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Semax

Russian-registered ACTH(4-10) analogue taken intranasally for focus, mental stamina and post-stroke recovery, which raises BDNF and NGF without any of the cortisol-releasing activity of the parent hormone.

Also known as ACTH(4-10)PGP, Met-Glu-His-Phe-Pro-Gly-Pro, heptapeptide Semax, Semaks, Semax

Human trials — Studied in people, typically early phase or small — promising rather than proven.

Semax is a registered prescription drug in Russia for stroke, transient ischaemic attack, optic neuropathy and cognitive disorders, so there is real human data behind it. Almost all of it is Russian-language, small, and has never been independently replicated in a Western trial, and the mechanistic BDNF/NGF work is rodent. Treat it as clinically plausible rather than proven.

How it works

The Pro-Gly-Pro tail was added to the natural ACTH(4-10) fragment specifically to block exopeptidase degradation, and it also strips the corticotropic activity so Semax raises no cortisol. Rat work from Dolotov's group showed Semax binds in the basal forebrain and increases BDNF protein and NGF expression within hours, with downstream effects on TrkA/TrkB signalling. It also shifts expression of a large block of neurotrophin, inflammation and vascular genes after ischaemia, which is the mechanism the Russian stroke indication rests on. Effects on dopamine and serotonin turnover are documented in rodents and are the likely reason users describe it as stimulating rather than merely restorative.

Targets: BDNF, NGF, TrkA/TrkB signalling, Melanocortin receptors, Dopaminergic and serotonergic systems

Dosing

ProtocolDoseFrequencyRoute
Standard nootropic intranasal protocolMorning, and early afternoon if a second dose is used. Avoid after about 4 pm — it is stimulating enough to cost you sleep.300 mcg – 600 mcgonce or twice dailyintranasal
High-dose recovery protocol (mirrors the Russian stroke indication)Spread across the waking day, last dose by mid-afternoon.6 mg – 18 mgdaily, divided into 3-4 administrationsintranasal
  • · Corresponds to the Russian 0.1% nasal solution. Reconstituting a 30 mg vial in 3 mL gives 10 mg/mL, so a 0.05 mL spray is 500 mcg. Split the dose between nostrils.
  • · This is the 1% solution used in acute ischaemic stroke wards for 10-14 days, not a lifestyle dose. People run it for TBI or post-concussion recovery; it burns through vials fast and the stimulation at this dose is significant.

Titration

Start at 300 mcg once in the morning for three days before adding a second dose. People sensitive to stimulants often find 600 mcg twice daily produces irritability and flat mood.

Cycling

Most people run 2-4 weeks on, then 2-4 weeks off. Tolerance to the acute stimulant-like feel builds within about two weeks, which is the usual reason to break rather than any known toxicity.

Work out your exact syringe units →

Pharmacology

Half-life
Cleared from plasma within minutes by peptidases, yet gene-expression and behavioural effects are reported to run 20-24 hours after a single intranasal dose.
Onset
Subjective focus and alertness within 15-60 minutes of an intranasal dose; the neurotrophic effects people actually want build over 1-2 weeks of daily use.
Routes
intranasal, subcutaneous
Molecule
Synthetic heptapeptide (ACTH(4-10) fragment with a C-terminal Pro-Gly-Pro tail)
Sequence length
7 amino acids
Molecular weight
813.9 Da

Handling

Diluent
Bacteriostatic water
Typical mix
2 or 3 mL
Vial sizes
5, 10, 30 mg
Lyophilised
Room temperature is fine for a few weeks in transit; fridge for months, freezer for years.
Reconstituted
Refrigerated, used within about 30 days. Nasal spray bottles carried at room temperature degrade noticeably faster — assume two weeks.
Light sensitive
Yes — keep it out of the light

Intranasal — usable, with a caveat

Nasal is this compound's intended route, not a workaround - Semax is registered in Russia as nasal drops and the entire clinical literature behind it uses that route. It was designed as an ACTH(4-10) fragment for nose-to-brain delivery, which is why it has no injectable tradition. Practical catch: the Russian clinical product is a defined-concentration drop, and grey-market spray bottles vary widely in concentration and in whether they contain a preservative system at all.

