Semax: Nootropic Peptide Research Profile

Your brain makes a protein called BDNF -- brain-derived neurotrophic factor -- that acts like fertilizer for neurons. It helps them grow, form new connections, and survive under stress. What if a nasal spray could turn up your brain's BDNF production on demand?

That's the basic promise behind Semax, a synthetic peptide developed in Soviet-era Russia that has since become one of Eastern Europe's most widely prescribed brain medications. Approved in Russia for conditions ranging from stroke recovery to cognitive impairment, Semax sits in an unusual position: it has decades of clinical use behind it, but almost none of that evidence meets the gold-standard trial designs that Western regulators expect.

This profile covers what Semax is, how it works, what the research actually shows, and where the evidence falls short.

Quick Facts

Detail	Information
Full name	Semax (ACTH 4-10 analog with Pro-Gly-Pro)
Amino acid sequence	Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP)
Molecular weight	813.93 g/mol
Type	Synthetic heptapeptide, ACTH fragment analog
Developed by	Institute of Molecular Genetics, Russian Academy of Sciences
Year created	1982
Primary route	Intranasal (nasal spray/drops)
Approved in	Russia, Ukraine, and several CIS countries
Not approved in	United States, EU, Canada, Australia
Primary research areas	Cognitive function, neuroprotection, stroke recovery, optic nerve disease
Key mechanism	BDNF upregulation, neurotrophic factor modulation

What Is Semax?

Semax is a synthetic peptide made of seven amino acids. Its sequence -- Met-Glu-His-Phe-Pro-Gly-Pro -- is based on a fragment of adrenocorticotropic hormone (ACTH), specifically the segment spanning positions 4 through 10. The researchers who designed it added a tripeptide tail (Pro-Gly-Pro) to the original ACTH fragment to improve its stability and biological activity.

The important distinction: Semax keeps the neurotrophic (brain-supporting) properties of ACTH without triggering the hormonal effects that full-length ACTH produces, like cortisol release. This was the whole point of its design -- a neuropeptide that helps the brain without disrupting the endocrine system.

Semax belongs to a broader category of peptides studied for nootropic (cognitive-boosting) and neuroprotective effects. It shares some conceptual ground with other peptides in the neuroprotection space, like BPC-157 and Thymosin Beta-4, though each works through different pathways.

Development History

Semax was created in 1982 at the Institute of Molecular Genetics within the Russian Academy of Sciences in Moscow. The same lab would later produce Selank, its "sister peptide" -- more on that comparison below.

The context matters. Soviet and post-Soviet scientists had a strong interest in compounds that could protect brain function under extreme conditions. The military wanted drugs for soldiers and cosmonauts operating under stress, fatigue, and oxygen deprivation. Researchers began exploring whether small fragments of ACTH could deliver neuroprotective benefits without hormonal side effects, and Semax emerged from that work.

The peptide was developed in collaboration with the Institute of Pharmacology in Moscow and later with Peptogen Inc., a company specializing in peptide synthesis. It was first formally described in the scientific literature by 1991.

After years of Russian clinical trials -- primarily in stroke patients -- Semax was added to the Russian List of Vital and Essential Drugs on December 7, 2011. In Russia and several CIS countries, it is an officially approved pharmaceutical, available by prescription as a 0.1% or 1% nasal solution for a range of neurological conditions.

Outside of Russia, however, Semax has never been evaluated or approved by the FDA, the European Medicines Agency, or comparable regulatory bodies.

How Semax Works: Mechanisms of Action

Semax's full mechanism isn't completely mapped, but decades of research point to several overlapping pathways. Here are the ones with the strongest evidence.

BDNF and Neurotrophic Factor Upregulation

This is the mechanism that gets the most attention, and for good reason. Brain-derived neurotrophic factor (BDNF) is one of the most important proteins for brain health. It supports neuron survival, drives the formation of new synapses, and is essential for learning and memory.

In animal studies, a single dose of Semax (50 micrograms per kilogram of body weight) produced a 1.4-fold increase in BDNF protein levels in the rat hippocampus, along with a 1.6-fold increase in the activation of TrkB, the receptor that BDNF signals through. At the gene level, the effects were even more pronounced: BDNF mRNA increased 3-fold, and TrkB mRNA doubled.

