Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is a synthetic heptapeptide derived from the 4–7 fragment of adrenocorticotropic hormone (ACTH 4-7). Developed at the Institute of Molecular Genetics, Moscow, and registered as a pharmaceutical in Russia and Ukraine, Semax has been extensively studied for neuroprotective, nootropic, and cerebrovascular applications with a substantial body of Russian clinical and preclinical literature.
The parent fragment ACTH 4-7 (Met-Glu-His-Phe) has known cognitive-enhancing properties first characterised by David de Wied in the 1970s — work that established the "neuropeptide cognition" field. ACTH 4-10 and related fragments improve learning and memory in rodent models without activating adrenal steroid production (requiring the ACTH 1-3 sequence for adrenal stimulation). Semax incorporates the active tetrapeptide ACTH 4-7 with a stabilising Pro-Gly-Pro extension that increases plasma half-life from minutes to approximately 20 minutes, substantially improving its research utility.
A key mechanism underlying Semax's neuroprotective and cognitive effects is upregulation of BDNF (brain-derived neurotrophic factor) and its high-affinity receptor TrkB. Russian preclinical data demonstrates that acute Semax administration increases BDNF mRNA and protein in the hippocampus, frontal cortex, and striatum within 30–60 minutes, with effects persisting for several hours. BDNF is essential for long-term potentiation, synaptic plasticity, and neuronal survival — providing a mechanistic basis for both cognitive and neuroprotective effects.
Semax has been most extensively clinically studied in ischaemic stroke and transient ischaemic attack (TIA). Published Russian clinical trials (Gusev et al., 1997; Mjasoedov et al.) demonstrated that intranasal Semax administration in acute ischaemic stroke significantly reduced stroke severity scores, improved neurological recovery at 3 months, and reduced lesion volume on neuroimaging versus placebo controls. The compound is registered in Russia for this indication.
Mechanistic data suggests Semax reduces neuroinflammation (decreased IL-1β, IL-6 in ischaemic tissue), reduces apoptotic signalling via BDNF/TrkB activation, and promotes angiogenesis and VEGF expression in peri-ischaemic tissue. In optic nerve ischaemia models, Semax significantly reduces retinal ganglion cell loss.
In addition to neuroprotection, Semax has been studied for cognitive effects in both healthy subjects and disease models. Russian clinical data describes improvements in attention, memory, and psychomotor speed in patients with cognitive impairment due to vascular dementia and encephalopathy. Preclinical data demonstrates enhanced learning in maze tasks and improved memory consolidation.
Dopaminergic and serotonergic system modulation has been proposed as a mechanism for cognitive effects: Semax increases dopamine and its metabolites in striatum and frontal cortex of rodents, and modulates 5-HT receptor expression in limbic areas.
At higher doses, Semax shows anxiolytic effects in rodent models, potentially related to its BDNF-upregulating and serotonergic effects. Russian clinical studies in depression and anxiety disorders report modest benefits, though the primary clinical indication remains neuroprotection rather than mood disorders.
Like Selank, Semax is well-suited to intranasal delivery for CNS research. The olfactory route provides direct CNS access and is the standard delivery method used in Russian clinical trials. Research comparing intranasal vs systemic delivery shows intranasal administration achieves higher brain/plasma ratios for this peptide class.
