A reference work, not a recommendation to use: this profile describes mechanism and evidence and does not replace medical advice. The claims come from marketing and forums and are tested here, not endorsed.

Mechanism of action

Evidence map: Semax

Each line stands for a published finding; line style and color show where it comes from. The filter hides weaker evidence levels. Sources: see references.

Semax combines the fragment ACTH(4–7) of the adrenocorticotropic hormone with the tripeptide Pro-Gly-Pro, which slows degradation by peptidases; according to the developer group, it has no hormonal action [1]. In the forebrain of rats, radiolabeled semax binds with high affinity (dissociation constant 2.4 nM) to a binding site whose protein is unknown, and raises BDNF there [2]. A single intranasal dose increased BDNF in the hippocampus 1.4-fold and phosphorylation of the receptor TrkB 1.6-fold; the animals showed more learned avoidance responses [3].

The second focus is stroke models in rats. After occlusion of a cerebral artery, semax mainly altered genes of the immune and vascular systems [4]; after reperfusion, 394 genes were regulated differently, inflammation-related genes were dampened and signal transduction genes were activated [5]. Almost all of these studies come from one Moscow research consortium. After intranasal administration, 0.093% of the radioactivity per gram reached the rat brain after 2 minutes; semax is cleaved rapidly, and the tripeptide Pro-Gly-Pro predominates [6]. Pro-Gly-Pro alone did not protect in an ischemia model [7].

In cell culture, the peptide with the semax sequence blocked activation of the melanocortin receptors MC4 and MC5 by α-MSH, but not of MC3 [8]. In rodents, semax alone did not change the dopamine level in the striatum, but raised the serotonin breakdown product 5-HIAA and enhanced dopamine release by amphetamine [9]. In the laboratory, semax binds copper(II) ions and reduced copper-induced cell damage [10]; it also inhibits enkephalin-degrading enzymes in human serum, though only in the micromolar range [11].

Targets

TargetTypeActionKey dataEvidence
Binding site in the forebrain (protein unknown)OtherBindingKd 2.4 nM (rat membranes) Laboratory[2]
Melanocortin receptor MC4ReceptorAntagonist Laboratory[8]
Melanocortin receptor MC5ReceptorAntagonist Laboratory[8]
Enkephalin-degrading enzymes (serum)EnzymeInhibitorIC50 ≈ 10 µM (human serum) Laboratory[11]
Copper(II) ionsOtherBinding Laboratory[10]

Effect profile

Which signaling systems the compound affects according to current data. ↑ enhanced, ↓ dampened, ≈ modulated, ○ no effect; dots = evidence level.

  • Dopaminemodulated · no effect on dopamine alone; enhances release by amphetamine (rodent)[9]
  • Noradrenalineno data
  • Serotonin↑ · Serotonin breakdown product 5-HIAA raised in the striatum (rodent)[9]
  • Acetylcholineno data
  • Glutamate · AMPAno data
  • Glutamate · NMDAno data
  • GABAno data
  • Histamineno data
  • Orexinno data
  • Adenosineno data
  • Opioidsmodulated · inhibits enkephalin-degrading enzymes in serum, only at high concentration[11]
  • Melatoninno data
  • Neurotrophins↑ · BDNF and TrkB activation raised in the rat hippocampus[2][3]
  • Blood flowmodulated · Vessel-related genes altered after ischemia (rat)[4]
  • Nitric oxideno data
  • Energy metabolismno data
  • Insulin · glucoseno data
  • Inflammation · oxidative↓ · Inflammatory genes dampened after ischemia (rat); less copper-induced cell damage (laboratory)[5][10]
  • Stress axisno data
  • Testosterone axisno data
  • Endocannabinoidsno data
  • Autophagy · senescenceno data
  • Immune systemno data
  • Lipid metabolismno data
  • Coagulation · fibrinolysisno data
  • Methylationno data

Human studies

  • Rehabilitation after ischemic stroke

    controlled, randomization not described · Patients: after ischemic stroke · n = 110 · 5 months of observation

