Research Applications
Ischemic Stroke Recovery
Semax is approved in Russia (1% solution) for treatment of acute ischemic stroke and post-stroke cognitive rehabilitation. Clinical studies demonstrate reduced infarct volume, accelerated neurological recovery, and improved cognitive outcomes when administered within the acute window. The neuroprotective mechanism involves BDNF-mediated neuronal survival and reduced excitotoxic damage.
Cognitive Enhancement
The primary nootropic application. Clinical studies in healthy volunteers and cognitively impaired patients show improvements in working memory, attention, learning speed, and information processing. Effects are attributed to BDNF-mediated synaptic plasticity and enhanced monoaminergic neurotransmission.
Optic Nerve Atrophy
Semax is approved for treatment of optic nerve atrophy in Russia. Clinical trials demonstrate improved visual acuity, expanded visual fields, and enhanced retinal ganglion cell survival through BDNF-mediated neuroprotection of optic nerve fibers.
ADHD and Attention Disorders
Research demonstrates semax improves sustained attention and reduces impulsivity, with effects mediated through dopaminergic enhancement in prefrontal cortex. Clinical studies show improved performance on attention tasks.
Neurodegenerative Disease Research
Preclinical studies show semax reduces amyloid-beta toxicity, enhances cholinergic neuron survival, and improves cognitive function in Alzheimer's disease models. Similar neuroprotective effects are observed in Parkinson's disease models through GDNF upregulation and dopaminergic neuron protection.
Peptic Ulcer Disease
Approved in Russia for this indication, semax enhances gastric mucosal protection and accelerates ulcer healing through melanocortin-mediated effects on gastric microcirculation and cytoprotection.
Mechanism of Action
BDNF Upregulation (Primary Mechanism)
Semax is one of the most potent pharmacological inducers of brain-derived neurotrophic factor. It increases BDNF mRNA expression in hippocampus and cortex by 2-5 fold through activation of the BDNF gene promoter (exon IV). BDNF drives dendritic branching, synaptic plasticity (LTP), neuronal survival, and neurogenesis — the biological substrates of learning, memory, and cognitive resilience.
Melanocortin System Activation
Semax acts through melanocortin receptors (MC3R and MC4R) in the brain, which are Gs-coupled GPCRs that increase cAMP signaling. Melanocortin activation in hippocampus enhances memory consolidation, while cortical MC4R signaling improves attention and executive function. Importantly, semax lacks the MC2R (adrenal) activity of ACTH, explaining its absence of steroidogenic effects.
Serotonin and Dopamine Modulation
Semax increases serotonin and dopamine turnover in key brain regions. It enhances tryptophan hydroxylase and tyrosine hydroxylase activity, increases vesicular monoamine transporter expression, and modulates monoamine oxidase activity. This combined monoaminergic enhancement contributes to mood improvement, motivation, and sustained attention.
Neuroprotective Mechanisms
Semax protects neurons through multiple pathways: inhibition of glutamate excitotoxicity, reduction of intracellular calcium overload, suppression of oxidative stress (via SOD and catalase upregulation), and inhibition of apoptotic cascades (reduced caspase-3 activation, increased Bcl-2/Bax ratio). These neuroprotective mechanisms are particularly relevant in ischemic stroke and neurodegenerative conditions.
Anti-Inflammatory Neuroimmunomodulation
Semax reduces microglial activation and brain inflammation through downregulation of pro-inflammatory cytokines (TNF-α, IL-1β) and chemokines. This anti-neuroinflammatory effect is mediated through MC4R signaling and contributes to neuroprotection in inflammatory brain conditions.
Biological Pathways
BDNF/TrkB/CREB Pathway
Semax-induced BDNF binds TrkB receptors, activating PLCγ, PI3K/Akt, and MAPK/ERK cascades. ERK phosphorylates CREB in the nucleus, driving transcription of genes essential for synaptic plasticity and memory formation (Arc, Fos, Zif268). The BDNF-CREB positive feedback loop sustains neuroplastic changes beyond the acute treatment period.
cAMP/PKA/CREB via Melanocortin Receptors
MC3R/MC4R activation generates cAMP through Gαs-adenylyl cyclase coupling. PKA phosphorylates CREB, converging with BDNF/TrkB signaling to enhance transcription of plasticity genes. This dual pathway activation may explain semax's particularly robust cognitive effects.