Mixing

For a nasal spray, reconstitute in bacteriostatic water and transfer to a metered 0.05 mL or 0.1 mL spray bottle. Plain sterile saline works but has no preservative and should be treated as a one-week product.

Side effects

  • commonNasal irritation, dryness or sneezing— Worse with high-concentration solutions; dilute further if it persists.
  • commonIrritability, overstimulation or restlessness— Dose-related. Usually resolves by dropping to a single morning dose.
  • commonInsomnia— Almost entirely a function of dosing too late in the day.
  • uncommonHeadache— Typically in the first few days.
  • uncommonEmotional blunting on prolonged high-dose use— Reported anecdotally with continuous multi-month use; resolves off-cycle.

Do not use if

  • Pregnancy and breastfeeding - no safety data whatsoever.
  • Active psychosis or mania - a dopaminergic, activating peptide is a poor idea here.
  • Poorly controlled anxiety disorders - Semax tends to sharpen arousal, unlike its cousin Selank.

Combining it

  • synergyselank — The classic Russian pairing: Semax for drive and focus, Selank to take the edge off the arousal. Very commonly run together.
  • redundantn-acetyl-semax-amidate — Same pharmacophore. Pick one; running both just stacks the same mechanism.
  • synergycerebrolysin — Frequently combined in Russian and Eastern European post-stroke and TBI protocols.
  • cautionnoopept — Both push BDNF/NGF and both can be overstimulating. Combining them commonly produces headache and irritability.

What to monitor

  • · No routine bloodwork is established or needed.
  • · Track something objective - reaction-time tests, work output, sleep latency - because subjective 'sharpness' is exactly the thing a stimulating peptide will lie to you about.

Legal status

Registered prescription medicine in Russia and several CIS states. Not approved in the US, UK or EU and sold there as a research chemical.

References

  • Dolotov et al. 2006, Semax binds in rat basal forebrain and increases BDNF protein (preclinical)
  • Gusev & Skvortsova, Semax in acute ischaemic stroke, Zhurnal Nevrologii i Psikhiatrii (trial)
  • Medvedeva et al., transcriptome response to Semax after focal cerebral ischaemia in rats (preclinical)

Mechanism in depth

The interesting thing about Semax is the mismatch between how fast it disappears and how long it acts. It is gone from plasma in minutes, yet transcriptional and behavioural effects run for the best part of a day. The resolution is that Semax is not a receptor occupancy drug - it is a transcriptional trigger. Radioligand work shows specific, saturable binding sites in rat basal forebrain and a regionally uneven distribution across the brain, and within hours of a single dose BDNF protein rises in that same region. Genome-wide analysis after focal ischaemia in rats shows the response is not a tidy neurotrophin cascade but a broad shift across immune-response, vascular and neurotrophin gene families, with the immune-gene block being one of the largest movers. Practically, that means the acute focus most users feel and the neurotrophic effect they are actually buying are two different phenomena on two different timescales: the first is monoaminergic and shows up in an hour, the second is transcriptional and takes a fortnight. People who judge Semax on day two are judging the wrong thing. It also explains the tolerance pattern - the monoaminergic feel fades well before the neurotrophic effect would, so a user perceives the compound as stopping working while the mechanism they wanted is still running.

What usually goes wrong

Four failure modes, in order of how often they actually happen. First, dosing too late: Semax is stimulating for 6-8 subjective hours and a 3 pm dose costs you sleep, which then costs you the cognition you were chasing. Second, the tolerance trap: the acute stimulant feel fades in about two weeks, users read that as the compound failing, escalate the dose, and land in irritability and emotional flattening. The fix is to stop escalating and either hold or break. Third, degraded product: a nasal bottle carried in a pocket or bag is warm and constantly agitated, and a batch that 'stopped working' after three weeks is usually a storage problem rather than tolerance. Fourth, product identity: Semax is one of the most commonly counterfeited grey-market peptides, and an inert vial is indistinguishable from tolerance if you have never had a working one. If a new vial feels like nothing on day one at 600 mcg, suspect the vial before you suspect yourself.