    Measured: Plasma BDNF, Barthel index, motor function

    Result: With semax, BDNF and Barthel index rose faster.[14]

    Human, non-randomised

  • Resting-state fMRI in healthy people

    placebo-controlled · healthy · n = 24 · Single dose, measurement after 5 and 20 minutes

    Measured: Default mode network on fMRI

    Result: Larger rostral subcomponent of the network; no cognitive tests.[15]

    Human, randomised

Risks and warnings

  • Lack of safety data

    No systematic safety data by Western standards; long-term safety unknown [12].

    No data

  • Unclear identity and purity

    Freely available on the internet as a “research peptide”; detected in confiscated products, quality not controlled [13].

    No data

Interactions

  • Amphetamin: In rodents, enhanced amphetamine-induced dopamine release and locomotor activity [9].

Fact check: common claims

  • not supported

    “Semax is a dopamine booster”

    Alone, semax did not change the dopamine level in rodents; it only enhanced the effect of amphetamine [9].

  • not supported

    “Semax improves focus and concentration in healthy people”

    No controlled study with cognitive endpoints in healthy people; the parent compound ACTH(4–10) worsened measures of attention [16][17].

  • partly supported

    “Semax raises BDNF”

    Shown in the rat brain [2][3]; in humans only plasma BDNF in a nonrandomized study [14].

Pharmacokinetics

Absorption
Intranasal administration in the studies.
Half-life
Not studied in humans.
Metabolism
Rapid enzymatic cleavage; in the rat brain, Pro-Gly-Pro soon predominates [6].
Entry into the brain
After 2 minutes, 0.093% of the radioactivity per gram of brain tissue (rat) [6].

Legal status

Germany
No marketing authorization known; not checked in the German medicines register.
EU
According to a review, not approved by the FDA or comparable agencies [12].
USA
Not approved by the FDA [12].
Other countries
Russia: on the state list of vital and essential medicines (Government Order 2406-r of October 12, 2019) [1].

Related compounds

N-Acetyl-Semaxderivative (German only)Adamaxderivative (German only)Selanksame class

Open questions

  • Which protein is the high-affinity binding site in the forebrain?
  • Can the findings on BDNF and gene expression be replicated by independent groups?
  • How does semax act in randomized, blinded studies with cognitive endpoints in healthy people?

