PwPepwise

Semax

Brain & Focus

ACTH(4-10) heptapeptide analog

Semax is a synthetic peptide derived from a fragment of adrenocorticotropic hormone (ACTH).

§Dosing at a glance

4 protocols · from the research
What it's forDoseHow oftenHowFor how long
Ischemic Stroke / Neurological Rehabilitation6,000 mcg/dayDailyIntranasalSprayed into the nose.10 days
Motor Neuron Disease (ALS)12 mg/dayDailyIntranasalSprayed into the nose.—
Cognitive / Nootropic Effects (Animal Reference Dose)50 µg/kgDailyIntranasalSprayed into the nose.—
Lipid Metabolism (Psoriasis with Metabolic Syndrome)600 mcg/dayDailyIntranasalSprayed into the nose.10 days

Approximate values pulled from the research — double-check before dosing.

§01Summary

Semax is a synthetic peptide derived from a fragment of adrenocorticotropic hormone (ACTH), specifically the ACTH(4-7) sequence with an added Pro-Gly-Pro tripeptide tail. Originally developed in Russia, it is administered intranasally and reaches the brain within minutes of application20, making it a practical candidate for neurological applications. Semax appears to support brain health through several overlapping mechanisms, most notably by promoting the production of brain-derived neurotrophic factor (BDNF), a protein critical for the survival and growth of neurons2,4,8. In animal studies, a single intranasal dose has been reported to increase hippocampal BDNF protein levels and activate its receptor within hours2. In early human studies, Semax has been reported to elevate plasma BDNF levels in stroke patients and may contribute to improved functional recovery when combined with rehabilitation12. Beyond neurotrophic effects, Semax appears to modulate immune signaling, serotonergic activity, and stress-related gene expression in the brain3,5,19. It has been studied across a range of neurological contexts including ischemic stroke, motor neuron disease, spinal cord injury, and cognitive enhancement, with the evidence base actively developing across both preclinical and early clinical settings.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is a heptapeptide analog of the ACTH(4-10) fragment, extended at its C-terminus with the Pro-Gly-Pro (PGP) tripeptide to confer resistance to enzymatic degradation and extend biological activity. Its primary characterized mechanism involves potent upregulation of neurotrophic signaling. Semax demonstrates specific, reversible, calcium-dependent binding to rat basal forebrain cell membranes with a dissociation constant (KD) of approximately 2.4 nM and a maximum binding capacity (BMAX) of 33.5 fmol/mg protein, suggesting a receptor-mediated or high-affinity carrier-mediated mechanism distinct from classical ACTH receptors4. Downstream of this binding, Semax rapidly activates transcription of BDNF (up to 8-fold in glial cultures at 30 minutes8; 3-fold exon III BDNF mRNA in hippocampus2) and NGF (5-fold in glial cultures8), and promotes trkB tyrosine phosphorylation (1.6-fold)2, indicating activation of the full ligand-receptor neurotrophic signaling axis.

A recent study identified the µ-opioid receptor (Oprm1) as a molecular target of Semax in the context of spinal cord injury, where receptor engagement drives USP18-mediated deubiquitination of the fat mass and obesity-associated protein FTO, inhibiting lysosomal membrane permeabilization-related pyroptosis and reducing oxidative stress6. This represents a previously unreported signaling axis for a peptide structurally classified as an ACTH fragment analog.

At the transcriptomic level, Semax exerts pleiotropic effects in ischemic brain tissue. In focal ischemia models, it selectively activates neurotrophin and receptor gene expression in ischemic (but not healthy) cortex across multiple time points1, and modulates over 1,170 immune and neurosignaling pathway genes, normalizing ischemia-induced transcriptomic disruption13. Immune response genes comprise over 50% of Semax-altered gene expression at 24 hours post-ischemia, encompassing immunoglobulin, chemokine, interferon signaling, and antigen presentation pathways3,10. Simultaneously, Semax suppresses inflammatory markers (MMP-9, c-Fos, phospho-JNK) and promotes neuroprotective signaling (phospho-CREB) at the protein level11.

