published literature, regardless of evidence strength. See the grade matrix above for which ones have actually held up.

  • Acute ischemic stroke (adjunctive, within the therapeutic window)

    Russian registration since mid-1990s; Gusev 1997, 2018; Kostenko 2018. No independent Western RCT.

  • Transient ischemic attack

    Russian label indication; clinical-series evidence only.

  • Post-stroke neurological and cognitive rehabilitation

    Russian clinical use; open-label and small comparative trials.

  • Optic nerve disease and ophthalmic neuroprotection

    Russian label indication; clinical-series evidence from Russian ophthalmology centers.

  • Cognitive enhancement in healthy adults

    Off-label; two small acute-dose human studies (n=8 behavioral; n=24 fMRI DMN). Grade D.

  • ADHD and attention disorders

    Russian pediatric-neurology practice; case series only. Grade D.

  • Anxiety and stress-related disorders

    Animal models; Selank is the better-studied anxiolytic peer. Grade D.

  • Alzheimer's disease / anti-amyloid hypothesis

    In-vitro Cu²⁺/Aβ₁₋₄₀ work (Medvedeva 2022). No animal AD-model or human data. Grade D.

  • Peptic ulcer (adjunct)

    Listed historical Russian indication; very limited published data in English.

§ The honest gaps

What we don’t
know yet.

Every peptide page on this site is required to include this section. Absence of evidence is information. If we don’t flag the gaps, we’re lying by omission.

  • !

    No independent Western RCT has been published for any Semax indication. The Russian registration dossier and subsequent Russian trials are largely open-label, non-randomized, or small-n; they do not meet the Phase 3 RCT standard used by FDA/EMA.

  • !

    No modern placebo-controlled trial exists for cognitive enhancement in healthy adults. The frequently-cited 'n=8' and 'n=24' human cognitive studies are small, acute-dose, and have not been independently replicated.

  • !

    Human pharmacokinetics of intranasal Semax (plasma half-life, CNS bioavailability, dose-linearity, repeat-dose accumulation) are essentially absent from English-language peer-reviewed literature.

  • !

    No specific high-affinity mammalian receptor for Semax has been identified. The proposed mechanisms (BDNF/TrkB upregulation, monoaminergic activation, MC4R modulation, enkephalinase inhibition) are characterized downstream — not at a receptor-pharmacology level — which limits structure-activity optimization and dose-finding.

  • !

    Long-term safety data in humans exists only as Russian post-marketing surveillance. Published English-language safety reports at the depth typical for FDA-reviewed drugs do not exist. Repeated-dose immunogenicity has not been characterized.

  • !

    No head-to-head comparison trial against standard-of-care acute stroke management (tPA / thrombectomy era) has been published. Most Russian efficacy data predates the modern reperfusion era and may not reflect incremental benefit on top of current standard care.

  • !

    No blinded replication of the Cu²⁺/Aβ anti-aggregation finding in transgenic AD mouse models has been published. The Alzheimer's-relevance claim is currently a biochemical hypothesis, not a preclinical efficacy result.

  • !

    WADA status is ambiguous by silence — Semax is not explicitly named on the 2026 list. The prudent read for athletes is that S0 (Non-Approved Substances) captures it; TUE guidance from the relevant federation has not been formally clarified.

§ On YouTube

What experts and
influencers say.

We index YouTube content discussing Semaxand tag every speaker by credential and trust level. The goal is not to summarize the internet — it’s to tell you which voices to weight.

  • Semax & Selank — Russian Nootropics: What the Evidence Actually Says

    Huberman Lab·PhD Neurobiology, Stanford

    Explicitly flags the Russian-language literature problem and the absence of independent Western replication. Distinguishes the registered stroke indication in Russia from the unsupported 'healthy-adult nootropic' marketing claim.

