Semax

Semax is a synthetic regulatory peptide consisting of seven amino acids in the sequence methionine-glutamate-histidine-phenylalanine-proline-glycine-proline (Met-Glu-His-Phe-Pro-Gly-Pro). ^(1,2) Its name derives from the Russian abbreviation for “seven amino acids” (SEM AminoKiSlot). The peptide was created by combining the ACTH(4-7) fragment, the portion of adrenocorticotropic hormone associated with cognitive and neurotrophic effects, with a stabilizing (also spelled stabilizing in US literature) C-terminal Pro-Gly-Pro tripeptide that increases resistance to enzymatic degradation and extends biological activity from minutes to 20-24 hours in animal models. ^(1,5)

The critical design achievement of Semax is the separation of ACTH’s neurotrophic properties from its hormonal activity. Native ACTH stimulates cortisol release from the adrenal glands as part of the stress response. Semax retains the cognitive and neuroprotective effects mediated by the ACTH(4-10) region while producing no measurable interaction with glucocorticoid receptors, meaning it does not stimulate cortisol production or trigger the hypothalamic-pituitary-adrenal axis. ^(1,2) In practical terms, researchers get the brain-supporting properties of ACTH without the stress hormone consequences.

Semax was developed at the Institute of Molecular Genetics at the Russian Academy of Sciences and has been used as a prescription medication in Russia since the 1990s. ⁽²⁾ It was added to the Russian List of Vital and Essential Drugs in 2011. ⁽²⁾ Approved medical uses in Russia include the treatment of ischemic stroke, transient ischaemic attack, dyscirculatory encephalopathy, cognitive impairment following cerebrovascular events, optic nerve atrophy, and traumatic brain injury. ^(2,5) Two formulations are approved: 0.1% nasal drops for cognitive and mild neurological indications, and 1% nasal drops for acute stroke treatment. ⁽⁵⁾

Outside Russia and the CIS countries, the FDA, MHRA (UK), and TGA (Australia) have not approved Semax for any therapeutic indication. It is available as a research peptide for laboratory and investigational use. The peptide has poor oral bioavailability due to gastrointestinal peptidase degradation and is therefore administered intranasally or subcutaneously in research settings. ⁽²⁾

Healius supplies Semax as a lyophilized (also referred to as lyophilized in US research literature) powder in 10mg vials, intended strictly for laboratory and research applications.

Semax exerts its neuroprotective and nootropic effects through multiple overlapping molecular pathways, operating simultaneously on neurotrophic factors, neurotransmitter systems, immune signaling, and gene expression. ^(1,3,4)

The most extensively studied mechanism involves the upregulation of brain-derived neurotrophic factor (BDNF) and its signaling receptor tropomyosin receptor kinase B (TrkB). Dolotov et al. demonstrated that a single intranasal application of Semax (50 mcg/kg body weight) in rats produced a 1.4-fold increase in BDNF protein levels, a 1.6-fold increase in TrkB tyrosine phosphorylation, a 3-fold increase in exon III BDNF mRNA, and a 2-fold increase in TrkB mRNA in the hippocampus. ⁽³⁾ BDNF is considered one of the most important proteins for brain health: it supports neuronal survival, promotes the growth of new neurons and synapses, and is a key driver of neuroplasticity, the brain’s ability to reorganize and form new neural connections. ⁽³⁾ Semax also upregulates nerve growth factor (NGF) in the frontal cortex and hippocampus, providing complementary neurotrophic support to the cholinergic system, which is critical for memory and attention. ^(1,6)

Semax activates both serotonergic and dopaminergic brain systems. ⁽²⁾ These neurotransmitter pathways regulate mood, motivation, attention, and cognitive processing speed. Research has shown that Semax can augment the effects of psychostimulants on central dopamine release. This property has attracted interest in research into conditions involving dopaminergic dysfunction, including attention-deficit disorders. ^(2,7) The peptide also inhibits enkephalinase enzymes, which are responsible for degrading enkephalins, the body’s endogenous opioid peptides. ⁽²⁾ By slowing enkephalin breakdown, Semax extends the duration of the body’s natural analgesic and mood-regulating molecules without artificial stimulation.

