Semax

Semax is a synthetic heptapeptide derived from the N-terminal fragment of adrenocorticotropic hormone (ACTH), specifically the 4-7 sequence with a C-terminal Pro-Gly-Pro tripeptide extension that confers enzymatic stability. It was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences and has been approved in Russia since 1996 for the treatment of stroke, cognitive disorders, and peptic ulcers. Unlike full-length ACTH, Semax lacks steroidogenic activity and exerts its effects primarily through neurotrophic and neuroprotective mechanisms.

The peptide has gained attention in the nootropic community for its cognitive-enhancing properties, though the majority of clinical evidence originates from Russian-language literature. Its favorable safety profile at approved doses and non-hormonal mechanism of action distinguish it from other ACTH-derived peptides.

Semax exerts its effects through multiple converging pathways. It upregulates the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus and cortex, promoting neuronal survival, synaptic plasticity, and long-term potentiation. This neurotrophic upregulation is considered the primary driver of its cognitive-enhancing effects. Additionally, Semax modulates the melanocortin system, interacting with MC4 and MC5 receptors, although its binding profile differs substantially from that of alpha-MSH or full-length ACTH.

In the context of ischemic injury, Semax suppresses pro-inflammatory cytokine expression and modulates immune response gene activity in the penumbral zone. It has also been shown to influence dopaminergic and serotonergic neurotransmission, which may contribute to its reported anxiolytic and antidepressant-adjacent effects. The C-terminal PGP tripeptide is itself a bioactive fragment with anti-inflammatory properties, suggesting that Semax may function as a prodrug releasing multiple active components upon enzymatic degradation.