Semax

What Is Semax?

Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro, made by joining the adrenocorticotropic hormone fragment ACTH(4-7) to a C-terminal Pro-Gly-Pro tripeptide. Published papers describe it as an analogue of ACTH(4-10) that has been studied for nootropic and neuroprotective activity.^[1][2][3]

Most research on Semax concerns the central nervous system. A 2006 rat study summarized earlier work reporting effects on learning and memory formation in rodents and humans, and connected those effects in part to brain-derived neurotrophic factor (BDNF) in the basal forebrain.^[1] Later laboratory work has examined copper binding, amyloid-beta aggregation, neuronal calcium signaling and recovery after spinal cord injury.^[4][5][6][3]

The evidence base is dominated by cell, biochemical and animal studies. A 2026 review of therapeutic peptides noted a general lack of clinical trials for neuroactive peptides including Semax, and a 2026 gerontology review described non-approved peptides as having promising preclinical but limited clinical evidence and lacking long-term safety data.^[7][8]

Chemical Structure and Molecular Identity

Semax is a linear seven-residue peptide, MEHFPGP, with a free N-terminal amine and a free C-terminal carboxylic acid. PubChem lists it under CID 9811102 with the molecular formula C37H51N9O10S and a molecular weight of 813.9 g/mol.

The first four residues, Met-Glu-His-Phe, correspond to positions 4 to 7 of ACTH; the Pro-Gly-Pro extension completes the heptapeptide.^[3] The same C-terminal Pro-Gly-Pro motif ends the sequence of Selank, and a 2006 study grouped Semax, Selank and glyprolines together as regulatory proline-containing oligopeptides when comparing their effects on blood coagulation.^[9] The single sulfur atom in the formula comes from the N-terminal methionine.

Key identifiers

• InChIKey: AFEHBIGDWIGTEH-AQRCPPRCSA-N
• CAS number: 80714-61-0
• UNII: I5FAL2585H
• Synonyms: ACTH(4-7)-Pro-Gly-Pro; Pro-Gly-Pro-ACTH(4-7); MEHFPGP

Semax is strongly polar, with a computed XLogP of -2.8 and a topological polar surface area of 312. Biochemically, it is notable for a high affinity for Cu(II) ions and the ability to form a stable complex with copper, a property central to several recent in-vitro studies.^[4][5]

Research History and Development

Semax was built around a short fragment of ACTH, and its indexed literature runs from receptor-binding work in the 2000s to mechanistic studies published in 2025 and 2026. Much of it appears in Russian journals such as Doklady Biological Sciences, the Bulletin of Experimental Biology and Medicine and Acta Naturae.^[10][6][11]

A 2006 paper in the Journal of Neurochemistry addressed how the peptide might act. It built on an earlier observation that Semax stimulates BDNF synthesis in cultured basal forebrain astrocytes and went on to identify specific Semax binding sites in rat brain membranes.^[1]

Subsequent research broadened in several directions:

• Behavioral models: rat models of 6-hydroxydopamine-induced parkinsonism and of early-life exposure to the antidepressant fluvoxamine.^[10][2]
• Human imaging: a resting-state fMRI study of brain connectivity in healthy participants.^[12]
• Neurodegeneration chemistry: in-vitro work on copper, amyloid-beta and reactive oxygen species, followed by a transgenic Alzheimer’s mouse study that also tested a Semax derivative.^[5][4][11]
• Injury models: a 2025 mouse spinal cord injury study using RNA sequencing and molecular docking.^[3]

Mechanisms Studied in Research

Studies have linked Semax to several mechanisms: increased BDNF, specific high-affinity brain binding sites, copper chelation, modulation of neuronal calcium activity and, in one mouse study, the mu-opioid receptor. None of these has been established as its single primary mechanism.

BDNF and specific binding sites

In rat basal forebrain membranes, tritium-labelled Semax bound in a time-dependent, specific and reversible way that required calcium ions, with a dissociation constant (KD) of 2.4 nM. After intranasal application in rats, BDNF protein rose in the basal forebrain within 3 hours but not in the cerebellum.^[1] A 2026 review likewise grouped Semax with neuroactive peptides described as enhancing BDNF pathways.^[7]

Copper binding and amyloid-beta

In vitro, Semax extracted Cu(II) from Cu(II)-amyloid-beta complexes, altered the complex’s redox cycling and lowered associated reactive oxygen species; it also protected SH-SY5Y neuroblastoma cells from copper-catalyzed oxidative stress.^[4] A separate study using spectrofluorometric, calorimetric and MTT assays found that Semax prevented formation of amyloid-beta:Cu2+ complexes and inhibited fiber formation, with the strongest effect in the presence of copper.^[5]

Calcium signaling and opioid receptor targets

In rat hippocampal slices, Semax increased the frequency of spontaneous intracellular calcium fluctuations in CA1 pyramidal neurons but did not change proton-induced calcium rises in cerebellar granule cells, suggesting its neuroprotective action is not explained by blocking acid-sensing ion channels.^[6] In a mouse spinal cord injury model, network pharmacology and docking identified the mu-opioid receptor as a target, with downstream regulation of the deubiquitinase USP18 and the protein FTO.^[3]

Key Findings From Published Studies

Published findings on Semax come almost entirely from animal and in-vitro models, with one small human imaging study. The table summarizes the main results by model.

Animal studies

In the spinal cord injury study, recovery was assessed with footprint analysis, Basso scores and inclined plane tests, and knockdown of USP18 confirmed its role in the effect.^[3] In the Alzheimer’s model, both Semax and an unnamed derivative improved results in open field, novel object recognition and Barnes maze tests.^[11] In the fluvoxamine study, rat pups were exposed to the drug during a window equivalent to late human fetal development, then given Semax; treated animals showed less anxiety-like behavior and better maze learning than untreated exposed animals.^[2] In the parkinsonism model, neither Semax nor Selank altered motor activity, although Selank lowered anxiety measures.^[10]

Human data

In a study of 52 healthy participants, resting-state fMRI was recorded before and 5 and 20 minutes after Semax, Selank or placebo. The authors reported between-group differences in functional connectivity between the right amygdala and regions of the right temporal cortex, and described both shared and peptide-specific effects.^[12] No randomized clinical outcome trials appear in the abstracts reviewed for this page.

Semax differs from its acetylated, amidated analog by only a few atoms, so mass spectrometry on a certificate of analysis is the clearest identity check.

Regulatory and Research Status

Semax is not approved by the US Food and Drug Administration for any use and is studied in the United States as a research compound. A 2026 review of peptides in aging research noted that non-approved peptides, Semax among them, have limited clinical evidence and lack long-term safety data.^[8]

A 2026 orthopaedic review stated that, although preclinical studies of neuroactive peptides such as Semax are promising, clinical trials are lacking.^[7] Findings described on this page come from cell cultures, brain slices, rodent models and one small imaging study, and should be read with that limitation in mind.

Because Semax is a short, unmodified peptide that differs from related research compounds such as N-acetyl Semax amidate only by terminal groups, analytical confirmation of identity and purity matters for laboratory work. Mass spectrometry readily separates Semax (813.9 g/mol) from its N-acetylated, C-amidated analog (855.0 g/mol in PubChem).