Semax interacts with the melanocortin receptor system, specifically acting as an antagonist or partial agonist at MC4 and MC5 receptors. ⁽²⁾ These receptors are involved in stress signaling, inflammatory regulation, and central nervous system function. The peptide did not antagonize alpha-melanocyte-stimulating hormone at the MC3 receptor in published assays, though this receptor could still be a target. ⁽²⁾

Genome-wide transcriptional analysis has revealed the extraordinary breadth of Semax’s effects on gene expression. Medvedeva et al. ⁽²⁰¹⁴⁾, published in BMC Genomics, used a permanent middle cerebral artery occlusion (pMCAO) model in rats and identified 394 differentially expressed genes in Semax-treated subjects compared with controls. ⁽⁴⁾ The peptide predominantly enhanced the expression of genes related to the immune system, including immunoglobulins and chemokines. It influenced genes that promote the formation and functioning of the vascular system during ischemia. ⁽⁴⁾ This genome-wide study was the first to uncover Semax’s action on the immune system, a mechanism previously unrecognized (also spelled unrecognized) for this peptide.

A 2025 study published in Frontiers in Research identified the effects of Semax on intracellular calcium dynamics, adding another dimension to understanding its cellular mechanisms. ⁽¹⁾ The convergence of neurotrophic support, neurotransmitter modulation, immune activation, vascular protection, and broad gene expression changes explains why Semax has demonstrated effects across such a diverse range of neurological research models.

Ischaemic stroke and neuroprotection represent the original and most extensively studied clinical applications of Semax, forming the basis for its regulatory approval in Russia. ^(2,5)

In a study of 110 stroke patients, Gusev et al. ⁽²⁰¹⁷⁾ demonstrated that treatment with Semax (two courses of 6,000 mcg/day for 10 days, separated by a 20-day interval) increased plasma BDNF levels, and patients with elevated BDNF showed improved rehabilitation timing. ⁽⁸⁾ The 1% Semax nasal solution is the formulation used in acute stroke protocols, with dosages ranging from 6,000 to 20,000 mcg per day divided across multiple daily administrations for up to 10 days. ⁽⁵⁾

For cognitive enhancement, a pilot study in 24 healthy subjects found that intranasal 1% Semax solution (total dose 1.2mg) improved attention and short-term memory, with EEG changes similar to those observed with other established neuroprotective compounds. ⁽⁵⁾ Semax-treated animals in conditioned avoidance reaction experiments showed a distinct increase in the number of learned responses, providing a behavioral correlate to the BDNF upregulation observed at the molecular level. ⁽³⁾

In December 2025, a study published in Acta Naturae demonstrated significant findings in APP/PS1 transgenic mice, a standard Alzheimer’s disease model. ⁽⁹⁾ Thirty-day intranasal Semax administration improved cognitive performance across multiple behavioral assessments, representing the first robust preclinical evidence for Semax in Alzheimer ‘s-related pathology. ⁽⁹⁾ Separately, research published in the British Journal of Pharmacology in July 2025 identified a novel mechanism: Semax targets the mu-opioid receptor gene (Oprm1) to promote deubiquitination and functional recovery after spinal cord injury, opening a new avenue of investigation for the peptide’s neuroprotective effects. ⁽¹⁰⁾

Additional research domains include Parkinson’s disease models, in which intranasal Semax improved certain behavioral parameters in MPTP-treated animals. ⁽²⁾ Inozemtsev et al.  ⁽²⁰¹⁶⁾ demonstrated that Semax prevented learning and memory inhibition caused by heavy metal exposure in rats, suggesting neuroprotective applications in environmental toxicology. ⁽¹¹⁾ Semax has also been studied in optic nerve atrophy and glaucoma, where 0.1% intranasal solution has been used for up to 30 days in clinical settings. ⁽⁵⁾

It is important to note that, while the Russian clinical evidence base is substantial, many key clinical studies are published in Russian-language journals with limited English-language access. Molecular and preclinical data are more widely available in international peer-reviewed literature. Comprehensive English-language controlled clinical trials meeting Western regulatory standards have not been published, which is one reason the peptide remains unapproved outside Russia and the CIS countries.

Semax and Selank are the two most frequently compared neuropeptides in the nootropic and neuroscience research communities, and understanding their differences is essential for researchers designing cognitive or neurological protocols. ^(1,2)

Semax is derived from the ACTH (4-7) fragment and functions primarily as a nootropic and neuroprotective agent. Its core mechanisms involve upregulation of BDNF, activation of the dopaminergic and serotonergic systems, and broad modulation of gene expression. ^(1,3,4) The practical research profile is one of cognitive enhancement: improved focus, memory consolidation, attention, and neuroprotection under stress or injury conditions.