Semax also boosts nerve growth factor (NGF), another neurotrophic protein. One study found region-specific and time-dependent changes in both BDNF and NGF across the hippocampus, frontal cortex, and retina after intranasal Semax administration. The response wasn't uniform -- some brain regions showed increases within 20 minutes, while others took hours -- but the overall direction was toward greater neurotrophic support.

In a clinical context, treatment with Semax (two 10-day courses at 6,000 micrograms per day) increased plasma BDNF levels in stroke patients, and those with higher BDNF levels showed faster functional recovery.

Dopamine and Serotonin Modulation

Semax activates both serotonergic and dopaminergic systems in the brain. In rodent studies, it increases the turnover of these monoamine neurotransmitters, which are central to mood, motivation, and attention. This dopamine connection may explain why some users report improved focus and mental energy, though the human data on this specific pathway remains limited.

Melanocortin Receptor Activity

There is evidence that Semax interacts with melanocortin receptors -- specifically, it appears to competitively antagonize alpha-melanocyte-stimulating hormone (alpha-MSH) at the MC4 and MC5 receptors. The melanocortin system is involved in everything from appetite to inflammation to neuroprotection, and this interaction could explain some of Semax's broader effects.

Immune and Vascular Gene Expression

A genome-wide transcriptional analysis of Semax in a rat stroke model found that the peptide significantly modulated over 1,500 genes. The most affected categories were immune system genes and vascular system genes. At 3 hours after ischemia, Semax increased the expression of genes related to immune cell activity, and this effect grew substantially by the 24-hour mark. The peptide also appeared to promote new blood vessel formation in early stroke stages.

Cognitive Research: Memory, Focus, and Learning

Semax has been studied for nootropic effects in both animals and, to a lesser extent, humans.

In rodent learning paradigms, Semax-treated animals show a distinct increase in conditioned avoidance reactions -- a standard measure of learning and memory. The peptide appears to be particularly effective when given intranasally. A 2012 study found that intranasal Semax produced more pronounced improvements in learning compared to the same dose given by injection, suggesting the nasal route may offer better brain delivery for this peptide.

The researchers behind this work attribute the cognitive effects primarily to BDNF/TrkB pathway activation in the hippocampus, combined with dopamine and serotonin modulation.

In human studies, the data is thinner but still suggestive. One small study with eight patients showed improved cognitive function after a single dose. A slightly larger study with 24 patients used MRI to show that Semax boosted activity in the brain's Default Mode Network, a system involved in self-referential thought, memory consolidation, and rest-state cognition.

In Russia, Semax's 0.1% nasal solution is prescribed for cognitive complaints ranging from mental fatigue to age-related memory decline. The official Russian protocols call for 400-900 micrograms per day for mental fatigue (split across 2-3 doses for 3-5 days), and higher doses -- up to 8,000 micrograms per day -- for more significant amnestic impairment over 10-14 day courses.

Still, it is worth being direct: there are no large, randomized, placebo-controlled trials of Semax for cognitive enhancement in healthy individuals, and most of the human cognitive data comes from small Russian studies with limited methodological transparency.

Neuroprotection Research: Stroke, Brain Injury, and Beyond

Neuroprotection is where Semax has its deepest clinical roots. It was originally developed as a treatment for stroke and traumatic brain injury, and its Russian approval is based largely on this body of work.

Stroke Recovery

The most substantial clinical study involved 110 patients after ischemic stroke, divided into early and late rehabilitation groups. Patients who received intranasal Semax (two 10-day courses of 6,000 micrograms per day, with a 20-day break between courses) showed increased plasma BDNF levels, improved motor performance on the British Medical Research Council scale, and better functional independence scores on the Barthel Index compared to controls.

Early rehabilitation combined with Semax produced the best outcomes -- suggesting the peptide works best when given during the brain's most active recovery window.

In Russia, the 1% Semax solution is specifically indicated for stroke, with dosing protocols of 2-4 drops (each containing roughly 500 micrograms) applied 3-4 times daily during acute and subacute phases.