Nrf2/HO-1 Neuroprotection
Semax activates the Nrf2 pathway, inducing heme oxygenase-1 (HO-1) and other cytoprotective enzymes. Carbon monoxide and biliverdin produced by HO-1 provide additional anti-inflammatory and antioxidant neuroprotection.
NGF/GDNF Neurotrophic Cascade
Beyond BDNF, semax upregulates nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF), supporting survival of cholinergic and dopaminergic neurons respectively. This broad neurotrophic support distinguishes semax from single-target cognitive enhancers.
Dosage Information
Calculation Results
Syringe Fill Level (100u syringe)
Protocols
Semax + Selank Cognitive StackBeginner🧠Cognitive4-8 weeks
Nootropic peptide stack for focus, memory, anxiety reduction, and neuroprotection.
Warning: May cause restlessness at high doses. Start low.
Stability & Storage
Semax is commercially available as 0.1% and 1% nasal spray solutions (in Russia) with a shelf life of 2 years at 2-8°C. The higher concentration (1% / 10mg/mL) is used for stroke treatment, while the 0.1% solution is used for nootropic indications.
Lyophilized semax powder should be stored at -20°C for long-term stability (18-24 months) or 2-8°C for 6 months. Protect from light due to the methionine residue's sensitivity to photooxidation.
The Pro-Gly-Pro C-terminal extension provides significant protection against carboxypeptidase degradation (same stabilization strategy as selank). However, the N-terminal methionine is susceptible to oxidation. Adding antioxidants (ascorbic acid, methionine) to formulations can extend solution stability. Intranasal administration is preferred for direct CNS delivery.
Side Effects & Precautions
Generally Well-Tolerated
Semax has an excellent safety profile documented across decades of clinical use in Russia. No serious adverse effects have been reported at approved dosing regimens.
Nasal Irritation
Mild burning or tingling in the nasal passages immediately after administration, typically lasting less than 1 minute. Most common with the 1% (high-concentration) formulation.
No Cortisol Stimulation
Despite its ACTH-derived structure, semax does not activate MC2R (adrenal) receptors and produces no measurable increase in cortisol or adrenal steroids — a critical safety feature validated in multiple studies.
No Dependence or Withdrawal
No evidence of tolerance, dependence, or withdrawal syndrome with chronic semax use. It can be discontinued abruptly without adverse effects.
Mild Headache
Occasional mild headache during initial use has been reported, typically self-limiting.
Possible Irritability
Some users report mild restlessness or irritability, possibly related to enhanced dopaminergic and noradrenergic tone. This effect is typically dose-dependent and resolves with dose adjustment.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Regulatory Status
Semax is approved in the Russian Federation as a nootropic (0.1%, registration number: P N000529/01) and neuroprotective agent (1%, for stroke treatment). It is also approved in Ukraine. Available without prescription for the nootropic indication in Russia.
Semax is not approved by the FDA, EMA, or regulatory authorities outside of Russia/CIS countries. It is classified as a research peptide in Western countries and available through research chemical suppliers.
The peptide is not on the WADA prohibited list. However, its ACTH-derived structure may warrant caution, as ACTH itself is prohibited by WADA under the S2 category. Semax's lack of steroidogenic activity distinguishes it pharmacologically from ACTH.
Research Studies
Semax (MEHFPGP) Enhances BDNF Expression and Cognitive Function
Dolotov OV, Karpenko EA, Inozemtseva LS, et al.
Semax in Acute Ischemic Stroke: A Clinical Study
Gusev EI, Skvortsova VI, Miasoedov NF, et al.
Neuroprotective Properties of the ACTH(4-10) Analog Semax
Levitskaya NG, Glazova NY, Sebentsova EA, et al.
Semax Modulates the Transcription of Genes Related to Immune Response
Medvedeva EV, Dmitrieva VG, Povarova OV, et al.
Melanocortin Peptides and Their Role in Neuroprotection
Adan RAH, Tiesjema B, Hillebrand JJG, et al.