Titration ladder

  1. 300 mcgDays 1-3 — One morning intranasal dose only. Three days is enough to find out whether you are one of the people this compound makes irritable rather than sharp.
  2. 600 mcgDays 4-7 — Still one morning dose. Most people who are going to get a clean effect get it here.
  3. 900 mcgWeek 2 onward — 600 mcg morning plus 300 mcg early afternoon, if and only if the morning dose is clearly wearing off by midday. Nothing after 4 pm.
  4. 1.2 mgWeek 2 onward, optional ceiling — 600 mcg twice daily. This is the practical ceiling for lifestyle use. Above this you are into the territory where emotional flattening and irritability are the dominant reported effects rather than focus.

Bloodwork worth running

MarkerWhenWhy it matters
Morning serum cortisolBaseline, and once more after two weeks if you are running the 6-18 mg high-dose protocol.Only worth doing once, and specifically to confirm a negative. Semax is an ACTH fragment and the single most common worry people bring to it is adrenal stimulation. It does not stimulate the adrenal cortex, and a normal morning cortisol on a high-dose protocol is the cheapest way to stop worrying about it.Act if: A genuinely elevated morning cortisol on Semax is not an expected finding. If it happens, look for another cause rather than assuming the peptide - and consider that what you have may not be Semax.
Resting blood pressure and heart rateBaseline, then again 60-90 minutes after a dose in week one.Not bloodwork, but it is the only objective physiological measure that reliably moves on this compound. The overstimulation people report at 600 mcg twice daily often shows up here before they admit it subjectively.Act if: A sustained rise of more than about 10 mmHg systolic, or a resting heart rate consistently 10-15 bpm above your baseline, means drop to a single morning dose.

Pharmacokinetics

Tmax
0.033 h
Crosses blood-brain barrier
partial
Metabolism
Sequential proteolysis. The dominant route is loss of the N-terminal Met-Glu and the C-terminal Gly-Pro, generating pentapeptide and tripeptide fragments. The end product that accumulates in tissue is Pro-Gly-Pro, which is itself biologically active on brain transcription - a rat study of Pro-Gly-Pro alone found it changes the ischaemic brain transcriptome in its own right. So part of what you get from Semax is arguably its own metabolite.
Elimination
Renal excretion of small peptide fragments and free amino acids after proteolysis. No intact-drug elimination pathway of any consequence.

Receptor targets

  • Specific brain binding site (basal forebrain, uncharacterised molecular identity) — Saturable specific binding demonstrated with tritiated Semax; the receptor has never been molecularly identified and no Kd has been reported that survives scrutiny

    Binding correlates with the rise in BDNF protein in the same region within hours.

  • BDNF / TrkB signalling — Indirect - Semax raises BDNF expression rather than binding TrkB

    Increased BDNF protein in basal forebrain and hippocampus, with downstream TrkB-CREB signalling. This is the mechanism the long-term cognitive claims rest on.

  • NGF / TrkA signalling — Indirect - rapid induction of neurotrophin mRNA in glial cell cultures within minutes to hours of exposure

    NGF mRNA induction in glia, supporting cholinergic neuron maintenance.

  • Melanocortin receptors (MC3R/MC4R) — Weak and poorly quantified. Notably, a human study found the far higher-affinity melanocortin ligand desacetyl-alpha-MSH produced almost no cognitive effect while ACTH(4-10) did, which argues melanocortin receptors are not the main route

    Contributes to arousal and attention, but the melanocortin account of these peptides is weaker than it is usually presented.

  • Melanocortin MC2R (adrenal ACTH receptor) — No meaningful activity - the 4-10 fragment lacks the residues required for steroidogenesis

    No cortisol release. This is the defining pharmacological property that separates Semax from ACTH and is why it can be dosed daily without adrenal consequences.

  • Dopaminergic and serotonergic turnover — Not quantified at receptor level

    Altered monoamine turnover in rodents; the plausible substrate for the acute stimulant-like subjective effect and for the irritability at higher doses.

Trials

  • Semax in the acute period of hemispheric ischaemic stroke (Gusev, Skvortsova et al.) Clinical, open comparative · n=110 · 1.5 weeks · 1997

    Recovery of neurological function and electrophysiological (evoked potential) measures. 30 patients received Semax against 80 controls; the authors identified 12 mg/day for moderate strokes and 18 mg/day for severe strokes over a 5-10 day course as optimal, and reported better functional recovery in the treated group. Small, unblinded, and the source of the high-dose protocol people copy.

