Semax: Complete Guide

Semax was developed in the 1980s by a research team led by Nikolai Myasoedov at the Institute of Molecular Genetics in Moscow. The starting point was ACTH(4-10) — a seven-amino-acid fragment of adrenocorticotropic hormone that had been shown to improve attention and memory in animal studies without the hormonal (adrenal-stimulating) effects of full-length ACTH.

The native ACTH(4-10) fragment degrades rapidly in vivo. The Semax modification replaces the C-terminal amino acids with a Pro-Gly-Pro tripeptide, dramatically improving metabolic stability. The resulting peptide maintains the neurotrophic properties of ACTH(4-10) with a significantly extended half-life.

In Russia, Semax has received regulatory approval for three indications: (1) cognitive disorders and intellectual-mnestic impairment, (2) ischemic stroke and transient ischemic attack recovery, and (3) optic nerve atrophy. It is available as a 0.1% and 1% nasal spray.

Critically, despite being derived from ACTH, Semax does not activate the hypothalamic-pituitary-adrenal (HPA) axis. It does not stimulate cortisol production, does not affect adrenal function, and does not produce the metabolic side effects associated with corticosteroids.

Semax's neuroprotective and cognitive effects operate through multiple mechanisms:

• Neurotrophic factor upregulation: Semax significantly increases the expression of BDNF and NGF in the hippocampus, cortex, and basal forebrain. BDNF is essential for long-term potentiation (the cellular basis of learning), synaptic plasticity, and neuronal survival. NGF supports the survival and function of cholinergic neurons critical for memory.
• Serotonergic modulation: Semax modulates serotonin (5-HT) and its metabolite 5-HIAA in the hippocampus, striatum, and hypothalamus. This contributes to mood regulation and may partially explain its effects on motivation and emotional processing.
• Dopaminergic effects: Research shows Semax influences dopamine and its metabolites in the striatum and frontal cortex, which likely contributes to its effects on attention, motivation, and reward processing.
• Neuroprotection in ischemia: During oxygen and glucose deprivation (modeling stroke), Semax activates survival signaling pathways including PI3K/Akt and MAPK/ERK, while suppressing apoptotic pathways. This reduces neuronal death in the ischemic penumbra.
• Gene expression modulation: Transcriptomic studies have shown that Semax alters the expression of over 100 genes in the rat brain, with affected pathways including neurotransmission, immune function, vascular regulation, and cell survival.

Cognitive Enhancement

Multiple animal and human studies demonstrate Semax's cognitive effects. In rodent models, Semax improved performance on the Morris water maze (spatial memory), passive avoidance tests (associative learning), and novel object recognition (declarative memory). Human studies conducted during its Russian approval showed improvements in attention, short-term memory, and mental performance under stress.

The 0.1% nasal spray formulation is approved in Russia for cognitive enhancement in healthy individuals experiencing mental fatigue or high cognitive demands, as well as for patients with cognitive impairment from various etiologies.

Stroke and Neuroprotection

The 1% nasal spray formulation (10× concentration) is approved for use in ischemic stroke. Clinical studies showed that Semax administered within the first 12 hours of ischemic stroke improved neurological outcomes and reduced infarct size when added to standard therapy. The neuroprotective effect is attributed to BDNF upregulation, anti-apoptotic signaling, and reduction of glutamate excitotoxicity.

Optic Nerve Disease

Semax has been used in the treatment of optic nerve atrophy in Russian clinical practice. The proposed mechanism involves NGF-mediated support of retinal ganglion cell survival and axonal regeneration.

ADHD and Focus

Preliminary research suggests Semax may benefit attention-related conditions. Its modulation of dopaminergic and noradrenergic systems — the same neurotransmitter pathways targeted by conventional ADHD medications — has generated interest, though controlled clinical trials for ADHD have not been completed.

Semax dosing varies by application:

Application	Formulation	Dose	Frequency
Cognitive enhancement	0.1% nasal spray	200–600 mcg total	2–3 drops per nostril, 3× daily
Neuroprotection / stroke	1% nasal spray	2–6 mg total	2–3 drops per nostril, 3–4× daily
Research (SC injection)	Reconstituted solution	200–1000 mcg	Once daily

A typical research course lasts 10–14 days, with some protocols extending to 30 days. The approved Russian formulations recommend courses of 10–14 days with breaks between courses.

For injectable Semax, use the peptide calculator for reconstitution volumes. For detailed protocols, visit the Semax dosage guide.

Semax has a well-established safety profile from its clinical use in Russia:

• No hormonal effects: Despite being an ACTH analog, Semax does not stimulate cortisol production or affect the HPA axis — the most important safety distinction from its parent molecule
• No sedation: Semax is activating rather than sedating, improving alertness and focus
• Nasal irritation: Mild, transient nasal discomfort with intranasal administration
• Headache: Occasionally reported, typically mild
• No tolerance or dependence: No evidence of tolerance development or withdrawal symptoms in clinical use
• Low toxicity: Toxicological studies showed high therapeutic index with no mutagenic, teratogenic, or embryotoxic effects

Some users report mild stimulation that can interfere with sleep if administered too late in the day. For this reason, dosing earlier in the day is generally preferred. More details in the Semax side effects guide.

Two modified versions of Semax are used in research:

• NA-Semax (N-Acetyl Semax): An acetylated form with improved metabolic stability and potentially enhanced blood-brain barrier penetration. Some researchers report stronger effects at lower doses compared to standard Semax.
• NA-Semax Amidate: Features both N-acetylation and C-terminal amidation, providing the highest stability among Semax variants. The amidation protects against carboxypeptidase degradation, further extending the half-life.

These variants have not undergone formal clinical trials and are used exclusively in research settings. The standard (non-modified) Semax is the form with regulatory approval and the most extensive safety and efficacy data.

For a comparison with the related Russian neuropeptide, see the Selank guide.