# Semax Rating: Promising — Some human trials, or consistent animal work with a clear mechanism Type: Compound Updated: 2026-08-06 Canonical: https://heretic.bio/articles/semax-acth4-7-pgp-neurotrophic-peptide.html > Semax is a synthetic ACTH(4-7) analog developed at Moscow's Institute of Molecular Genetics in 1982 and approved in Russia for stroke, encephalopathy and optic nerve disease. Human evidence is Russian-language: a stroke study (n=110) reported raised plasma BDNF, and a pilot fMRI study (n=24) found default-mode-network effects in healthy volunteers. A 2023-2026 wave of animal and molecular studies identified new targets, but no English-language double-blind RCT exists. > **Aliases:** Semax® (0.1% and 1% solutions), Heptapeptide ACTH(4-7)-PGP **Sequence:** Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP, 7 amino acids) **Molecular Weight:** ~813 Da **Origin:** Synthetic analog of ACTH(4-7) fragment with added Pro-Gly-Pro C-terminus; developed at Institute of Molecular Genetics, Russian Academy of Sciences (1982) * * * ## Overview Semax is a synthetic heptapeptide derived from the **N-terminal fragment (4-7) of adrenocorticotropic hormone (ACTH)** — the part of ACTH responsible for neurotrophic (nerve-growth-promoting) effects, stripped of the hormonal (cortisol-stimulating) activity. The addition of **Pro-Gly-Pro** to the C-terminus extends its half-life from minutes to **20-24 hours** in animal models. Semax was developed in **1982** at the **Institute of Molecular Genetics** of the Russian Academy of Sciences in Moscow. It is **approved and clinically used in Russia** for stroke, dyscirculatory encephalopathy, Parkinson's disease, optic nerve atrophy, and neurological deficits in newborns. It is also widely used off-label as a **nootropic** (cognitive enhancer). **Evidence Level:** Moderate — Used clinically in Russia for 40+ years. Limited English-language publications. Most human data is in Russian-language journals. 207 PubMed-indexed publications total (as of 2026); research output reactivated 2023–2026 via transcriptomic and target-identification studies (see #Recent Research (2023–2026)). * * * ## Mechanism of Action ### BDNF Upregulation (Primary Mechanism) * **Increases BDNF (Brain-Derived Neurotrophic Factor)** expression in multiple brain regions: * Basal forebrain (peaks at 3 hours post-administration) — PMID [16635254](https://pubmed.ncbi.nlm.nih.gov/16635254/) * Hippocampus (confirmed in multiple studies) * Frontal cortex (BDNF + NGF increased at 8 hours) * BDNF is critical for **neuroplasticity, learning, memory formation** , and neuronal survival * Systemic (i.p.) administration also restores **hippocampal BDNF suppressed by chronic stress** in rats (PMID [39442746](https://pubmed.ncbi.nlm.nih.gov/39442746/)) ### μ-Opioid Receptor / USP18 Axis (2025 discovery) * Network pharmacology + docking + RNA-seq identified the **μ-opioid receptor (gene _Oprm1_)** as a direct Semax target in a spinal cord injury model (female C57BL/6 mice, T9-T10 impact) * Downstream: Semax upregulates **ubiquitin-specific protease USP18** → deubiquitinates and stabilizes **FTO (fat mass and obesity-associated protein, an m⁶A RNA demethylase)** → reduces lysosomal membrane permeabilization (LMP)–related **pyroptosis** and neuronal death, decreasing oxidative stress * USP18 knockdown abolished the protective effect; improved Basso scores, footprint analysis, inclined-plane performance — PMID [40692165](https://pubmed.ncbi.nlm.nih.gov/40692165/), Br J Pharmacol 182(22):5489–5516 (2025) ### Copper Chelation / Anti-Amyloid Redox Silencing (2025) * Semax acts as a **copper chelator peptide** : strips Cu(II) from amyloid-β, suppresses Cu(II)-catalyzed ROS production, and reduces Aβ cytotoxicity ("redox silencing") — in-vitro — PMID [40496623](https://pubmed.ncbi.nlm.nih.gov/40496623/), Bioinorg Chem Appl 2025:4226220 ### Neurotransmitter Modulation * **Increases serotonin** levels * Does not directly increase dopamine, but **potentiates** stimulatory effects of dopaminergic agents * Increases circulation of monoamines in the brain * Modulates **acetylcholine** transmission * Stabilizes **intracellular Ca²⁺ dynamics** in rat brain neurons (important for excitotoxicity resistance) — PMID [41171324](https://pubmed.ncbi.nlm.nih.gov/41171324/), Bull Exp Biol Med 2025 ### Cerebral Blood Flow * **Neuroprotective** in ischemic conditions * Reduces infarction size in stroke models * Reduces nitric oxide generation post-ischemia * Improves cerebrovascular function ### Anti-inflammatory & Antioxidant * Reduces neurological damage from oxidative stress * Protects against gravitation overload-induced brain damage * Modulates inflammatory cascades in brain tissue * Post-stroke: normalizes expression of **immune-response genes** (including anti-inflammatory cytokine pathways IL-4/IL-10 axis) in rat brain — PMIDs [37510287](https://pubmed.ncbi.nlm.nih.gov/37510287/) (Genes 2023), [39442746](https://pubmed.ncbi.nlm.nih.gov/39442746/) * * * ## Primary Uses & Applications Application | Evidence Level | Notes ---|---|--- **Stroke recovery** | Russian clinical use + studies | Primary approved indication in Russia **Cognitive enhancement** | Pilot human studies + preclinical | Improves attention, short-term memory **Dyscirculatory encephalopathy** | Russian clinical use | Chronic cerebral ischemia **Parkinson's disease** | Russian clinical use | Adjunct therapy **Optic nerve atrophy** | Russian clinical use | Neuroprotective **Neonatal neurological deficits** | Russian clinical use | Approved for newborns **Alzheimer's disease** | Animal model only (2025) | Reduced amyloid inclusions in APPswe/PS1dE9 mice — PMID [41479572](https://pubmed.ncbi.nlm.nih.gov/41479572/) **Spinal cord injury** | Animal model only (2025) | μ-opioid receptor/USP18 mechanism — PMID [40692165](https://pubmed.ncbi.nlm.nih.gov/40692165/) **Depression / stress-related disorders** | Animal model (2024) | Antidepressant-like, restores hippocampal BDNF — PMID [39442746](https://pubmed.ncbi.nlm.nih.gov/39442746/) **ADHD-like symptoms** | Preclinical + anecdotal | Attention improvement * * * ## Clinical Evidence ### Human Studies **Pilot fMRI Study (n=24, healthy subjects):** Intranasal 1% Semax (total 1.2 mg) increased resting fMRI signal in the **default mode network rostral subcomponent** relative to placebo. _Lebedeva et al., 2018_ — full fMRI series later extended via a functional connectomic approach comparing Selank and Semax (Dokl Biol Sci 2020, PMID [30225715](https://pubmed.ncbi.nlm.nih.gov/30225715/) / [32342318](https://pubmed.ncbi.nlm.nih.gov/32342318/)) **Healthy Subject Study:** Semax (250-1000 µg/kg) improved **attention and short-term memory** and caused EEG changes similar to other neuroprotective drugs. _Referenced in Kolomin et al., 2013 (Russian-language)_ **Stroke Study (n=110):** Treatment with Semax (2 courses — 6000 µg/day for 10 days with 20-day interval) **increased plasma BDNF levels**. Patients with high BDNF levels had improved timing of rehabilitation. _Gusev et al., 2017_ — PMID [29798983](https://pubmed.ncbi.nlm.nih.gov/29798983/) **Stroke Study:** Semax improved neurological function when added to standard of care. _Gusev et al., 1997 (Russian-language, abstract only)_ > ⚠️ **Evidence caveat:** No English-language double-blind RCTs. Human efficacy claims rest on Russian-language trials of variable methodological quality, mostly open-label or vs-active-comparator without rigorous blinding. ### Preclinical Studies * Intranasal administration binds in rat basal forebrain and increases BDNF at 3 hours (Dolotov et al., 2006 — PMID [16635254](https://pubmed.ncbi.nlm.nih.gov/16635254/)) * Reduced infarction size and improved passive avoidance performance in photothrombosis model (Romanova et al., 2006) * Improved cognition in healthy rats at 15 minutes post-treatment (Manchenko et al., 2012) * Increased BDNF and NGF in frontal cortex and hippocampus at 8 hours (Shadrina et al., 2010) * * * ## Recent Research (2023–2026) The Semax literature reactivated after 2023, driven by Russian (IMG RAS, Engelhardt IMB, Belgorod State) and — — **Chinese groups** adopting the molecule. Key findings: ### Alzheimer's Disease Model (2025) Transgenic **APPswe/PS1dE9/Blg mice** : both Semax and a novel derivative improved open-field, novel-object-recognition, and Barnes-maze performance, and **reduced amyloid plaque counts in cortex and hippocampus** on histology. Acta Naturae 17(4):110–120 — PMID [41479572](https://pubmed.ncbi.nlm.nih.gov/41479572/), free full text [PMC12755871](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755871/). Complements the Cu-chelation/redox-silencing mechanism (PMID [40496623](https://pubmed.ncbi.nlm.nih.gov/40496623/)). ### Spinal Cord Injury (2025) First receptor-level target identification: **μ-opioid receptor → USP18 → FTO deubiquitination** axis, inhibiting lysosomal-membrane-permeabilization-driven pyroptosis. Functional recovery in female mice. Br J Pharmacol — PMID [40692165](https://pubmed.ncbi.nlm.nih.gov/40692165/). Related: earlier F1000Research work showed ACTH(4-7)-PGP **upregulates IL-4, IL-10, IL-13** after SCI in rats (PMID [41179234](https://pubmed.ncbi.nlm.nih.gov/41179234/)). ### Transcriptomics of Stroke Neuroprotection (2023–2025) A series from Kolomin/Myasoedov's group mapped genome-wide effects: \- Semax family peptides **compensate ischemia-disrupted brain gene expression** 24 h post experimental stroke (Biomedicines 12(12):2830, PMID [39767736](https://pubmed.ncbi.nlm.nih.gov/39767736/)) \- Region-specific gene response depends on **degree of ischemic damage** (Int J Mol Sci 26(13):6256, PMID [40650034](https://pubmed.ncbi.nlm.nih.gov/40650034/)) \- Immune-gene expression modulation in early post-stroke period (Genes 14(7):1382, PMID [37510287](https://pubmed.ncbi.nlm.nih.gov/37510287/)) \- Baseline transcriptomic changes in healthy rat brain (Biochemistry Mosc 89(9), PMID [39418522](https://pubmed.ncbi.nlm.nih.gov/39418522/)) ### Antidepressant / Antistress Effects (2024) Chronic unpredictable stress (CUS) in rats: systemic low-dose Semax (60 nmol/kg i.p., 14 days) **reversed anhedonia, weight-loss, adrenal hypertrophy, and hippocampal BDNF depletion**. First-line evidence for stress-related psychiatric applications. Note: Semax shares this with **Melanotan II** (both ACTH(4-10) analogs) — Eur J Pharmacol 977:177068, PMID [39442746](https://pubmed.ncbi.nlm.nih.gov/39442746/). See [Dihexa](dihexa-n-hexanoic-tyr-ile-6-aminohexanoic-amide.html) and the ACTH(4-10) analog family in [Khavinson Peptides (Russian Bioregulators)](peptide-bioregulation-khavinson.html). ### Context: Peptide Gerontology Reviews (2025–2026) Semax is featured in current reviews of therapeutic peptides in gerontology (Front Aging 2026, PMID [42021992](https://pubmed.ncbi.nlm.nih.gov/42021992/)) and neurodegenerative oxidative-stress targeting (Neuropeptides 2025, PMID [41004910](https://pubmed.ncbi.nlm.nih.gov/41004910/)), signaling growing non-Russian interest. * * * ## Uses > ⚠️ **Disclaimer:** Research protocols. Semax is not FDA-approved. ### Uses Indication | Solution ---|--- Stroke | 1% solution Cognitive enhancement | 0.1% solution Chronic conditions | 0.1% solution ### Administration Notes * **Intranasal only** — primary route in all clinical and research use * **Rapid absorption** through nasal mucosa to brain * **Peak BDNF** at 3 hours, effects last up to 24 hours * Available