Semax

Semax is a synthetic heptapeptide, Met-Glu-His-Phe-Pro-Gly-Pro, that joins the adrenocorticotropic hormone fragment ACTH(4-7) to a C-terminal Pro-Gly-Pro tripeptide (PubChem CID 9811102). The Pro-Gly-Pro tail affords increased resistance to peptidases, and the peptide is described as having no hormonal activity (Radchenko et al., 2025). Published work on the Semax peptide covers neurotrophin signaling, rodent brain ischemia models, monoamine neurochemistry, amyloid and copper chemistry, and a small number of imaging studies in healthy volunteers.

It is not that medicine, it is not intended for any clinical use, and it is not for use in people.

Published work on Semax falls into six areas. Each summary below states the model used. The imaging studies used a Semax drug preparation, not the research material sold here.

Design, stability and metabolism

A review of glyproline peptides, the family that includes Semax and Selank, reported that Pro-Gly-Pro-containing peptides are about as stable as major pharmacological preparations (Ashmarin et al., 2005). In rats given tritium-labeled Semax by nasal administration, labeled material reached the brain within 2 minutes, about 80 percent of it as intact Semax, and the peptide was then degraded rapidly, with Pro-Gly-Pro predominating among the products (Shevchenko et al., 2006). Incubated with nerve cells, Semax broke down mainly to His-Phe-Pro-Gly-Pro and Pro-Gly-Pro (Zolotarev et al., 2006).

Neurotrophin signaling and neuronal cultures

Tritium-labeled Semax bound rat basal forebrain membranes in a specific, reversible, calcium-dependent manner with a dissociation constant of about 2.4 nM, and nasal administration raised BDNF protein in the basal forebrain at 3 hours but not in the cerebellum (Dolotov et al., 2006a).

In rat hippocampus, a single application raised BDNF protein up to 1.4-fold and trkB tyrosine phosphorylation 1.6-fold, roughly tripled exon III BDNF mRNA, doubled trkB mRNA and increased conditioned avoidance responses (Dolotov et al., 2006b). In primary rat basal forebrain cultures, Semax increased survival of cholinergic neurons about 1.5 to 1.7-fold and stimulated choline acetyltransferase activity at 100 nM (Grivennikov et al., 2008).

Brain ischemia models and gene expression

After permanent middle cerebral artery occlusion in rats, Semax raised cortical transcription of Bdnf, TrkC and TrkA at 3 hours, Nt-3 and Ngf at 24 hours and Ngf at 72 hours. Its effect was selective for ischemic cortex, while the Pro-Gly-Pro fragment alone acted mainly nonspecifically (Dmitrieva et al., 2010). A genome-wide study in the same model found that Semax predominantly enhanced immune-system genes, more than half of the genes it altered at 24 hours, with immunoglobulin and chemokine genes most prominent; 24 vascular-system genes changed at 3 hours (Medvedeva et al., 2014).

Monoamine systems and stress models

In mice, Semax raised striatal tissue 5-hydroxyindoleacetic acid by about 25 percent at 2 hours and gradually raised extracellular levels over 1 to 4 hours, without changing dopamine on its own. Given before D-amphetamine, it enhanced amphetamine-induced striatal dopamine release and locomotor activity (Eremin et al., 2005). In male rats under chronic unpredictable stress, repeated systemic administration of Semax reversed or attenuated anhedonia in the sucrose preference test, suppression of body-weight gain, adrenal hypertrophy and the fall in hippocampal BDNF, while forced-swim immobility did not change. Melanotan II was tested in parallel (Inozemtseva et al., 2024).

Amyloid and copper-binding studies

Semax forms a stable complex with copper(II). In biophysical, membrane-model and cell-viability assays, it prevented formation of amyloid-β:copper complexes and showed anti-aggregating and protective properties, especially in the presence of copper (Sciacca et al., 2022). A follow-up study reported that Semax extracts copper(II) from copper-amyloid-β species, lowers copper-catalyzed reactive oxygen species production and protects SH-SY5Y cells from the resulting oxidative stress (Tomasello et al., 2025).

In APPswe/PS1dE9 transgenic mice, a one-month course of Semax brought several open field, novel object recognition and Barnes maze measures closer to wild-type values and reduced amyloid plaque counts in cortex and hippocampus (Radchenko et al., 2025).

Imaging studies in healthy volunteers

Two resting-state functional MRI studies measured brain network activity, not clinical outcomes. In 24 volunteers given Semax or placebo by nasal administration, the Semax group showed a larger medial frontal subcomponent of the default mode network (Lebedeva et al., 2018). A study of 52 participants comparing Semax, Selank and placebo reported group differences in connectivity between the right amygdala and right temporal cortex (Panikratova et al., 2020).