Mechanisms of Neuroprotection

Preclinical research suggests several ways Semax protects neurons during injury:

Survival under hypoxia: Semax promotes neuron survival during oxygen deprivation and glutamate toxicity -- two of the primary mechanisms of cell death in stroke.
Mitochondrial stability: The peptide helps maintain mitochondrial function under stress, which is directly tied to cell survival.
Nitric oxide inhibition: Excessive nitric oxide production during a stroke contributes to tissue damage. Semax inhibits this synthesis.
Gene expression changes: That same genome-wide study mentioned above found Semax upregulated genes involved in immune defense and blood vessel formation while dampening inflammatory pathways during ischemia.

Spinal Cord Injury (2025)

Recent research published in the British Journal of Pharmacology in 2025 explored Semax in spinal cord injury models. The study found that Semax targets the mu opioid receptor gene Oprm1, promoting deubiquitination processes and functional recovery. This is a newer research direction and the findings are preliminary, but they suggest Semax's neuroprotective reach may extend beyond the brain.

Semax's neuroprotective properties place it in a broader peptide research category alongside TB-500 and BPC-157, both of which are studied for tissue repair and protection, though through different mechanisms.

Optic Nerve Research

One of the more distinctive areas of Semax research is optic nerve disease -- a use case that most Western nootropic discussions overlook entirely.

A 2000 study evaluated Semax in patients with vascular, toxic-allergic, and inflammatory diseases of the optic nerve, as well as partial optic atrophy. Patients who received Semax alongside standard neurotrophic therapy showed improved visual acuity, expanded visual fields, increased electrical sensitivity of the optic nerve, and better color vision compared to controls.

A follow-up study in 2001 focused specifically on glaucomatous optic neuropathy in patients whose intraocular pressure had already been normalized. The researchers used a combination of electrophoresis and intranasal delivery of 0.1% Semax solution for 10 days each. The results showed Semax was superior to traditional neuroprotective treatments by electrophysiological and computerized assessment measures.

The researchers attributed these benefits to Semax's ability to increase NGF (nerve growth factor) expression in the retina, providing neurotrophic support to damaged optic nerve fibers. This is one area where Semax's neurotrophic mechanism has a clear, clinically relevant application -- though again, the studies are from a single Russian research group and relatively small.

Alzheimer's Disease and Neurodegeneration

Recent research has opened a new chapter in the Semax story, connecting it to Alzheimer's disease through an unexpected pathway: copper chemistry.

Copper, Amyloid Beta, and Semax

Alzheimer's disease is partly characterized by the accumulation of amyloid beta (A-beta) protein plaques. Copper ions play a role in driving this aggregation and in generating toxic reactive oxygen species (ROS) through Fenton-like chemical reactions with A-beta.

Semax, it turns out, has a strong affinity for copper (II) ions. A 2022 study in ACS Chemical Neuroscience demonstrated that Semax can prevent the formation of A-beta/copper complexes and inhibit amyloid fiber formation in a concentration-dependent manner. This was especially effective in the presence of cell membranes, which are directly relevant to how A-beta damages neurons.

A 2025 follow-up study showed that Semax acts as a copper chelator, stripping Cu(II) from A-beta and silencing the redox cycling that generates cell-killing ROS. The authors found that Semax protected SH-SY5Y neuroblastoma cells from copper-catalyzed oxidative stress induced by A-beta.

Animal Model Results (2025)

In a 2025 study published in Acta Naturae, researchers tested Semax and a derivative in transgenic APPswe/PS1dE9 mice -- a standard Alzheimer's model. Both compounds improved cognitive function across multiple behavioral tests (open field, novel object recognition, Barnes maze). Perhaps more striking, histological examination showed that amyloid plaque counts in the cortex and hippocampus increased only slightly in treated mice, remaining 1.8 to 2.2 times lower than in untreated controls. These effects persisted for 1.5 months after the treatment ended.

This Alzheimer's research is still preclinical, but it provides a mechanistic rationale for why a Soviet-era stroke drug might have relevance to 21st-century neurodegeneration research. The copper-chelating angle is particularly interesting because it is a completely different mechanism from Semax's BDNF effects.