Semax also activates the serotonergic system, increasing striatal tissue 5-HIAA by 25% and extracellular 5-HIAA by up to 180% within 1–4 hours of intraperitoneal administration, and potentiates dopamine release in the presence of D-amphetamine through an indirect modulatory mechanism19. Pharmacokinetically, intranasal Semax reaches rat brain tissue within 2 minutes, with approximately 80% of early brain radioactivity representing intact peptide; it undergoes rapid enzymatic metabolism, with Pro-Gly-Pro as the predominant biologically active metabolite20. The calcium-dependence of Semax's receptor binding4 and its mitochondrial stabilizing effects under glutamate excitotoxicity17 further implicate calcium homeostasis pathways as central to its mechanism of action.

§04Evidence & efficacy

Evidence base
220Studies
29Human
105Animal

Semax has demonstrated the most consistent evidence in the domain of neuroprotection during ischemic brain injury. Across multiple independent animal studies, Semax selectively upregulates neurotrophin gene transcription (BDNF, NGF, NT-3 and their receptors) specifically in ischemic cortex1, rapidly induces BDNF and NGF mRNA in glial cultures (8-fold and 5-fold increases, respectively, within 30 minutes)8, increases hippocampal BDNF protein and trkB phosphorylation following a single intranasal dose2, and suppresses inflammatory while activating neurotransmission-related gene pathways in stroke models9,11. At the protein level, Semax reduces MMP-9, c-Fos, and phospho-JNK while enhancing phospho-CREB in ischemic brain tissue11. It also appears to protect neurons from glutamate excitotoxicity by preserving mitochondrial membrane potential and improving survival by approximately 30% in vitro17, and may attenuate nitric oxide overproduction and lipid peroxidation in global ischemia18.

In human studies, Semax has been reported to increase plasma BDNF levels in ischemic stroke patients and may contribute to improved Barthel Index functional scores when combined with early rehabilitation12. Neuroimaging in healthy volunteers suggests Semax may modulate default mode network topology within 20 minutes of intranasal delivery7. In a motor neuron disease study, Semax did not demonstrate effects on neurological disease progression but may improve quality of life through emotional and motivational dimensions16. In a chronic unpredictable stress animal model, Semax appears to attenuate anhedonia, body weight suppression, adrenal hypertrophy, and reduced hippocampal BDNF14. Early human data suggests possible beneficial effects on lipid profiles in metabolic syndrome15 and antistress transcriptomic correction in hippocampal gene expression5.

§05Safety

Across the human studies summarized, Semax administered intranasally at doses ranging from 600 mcg/day to 12 mg/day has been generally well tolerated, with no serious adverse events explicitly reported in any of the reviewed publications7,12,15,16. The study in healthy volunteers using 1% intranasal Semax reported acceptable tolerability with no described adverse effects within the observation window7. The open-label motor neuron disease study using 12 mg/day in two courses similarly reported no specific safety concerns16. In animal models, chronic intraperitoneal dosing at 60 nmol/kg did not negatively impact body weight gain, suggesting reasonable tolerability at tested preclinical doses14. One study conducted exclusively in female mice noted sex-specificity in its findings, indicating that sex-dependent safety and efficacy profiles are an area of active research6. No drug interaction data, contraindication profiles, or long-term safety studies were identified in the reviewed literature.

§06History

Semax was developed in the Soviet Union and subsequently Russia by researchers at the Institute of Molecular Genetics and the Russian Academy of Sciences, emerging from a program to create stable, therapeutically useful analogs of ACTH fragments. The foundational rationale was that ACTH(4-10) and related melanocortin peptide fragments possessed neurotrophic and cognitive-enhancing properties independent of their corticotropic activity, and that structural modification — specifically addition of the C-terminal Pro-Gly-Pro tripeptide — could extend peptide stability and potency. Semax received regulatory approval in Russia for clinical use in ischemic stroke and other cerebrovascular conditions and has been available there as a prescription intranasal formulation since the 1990s.

Early mechanistic research established Semax's capacity to upregulate BDNF and NGF in glial cell cultures8 and demonstrated rapid nose-to-brain delivery kinetics20. Subsequent studies through the 2000s characterized BDNF/trkB signaling as a central mechanistic axis2,4, and genome-wide transcriptomic analyses in the 2010s revealed the unexpected breadth of Semax's immunomodulatory and vascular gene expression effects in ischemic models3,10. Human clinical research has been conducted predominantly in Russia, with published studies addressing stroke rehabilitation12, motor neuron disease16, cognitive function7, and metabolic comorbidities15. More recently, a novel µ-opioid receptor mechanism was identified in a spinal cord injury model6, opening new mechanistic directions. The compound remains under active preclinical and clinical investigation, with the evidence base continuing to expand.

§07References