References

  1. Radchenko AI, Kuzubova EV, Apostol AA, Mitkevich VA, Andreeva LA, Limborska SA, et al. The potential of the peptide drug Semax and its derivative for correcting pathological impairments in the animal model of Alzheimer’s disease. Acta Naturae. 2025;17(4):110–20. doi:10.32607/actanaturae.27808 · PubMed
  2. Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, 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 1:82–6. doi:10.1111/j.1471-4159.2006.03658.x · PubMed
  3. Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, et al. 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. doi:10.1016/j.brainres.2006.07.108 · PubMed
  4. Medvedeva EV, Dmitrieva VG, Povarova OV, Limborska SA, Skvortsova VI, Myasoedov NF, et al. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics. 2014;15:228. doi:10.1186/1471-2164-15-228 · PubMed
  5. Filippenkov IB, Stavchansky VV, Denisova AE, Yuzhakov VV, Sevan’kaeva LE, Sudarkina OY, 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. doi:10.3390/genes11060681 · PubMed
  6. Shevchenko KV, Nagaev IIu, Alfeeva LIu, Andreeva LA, Kamenskiĭ AA, Levitskaia NG, et al. [Kinetics of Semax penetration into the brain and blood of rats after its intranasal administration]. Bioorg Khim. 2006;32(1):64–70. doi:10.1134/s1068162006010055 · PubMed
  7. Fadyukova OE, Kadi A, Bai O, Andzhusheva GM, Koshelev VB. C-terminal Pro-Gly-Pro tripeptide in contrast to full-length neuropeptide semax exhibits no neuroprotective effect in experimental cerebral ischemia. Bull Exp Biol Med. 2005;139(4):421–3. doi:10.1007/s10517-005-0311-5 · PubMed
  8. Adan RA, Oosterom J, Ludvigsdottir G, Brakkee JH, Burbach JP, Gispen WH. Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. Eur J Pharmacol. 1994;269(3):331–7. doi:10.1016/0922-4106(94)90041-8 · PubMed
  9. Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, et al. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochem Res. 2005;30(12):1493–500. doi:10.1007/s11064-005-8826-8 · PubMed
  10. Tabbì G, Magrì A, Giuffrida A, Lanza V, Pappalardo G, Naletova I, et al. Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal induced cell toxicity. J Inorg Biochem. 2015;142:39–46. doi:10.1016/j.jinorgbio.2014.09.008 · PubMed
  11. Kost NV, Sokolov OIu, Gabaeva MV, Grivennikov IA, Andreeva LA, Miasoedov NF, et al. [Semax and selank inhibit the enkephalin-degrading enzymes from human serum]. Bioorg Khim. 2001;27(3):180–3. doi:10.1023/a:1011373002885 · PubMed
  12. Mavrych V, Shypilova I, Bolgova O. Therapeutic peptides in gerontology: mechanisms and applications for healthy aging. Front Aging. 2026;7:1790247. doi:10.3389/fragi.2026.1790247 · PubMed
  13. Vanhee C, Francotte A, Janvier S, Deconinck E. The occurrence of putative cognitive enhancing research peptides in seized pharmaceutical preparations: an incentive for controlling agencies to prepare for future encounters of the kind. Drug Test Anal. 2020;12(3):371–81. doi:10.1002/dta.2717 · PubMed
  14. Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN. [The efficacy of semax in the treatment of patients at different stages of ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3 Vyp 2):61–8. doi:10.17116/jnevro20181183261-68 · PubMed
  15. Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, et al. Effects of Semax on the default mode network of the brain. Bull Exp Biol Med. 2018;165(5):653–6. doi:10.1007/s10517-018-4234-3 · PubMed
  16. Smolnik R, Perras B, Mölle M, Fehm HL, Born J. Event-related brain potentials and working memory function in healthy humans after single-dose and prolonged intranasal administration of adrenocorticotropin 4-10 and desacetyl-alpha-melanocyte stimulating hormone. J Clin Psychopharmacol. 2000;20(4):445–54. doi:10.1097/00004714-200008000-00009 · PubMed
  17. Smolnik R, Mölle M, Fehm HL, Born J. Brain potentials and attention after acute and subchronic intranasal administration of ACTH 4-10 and desacetyl-alpha-MSH in humans. Neuroendocrinology. 1999;70(1):63–72. doi:10.1159/000054460 · PubMed
How this profile was checked

Last reviewed: 2026-10-23. All sources with a DOI or PMID were resolved automatically via Crossref or doi.org and PubMed.

Translated from the German profile (version of 2026-10-23); translation checked on 2026-10-26.

Checked

  • All 17 DOIs resolved via Crossref, PMIDs match the DOIs.
  • Key figures checked against abstracts: Kd 2.4 nM [2]; BDNF 1.4-fold, TrkB 1.6-fold [3]; 394 genes [5]; 0.093%/g after 2 min, PGP predominates [6]; MC4/MC5, not MC3 [8]; 5-HIAA, amphetamine [9]; IC50 10 µM [11]; n = 110 [14]; 14 vs. 10 [15]; ACTH(4–10) n = 60 and 54 [16][17].
  • In the full text: list of vital medicines [1]; “not approved by the FDA or equivalent regulatory agencies” [12]; confiscated products [13].
  • ClinicalTrials.gov: 0 entries for semax (October 23, 2026).

Not verified

  • Authorization status in Germany and the EU not checked in medicines registers.
  • Exact indications approved in Russia (register not accessible).
  • Russian-language studies read as abstracts only.

No dosages, no sources of supply. This information does not replace medical advice.

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