For readers interested in other peptides studied for neurodegeneration, Epitalon -- another Russian-developed peptide -- is investigated for its effects on telomerase and aging, while GHK-Cu works through copper-dependent pathways in a different context.

Semax and Selank: Sister Peptides from the Same Lab

Selank was developed at the same Institute of Molecular Genetics that created Semax, and the two peptides are frequently discussed together. But they are quite different compounds targeting different brain systems.

Feature	Semax	Selank
Parent molecule	ACTH fragment (4-10)	Tuftsin (immune peptide)
Primary effect	Cognitive stimulation, neuroprotection	Anxiolytic (anti-anxiety)
Key mechanism	BDNF upregulation, dopamine/serotonin modulation	GABA modulation, serotonin pathways
Russian classification	Nootropic	Anxiolytic
Sequence	Met-Glu-His-Phe-Pro-Gly-Pro	Thr-Lys-Pro-Arg-Pro-Gly-Pro
Shared feature	Both have C-terminal Pro-Gly-Pro stability tail	Same stabilizing tail

Think of Semax as the "focus and performance" peptide and Selank as the "calm and stability" peptide. Semax pushes the dopaminergic and BDNF systems that drive learning and attention. Selank modulates GABA receptors -- the same system targeted by benzodiazepines -- but without the dependence or withdrawal risks those drugs carry.

Both are registered pharmaceuticals in Russia. Both are administered intranasally. And some Russian practitioners use them together, though formal data on the combination is limited.

The shared Pro-Gly-Pro tail is worth noting. This tripeptide sequence, also known as a fragment of the collagen-derived peptide PGP, was added to both compounds to improve enzymatic stability. It may also carry its own biological activity -- some research suggests PGP itself has immune-modulating and neuroprotective properties.

Variants: N-Acetyl Semax and Semax Amidate

Chemists have created modified versions of Semax to improve its stability and duration of action. The most discussed variants are:

N-Acetyl Semax

This version adds an acetyl group to the N-terminus (the beginning of the peptide chain). This protects the peptide from aminopeptidases -- enzymes that chew up peptides starting from the N-terminal end. The result is a longer-lasting compound.

N-Acetyl Semax Amidate

This variant combines both modifications: N-terminal acetylation and C-terminal amidation (replacing the free carboxyl group at the end of the chain with an amide group). The double protection increases resistance to enzymatic breakdown from both ends.

Feature	Standard Semax	N-Acetyl Semax Amidate
N-terminus	Free (unprotected)	Acetylated (protected)
C-terminus	Free (unprotected)	Amidated (protected)
Estimated duration	2-4 hours	6-12 hours
Dosing frequency	2-3 times daily	1-2 times daily
Research base	Extensive (decades)	Limited (mostly theoretical and anecdotal)

The tradeoff is straightforward: the modified versions likely last longer in the body, but nearly all of the published research -- including the clinical studies from Russia -- used standard Semax. The N-Acetyl Amidate variant has very little published data of its own.

One notable finding: a study on N-terminal acetylation and copper binding found that the acetyl modification changed how Semax interacts with copper (II) ions. Standard Semax's free amino terminus appears to be important for its cytoprotective effects against copper-induced toxicity, meaning the modified versions might actually lose some of the neuroprotective capacity related to copper chelation.

Administration and Dosing in Research

Semax is primarily given intranasally -- drops or spray applied directly to the nasal mucosa. Unlike many peptides that require injection, nasal delivery works well for Semax because of the direct nose-to-brain pathway through the olfactory region.

Russian Approved Formulations

Two formulations are approved in Russia:

0.1% Solution (General/Cognitive Use)

Mental fatigue: 400-900 mcg/day, divided into 2-3 doses, for 3-5 days
Cognitive impairment in children/adolescents (ages 7-18): 200-400 mcg/day, divided into 2 doses, for 30 days
Optic nerve disorders: 600-900 mcg/day for 7-10 days
Amnestic impairment: 800-8,000 mcg/day, applied 4 times daily, for 10-14 days

1% Solution (Stroke/Acute Neurological Use)

Ischemic stroke: 2-4 drops, 3-4 times daily (approximately 6,000 mcg/day total)
Typically administered in two 10-day courses with a 20-day rest period between them

These protocols come from the official Russian product labeling. They have not been validated in Western-style regulatory trials.