What to expect, and when

15-60 minutes for the acute focus and alertness after an intranasal dose - measurable rodent brain uptake peaks inside two minutes, so the delay is downstream signalling rather than delivery. 4-8 hours of useful subjective effect from a single dose. 3-7 days before sustained mental stamina rather than acute stimulation becomes the dominant feature. 10-14 days before the neurotrophic effects that justify the compound would be expected to show, based on the BDNF timecourse. Around 14 days is also when the acute stimulant feel typically fades. Post-stroke and TBI protocols run 10-14 days at 6-18 mg/day and outcomes are assessed at the end of the course, not during it.

Stacking and comparisons

The Semax plus Selank pairing is the one stack in this class with an actual rationale rather than a vibe: Semax reliably raises arousal, Selank reliably lowers it, and the two have non-overlapping mechanisms. Run them at different times of day rather than mixed in one bottle - Semax in the morning, Selank when the edge shows up, usually early afternoon. Do not mix them in the same nasal spray; you lose the ability to titrate them independently, which is the entire point. Stacking Semax with Noopept is the classic mistake: both push BDNF/NGF, both are stimulating, and the combination produces headache far more often than it produces cognition. If you want a neurotrophic partner with a genuinely different receptor, FGL (FGFR1) or Cerebrolysin are more coherent choices, though neither has combination data. Caffeine plus Semax is fine at low caffeine doses and unpleasant at high ones - the jitter stacks.

Against N-Acetyl Semax Amidate: same pharmacophore, but the capped version lasts longer per dose and is potent enough that carrying your Semax dose across is the single most common cause of a bad first experience. Plain Semax is easier to titrate and easier to stop mid-day. Against ACTH(4-10), the parent fragment: Semax exists because the parent is destroyed too fast to be useful at practical doses, and the human ACTH(4-10) literature is genuinely mixed - one well-run double-blind intranasal study in 60 healthy adults found increased error rates on vigilance and temporarily reduced word recall. Do not assume the parent is a cheaper Semax. Against Noopept: Noopept has a comparative human trial against piracetam and a Russian registration for mild cognitive disorders; Semax has a Russian registration for stroke. Both are real drugs at home and research chemicals everywhere else. Semax is more acutely stimulating; Noopept is milder and more often described as clarity than drive. Against modafinil or amphetamine, which is the honest comparison for what people use it for: Semax is far weaker as a stimulant and does not produce the same tolerance, dependence or cardiovascular load. Anyone expecting a comparable effect will be disappointed.

Rough cost

$25–$90/month. A 30 mg vial from a mainstream grey-market supplier runs roughly 40-70 USD and covers about 50 days at 600 mcg daily, so a standard nootropic protocol lands near 25-45 USD per month. The 6-18 mg/day recovery protocol burns a 30 mg vial in two to five days and costs several hundred dollars per course. Russian pharmacy 0.1% nasal solution, where obtainable, is often cheaper than research-chemical powder.

Genuinely uncertain

  • No human pharmacokinetic study of Semax has ever been published. Every PK statement here is extrapolated from rat tritium-label work.
  • The specific binding site in basal forebrain has never been molecularly identified. Nobody knows what protein Semax actually binds.
  • The 20-24 hour duration of gene-expression effects after a single dose is widely repeated but I could not resolve a primary source giving that number precisely.
  • Bioavailability by the intranasal route in humans is unknown. The rat figure of 0.093 percent of dose per gram of brain is not a bioavailability figure and should not be quoted as one.
  • Whether the melanocortin receptors contribute anything to the cognitive effect is genuinely unsettled - the human data showing a higher-affinity melanocortin ligand does less argues against it.
  • Volume of distribution, clearance and protein binding have never been measured for this peptide in any species.
  • The Russian stroke trials are small, unblinded and have never been independently replicated. The 1997 Gusev study used 30 treated patients against 80 controls.
  • How much of the effect is Semax itself versus its Pro-Gly-Pro metabolite is unresolved and the metabolite is independently active on brain transcription.
  • Nothing is known about what continuous multi-year use does. The emotional blunting reported anecdotally on prolonged high-dose use has no mechanistic explanation and no published documentation.

Papers