    Verified credentials

  • Semax in Clinical Practice — Off-Label Use, Intranasal Dosing, and Regulatory Caveats

    Dr. Kyle Gillett·MD, Family Medicine

    Walks through the intranasal 0.1% formulation typical in Russian practice, the BDNF/TrkB mechanistic story, and is explicit that no FDA IND exists and no Western RCT has been run.

    Verified credentials

  • I Tried Semax for 30 Days and My Focus is INSANE

    Anonymous biohacking influencer·Unverified

    Anecdotal 30-day self-experiment with no baseline cognitive testing, no placebo, and no objective outcome measure. Representative of the overstated-benefit pattern common in unverified nootropic content. Do not weight against the published literature.

    Caution — anecdotal

§ Citations

Every claim,
linked to source.

All 11 sources informing this page, with DOI or PubMed identifiers. Click through to the primary literature.

  1. [01]

    Investigation of mechanisms of neuro-protective effect of semax in acute period of ischemic stroke

    Gusev EI, Skvortsova VI, Miasoedov NF, Nezavibat'ko VN, Zhuravleva EIu, Vanichkin AV · Zh Nevrol Psikhiatr Im S S Korsakova · 1997

    Open-labelPMID 10358912
  2. [02]

    Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus

    Shadrina MI, Dolotov OV, Grivennikov IA, et al. · Brain Res · 2006

    AnimalPMID 16996037
  3. [03]

    Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain

    Dolotov OV, Karpenko EA, Inozemtseva LS, et al. · J Neurochem · 2006

    AnimalPMID 16635254
  4. [04]

    Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents

    Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS · Neurochem Res · 2005

    AnimalDOI
  5. [05]

    Semax, a synthetic regulatory peptide, affects copper-induced Aβ aggregation and amyloid formation in artificial membrane models

    Medvedeva M, Barinova K, Melnikova A, et al. · ACS Chem Neurosci · 2022

    In vitroDOI
  6. [06]

    Interaction of Semax and its metal complexes with oligomeric species of amyloid-β

    Medvedeva M, Barinova K, Melnikova A, et al. · ACS Chem Neurosci · 2022

    In vitroDOI
  7. [07]

    The effect of peptide Semax, an ACTH(4-10) analogue, on intracellular calcium dynamics in rat brain neurons

    Kolacheva AA, Pronina TS, Grivennikov IA, Ugrumov MV · Bull Exp Biol Med · 2025

    In vitroDOI
  8. [08]

    PubChem Compound Summary — Semax (CID 9811102)

    National Center for Biotechnology Information · PubChem · 2026

    RegistrationLink
  9. [09]

    Russian Federation List of Vital & Essential Drugs — Semax listing (nootropic class)

    Government of the Russian Federation · Russian Federation official publication · 2011

    RegulatoryLink
  10. [10]

    WADA 2026 Prohibited List (in force January 1, 2026) — Section S0 Non-Approved Substances

    World Anti-Doping Agency · WADA · 2026

    RegulatoryLink
  11. [11]

    ClinicalTrials.gov query for 'Semax' — no Phase 2 or Phase 3 interventional trial registered as of 2026-04-20

    U.S. National Library of Medicine · ClinicalTrials.gov · 2026

    RegistrationTrial

§ Adjacent peptides

Worth reading
alongside this.

Compare

Selank

Direct peer — also developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, same Ashmarin lineage, same Russian-registration / limited-Western-replication evidence pattern. Selank is positioned as the anxiolytic counterpart to Semax's nootropic positioning.

Read its grades

Compare

BPC-157

Shares the 'deep preclinical bench, thin human-trial record, no FDA approval' evidence shape — useful for calibrating what a C-grade peptide looks like when the research base is strong in animals but sparse in blinded human trials.

Read its grades

Compare

DSIP (Delta Sleep-Inducing Peptide)

Another Eastern-European-origin CNS peptide with extensive Soviet-era preclinical work and minimal independent Western replication. Similar evidence-quality caveats apply.

Read its grades

Where to research further

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for laboratory research?

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