as 0.1% (milder) and 1% (clinical strength) solutions * * * ## Safety Profile Aspect | Assessment ---|--- **Overall safety** | Good — used clinically in Russia for 40+ years **Common adverse events** | Nasal cavity discoloration (~10% of patients); increased blood glucose in diabetics (~7.4%) **Serious adverse events** | None reported in clinical literature **Hormonal effects** | None — ACTH hormonal activity removed **Addictive potential** | Not reported; the 2025 μ-opioid receptor finding (PMID [40692165](https://pubmed.ncbi.nlm.nih.gov/40692165/)) is mechanistic (receptor-mediated signal transduction) and does not imply abuse liability — no tolerance/dependence data exist **Long-term safety** | Extensive Russian clinical experience suggests good tolerability **FDA status** | Not approved in the United States; unregulated gray-market material dominates Western supply ### Supply-Chain Note Virtually all Western "Semax" is gray-market from peptide vendors with no batch certification. Given the 2025 copper-chelation findings (PMID [40496623](https://pubmed.ncbi.nlm.nih.gov/40496623/)), **copper contamination or mischelation in impure material is a plausible additional risk vector** — analytical testing (HMU/HPLC) advisable for any research use. * * * ## Source & Origin * **Developed:** 1982, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow * **Base compound:** ACTH(4-7) — the neurotrophic fragment of adrenocorticotropic hormone * **Key modification:** Pro-Gly-Pro C-terminus extends half-life from minutes to 20-24 hours * **Clinical status:** Approved in Russia as prescription medication * **Related:** [Selank](selank-tuftsin-derived-anxiolytic-peptide.html) — both developed at the same Russian research institute; joint connectomic fMRI comparison PMID [32342318](https://pubmed.ncbi.nlm.nih.gov/32342318/) * * * ## Sources 1. Dolotov OV et al. (2006). "Semax increases BDNF levels in rat basal forebrain." Neurosci Lett PMID 16635254 (PubMed 16635254) 2. Panieri E et al. (2024). "Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress." Eur J Pharmacol 977:177068. PMID 39442746 (PubMed 39442746) 3. Liu R et al. (2025). "Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice." Br J Pharmacol 182(22):5489–5516. PMID 40692165 (PubMed 40692165) 4. Tomasello MF et al. (2025). "Semax, a Copper Chelator Peptide, Decreases the Cu(II)-Catalyzed ROS Production and Cytotoxicity of Aβ by Metal Ion Stripping and Redox Silencing." Bioinorg Chem Appl 2025:4226220. PMID 40496623 / PMC12151629 (PubMed 40496623, PMC12151629) 5. PubMed 41171324 (PubMed 41171324) 6. PubMed 37510287 (PubMed 37510287) 7. Radchenko AI et al. (2025). "The Potential of the Peptide Drug Semax and Its Derivative for Correcting Pathological Impairments in the Animal Model of Alzheimer's Disease." Acta Naturae 17(4):110–120. PMID 41479572 / PMC12755871 (PubMed 41479572, PMC12755871) 8. Lebedeva NN et al. (2018). "fMRI study of Semax effects on default mode network in healthy subjects." Zh Nevrol Psikhiatr / connectomics extension PMID 30225715 (PubMed 30225715) 9. PubMed 32342318 (PubMed 32342318) 10. Gusev EI et al. (2017). BDNF plasma increase in stroke patients under Semax. PMID 29798983 (PubMed 29798983) 11. PubMed 41179234 (PubMed 41179234) 12. Kolomin T et al. (2024). "ACTH-like Peptides Compensate Rat Brain Gene Expression Profile Disrupted by Ischemia a Day After Experimental Stroke." Biomedicines 12(12):2830. PMID 39767736 (PubMed 39767736) 13. Filonova EA et al. (2025). "Genes Associated with Action of ACTH-like Peptides with Neuroprotective Potential in Rat Brain Regions with Different Degrees of Ischemic Damage." Int J Mol Sci 26(13):6256. PMID 40650034 (PubMed 40650034) 14. PubMed 39418522 (PubMed 39418522) 15. PubMed 42021992 (PubMed 42021992) 16. PubMed 41004910 (PubMed 41004910)