Safety Profile and Side Effects

For a peptide with decades of prescribed use, Semax has a relatively clean safety record -- at least based on the available data.

Common Side Effects

The most frequently reported issues are mild and related to the nasal delivery route:

Nasal irritation: Burning, congestion, or runny nose shortly after application. Usually resolves within 10-15 minutes.
Nasal discoloration: Reported in roughly 10% of patients in clinical observations.
Headache: Most common during the first week of use. May relate to changes in cerebral blood flow or neurotransmitter adjustment.

Less Common Effects

Blood pressure changes: Temporary increases have been reported, especially at higher doses.
Emotional sensitivity or irritability: Possibly related to dopamine pathway activation.
Insomnia: Particularly when administered later in the day.

The Anxiety Paradox

Here's something the marketing sites rarely mention: despite sometimes being promoted alongside anti-anxiety peptides, Semax can actually worsen anxiety in some individuals. A 1996 study identified an "anxiogenic component in the spectrum of Semax's behavioral effects" and suggested the peptide would work best in people without elevated baseline anxiety.

Later animal research painted a more nuanced picture. In rats, Semax had no effect on anxiety in a normal state but did normalize disrupted behavior caused by the anxiety-inducing compound CCK-4. This suggests Semax's relationship with anxiety is complex and likely varies between individuals.

Contraindications

Based on available data, the following groups should approach Semax with particular caution:

People with diabetes: Clinical observations show blood glucose increases in roughly 7.4% of diabetic patients using Semax. This appears dose-dependent.
People with anxiety disorders: Due to the anxiogenic potential described above.
Pregnant or breastfeeding women: Insufficient safety data exists for these populations.
People on neuroactive medications: Potential interactions with antidepressants, stimulants, and blood pressure medications have not been well-characterized.

Long-Term Safety

The honest answer: we don't have strong long-term safety data. Most Russian clinical studies tracked patients for weeks to months, not years. As the Alzheimer's Drug Discovery Foundation noted in its 2020 assessment, there is "very little human evidence for potential side effects" despite "many preclinical trials."

No consistent reports of severe toxicity, organ damage, or dependence have surfaced in the published literature -- but the absence of reported harm in limited data is not the same as proven safety.

Regulatory and Legal Status

Where Semax Is Approved

In Russia and several CIS countries, Semax is a registered pharmaceutical. It is on the Russian Federation's List of Vital and Essential Drugs, with approved indications including:

Stroke and transient ischemic attack
Memory and cognitive disorders
Optic nerve disease
Immune system support
Peptic ulcers (less commonly cited)

Where Semax Is Not Approved

Semax is not approved by:

The U.S. Food and Drug Administration (FDA)
The European Medicines Agency (EMA)
Health Canada
The Australian Therapeutic Goods Administration (TGA)

U.S. Status: Banned from Compounding

In the United States, the situation is particularly restrictive. The FDA classified Semax as a "Category 2" bulk drug substance with safety concerns, which effectively prohibits licensed compounding pharmacies from making it. This puts Semax in the same regulatory bucket as several other research peptides -- BPC-157, Thymosin Alpha-1, TB-500, and Selank among them.

The Alliance for Pharmacy Compounding challenged the FDA's reasoning, arguing that the agency did not publicly present detailed safety data for each peptide on the restricted list. Legal challenges from pharmacy groups are ongoing, and the political environment around peptide regulation remains in flux.

As of early 2025, Semax is available in the U.S. only as a "research chemical" -- a legal gray area that falls outside pharmaceutical regulation.

Limitations of the Evidence

Any honest assessment of Semax needs to address the elephant in the room: most of the clinical evidence comes from Russian studies published in Russian-language journals, many of which are not available in full-text English translation.

This matters for several reasons:

Trial design standards: Many of the Russian studies predate modern reporting requirements (like CONSORT guidelines for randomized trials) and lack the methodological transparency that Western peer review expects.
Small sample sizes: The largest stroke study involved 110 patients. Most cognitive studies had fewer than 30 participants.
Limited replication: Very few of the Russian findings have been independently replicated by research groups outside of Russia and the CIS countries.
Publication bias: We have limited insight into how many Semax studies may have been conducted but never published due to negative or inconclusive results.
Preclinical dominance: The strongest mechanistic evidence -- BDNF upregulation, gene expression changes, copper chelation -- comes from cell culture and animal studies. These don't always translate to humans.

