SEMAX (MET-HIS-PHE-PRO-GLY-PRO)

Mechanism of Action
Semax is a synthetic heptapeptide, an analog of amino acids 4–10 of corticotropin (ACTH), but without classical hormonal activity. Its precise mechanism of action is not fully understood, although several effects have been identified. In animal models, Semax rapidly increases levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus, and activates central serotonergic and dopaminergic systems. These neurochemical effects explain the antidepressant- and anxiolytic-like behaviors observed in preclinical studies, as well as improved adaptation to chronic stress. Semax also enhances dopamine release induced by psychostimulants (e.g., amphetamine).
It has been proposed that part of its action involves the melanocortin receptor pathway: evidence suggests that Semax can bind to melanocortin receptors MC4 and MC5, partially antagonizing α-MSH signaling. In addition, Semax (like Selank) inhibits enzymes that degrade enkephalins, thereby prolonging the action of endogenous opioid peptides with neuroprotective properties. These multiple targets contribute to its nootropic and neuroprotective effects. Because it is a peptide, Semax has low oral bioavailability and is typically administered as a nasal spray (or subcutaneously) to reach the central nervous system.
 
Clinical or Therapeutic Uses
Developed and primarily used in Russia, Semax is approved there as a neuroprotective and nootropic medication. It has been included in Russia’s list of essential medicines since 2011. Approved indications include the treatment of ischemic neurological events such as acute cerebral ischemic stroke and transient ischemic attack, where it is used to improve neurological recovery. It is also prescribed for cognitive and memory disorders of various etiologies, optic neuritis and optic nerve neuropathies, peptic ulcer disease (due to possible regulatory effects on the autonomic nervous system), and even as an immunomodulator to enhance resistance to infections. Outside the official Russian medical context, Semax is well known in the nootropic community for its purported cognitive benefits (improved focus and memory) and neuroprotective effects.
 
Side Effects or Risks
Semax is generally considered well tolerated. When administered intranasally, the most commonly reported adverse effects are mild irritation or discoloration of the nasal mucosa, occurring in approximately 10% of chronic users. In patients with diabetes, a transient increase in blood glucose has occasionally been observed (around 7% of cases). Some users report mild headache or transient agitation at the beginning of treatment, but Russian clinical studies have not documented serious adverse effects attributable to Semax. No significant drug interactions or addictive potential are known. Because it lacks significant hormonal activity, it does not produce the typical side effects associated with corticosteroids. However, the long-term effects of continuous use have not been well studied; although decades of use in Russia suggest relative safety, caution is advised in special populations (e.g., pregnancy or severe psychiatric disorders) until more data are available.