Selank, by contrast, is a synthetic analog of tuftsin, an endogenous immunomodulatory peptide. ⁽¹²⁾ Selank’s primary mechanisms involve GABAergic system modulation, producing anxiolytic (anti-anxiety) effects alongside cognitive support. While Selank also upregulates BDNF, its dominant research profile centers on stress reduction, anxiety management, and memory performance under conditions of psychological stress. ⁽¹²⁾ Selank does not activate dopaminergic systems to the same degree as Semax, giving it a calmer, less stimulating profile.

The complementary nature of these mechanisms is why combination use is a frequent topic of investigation. Semax provides cognitive stimulation and neuroprotective support through dopaminergic/serotonergic activation and robust elevation of BDNF. Selank provides anxiolytic balance through GABAergic modulation and immune support through its tuftsin-derived pathway. Together, they address both the excitatory and inhibitory sides of cognitive optimization (also spelled optimization). Research contexts that pair attention/focus demands with stress or anxiety components are where the combination approach is most frequently explored.

In terms of administration, both peptides are typically delivered intranasally and have a similar onset (15-30 minutes). Both are approved prescription medications in Russia and are available as research peptides elsewhere. For researchers interested in Selank, Healius offers Selank as a separate product, allowing independent or combination protocol design.

1. Oathpeptides. Semax Peptide Research: BDNF, Neuroprotection & Science. Comprehensive review of Semax mechanisms, including 2024-2025 research developments. December 2025.

2. Semax. Wikipedia. Accessed March 2026. (Comprehensive sourced overview with primary citation chain to Russian Academy of Sciences development, mechanism, clinical uses, and regulatory status.)

3. Dolotov OV, et al. Semax, an analog of ACTH (4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research. 2006;1117(1):54-60.

4. Medvedeva EV, 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. PMC3987924.

5. Kolomin TA, et al. Semax: comprehensive review of pharmacology, clinical applications, and dosing protocols. Referenced across multiple Russian-language clinical publications and package inserts for 0.1% and 1% Semax nasal drops.

6. Agapova TY, et al. Semax increases BDNF and NGF in the frontal cortex and hippocampus. Referenced in Dolotov et al. 2006 and subsequent neurotrophin studies.

7. Semax is suggested as a potential agent for ADHD treatment based on the augmentation of psychostimulant effects on central dopamine release and stimulation of brain BDNF synthesis. Referenced in neurodevelopmental disorder reviews citing Semax dopaminergic research.

8. Gusev EI, et al. Efficacy of Semax in treatment of patients at different stages of ischemic stroke: 110-patient study demonstrating increased plasma BDNF and improved rehabilitation timing with Semax treatment. 2017.

9. Acta Naturae. The Potential of the Peptide Drug Semax and Its Derivative for Alzheimer’s Disease: APP/PS1 transgenic mouse study. December 2025.

10. British Journal of Pharmacology. Semax peptide targets the mu-opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury. July 2025. doi:10.1111/bph.70122.

11. Inozemtsev AN, et al. Semax prevents heavy-metal-induced inhibition of learning and memory. Published 2016. PubMed indexed.

12. Selank: synthetic analog of tuftsin with anxiolytic and immunomodulatory properties, primarily acting through GABAergic system modulation. Approved in Russia alongside Semax for neurological and anxiety-related indications.

13. N-Acetyl Semax and N-Acetyl Semax Amidate: modified variants with enhanced enzymatic resistance through N-terminal acetylation and/or C-terminal amidation. Referenced in Peptides.org reviews and Wholisticresearch pharmacokinetic comparisons.

14. Tabbi G, et al. Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal-induced cell toxicity. Journal of Inorganic Biochemistry. 2015; 142:39-46.

15. Potaman VN, et al. Studies of Semax degradation in rat serum and entry to the rat brain via extraneuronal transport through olfactory epithelium. Referenced in Kolomin et al. 2013 comprehensive review.

16. Sudarkina OY, et al. Brain protein expression profile confirms the protective effect of the ACTH (4-7) PGP peptide (Semax) in a rat model of cerebral ischemia-reperfusion. International Journal of Molecular Sciences. 2021;22(12):6179.

17. Shadrina MI, et al. Rapid induction of BDNF and NGF mRNAs in rat glial cell cultures after Semax treatment. 2001. Referenced in PMC neurotrophin activation studies.

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