None of this means Semax doesn't work. It means the evidence base, while suggestive, doesn't reach the threshold that the FDA, EMA, or most evidence-based medicine practitioners would consider definitive. The peptide has a plausible mechanism, decades of prescribed use in Russia, and a growing body of preclinical data -- but it needs larger, well-designed trials to move from "promising" to "proven."

For comparison, LL-37 and DSIP face similar challenges -- strong preclinical profiles that outpace their clinical evidence base.

Frequently Asked Questions

What is Semax used for?

In Russia, Semax is prescribed for stroke recovery, cognitive disorders, optic nerve disease, and immune support. Outside of Russia, it is not approved for any medical use and is classified as a research chemical in most countries.

How does Semax compare to Selank?

Both come from the same Russian lab and are administered intranasally, but they target different systems. Semax primarily boosts BDNF and dopamine/serotonin for cognitive performance. Selank modulates GABA for anti-anxiety effects. They are complementary rather than redundant.

Is Semax safe?

Based on available data, Semax appears well-tolerated with mild, mostly nasal-related side effects. However, it can worsen anxiety in some individuals and may raise blood sugar in diabetics. Long-term safety data is limited. Always consult a healthcare provider before considering any peptide therapy.

What is N-Acetyl Semax Amidate?

It is a chemically modified version of Semax with protective groups on both ends of the peptide chain, designed to resist enzymatic breakdown and last longer. However, it has far less published research than standard Semax, and the modifications may alter some of its biological properties.

Can Semax be taken orally?

No. Like most peptides, Semax has poor oral bioavailability -- stomach acid and digestive enzymes would break it down before it could reach the bloodstream. It is administered intranasally or, less commonly, by subcutaneous injection.

Is Semax legal in the United States?

Semax is not FDA-approved and is banned from compounding by licensed U.S. pharmacies. It is currently available only as a "research chemical," which occupies a legal gray area. Its regulatory status could change as ongoing legal and political challenges to the FDA's peptide restrictions evolve.

How long do the effects of Semax last?

Standard Semax appears to have effects lasting 2-4 hours per dose, which is why Russian protocols call for multiple daily administrations. The N-Acetyl Amidate variant may last 6-12 hours, though this estimate is based on limited data.

Does Semax affect mood?

Research suggests Semax has mild antidepressant-like effects and modulates dopamine and serotonin systems. However, it can also produce anxiety in susceptible individuals. The mood effects appear to vary significantly between people.

The Bottom Line

Semax is one of the more interesting peptides in the nootropic research space -- and one of the more frustrating. The science behind it is compelling. BDNF upregulation is a legitimate mechanism with clear relevance to cognition and neuroprotection. The copper-chelation work in Alzheimer's models is genuinely novel. Decades of prescribed use in Russia provide a level of real-world experience that most research peptides lack entirely.

But the evidence gap between Russian clinical practice and Western evidence standards remains wide. The large, randomized, multicenter trials that would settle the question of Semax's efficacy have not been done -- and given the peptide's regulatory status in the West, they may not happen anytime soon.

For anyone following the peptide research space, Semax is worth tracking. The 2025 Alzheimer's data, the spinal cord injury research, and the continued elaboration of its neurotrophic mechanisms all point to a compound with genuine potential. Whether that potential translates to proven clinical benefit will depend on whether the research community -- or a pharmaceutical sponsor -- decides to invest in the trials that could answer that question definitively.

Until then, Semax occupies a position shared by many peptides on this site: strong rationale, growing preclinical evidence, meaningful but imperfect clinical data, and a regulatory environment that makes access complicated. Talk to a qualified healthcare provider before making any decisions about peptide therapies.

This article is for educational purposes only. PeptideJournal.org does not sell peptides or provide medical advice. The information presented here summarizes published research and is not a recommendation for or against any therapy. Always consult a qualified healthcare provider for medical decisions.