Overview
Overview
Semax is a synthetic heptapeptide analog of the ACTH(4–10) fragment, originally developed in Russia for its neuroprotective, nootropic, and neurotrophic properties[1][5]. It has been studied for cognitive enhancement, cerebrovascular recovery, and optic neuropathy support[3][6]. This educational protocol presents a once‑daily subcutaneous approach using a practical dilution for clear insulin‑syringe measurements. Reconstitute: Add 3.0 mL bacteriostatic water (max vial capacity) → ~1.67 mg/mL co
- Category
- Cognitive
- Routes
- nasal, subcutaneous
Mechanism
Semax
Mechanism of action
Mechanism of action
Plain English first: Semax appears to nudge brain plasticity programs and stress-response biology, especially when the brain is under load. Researchers most often describe it through three overlapping mechanism layers — neurotrophin signaling, neurotransmitter modulation, and stress/ischemia gene expression. None of these layers fully explains the molecule on its own. Single intranasal Semax administration increased BDNF protein and TrkB receptor signaling in rat hippocampus (Dolotov 2006). This is the most-cited mechanism behind Semax's nootropic and neuroprotective framing. Semax has been reported to modulate dopaminergic and serotonergic systems in rodents, including amphetamine-evoked locomotor effects (Eremin 2005). This is described as neuromodulation, not classic stimulant action. Semax may act as a partial agonist or antagonist at MC4 and MC5 melanocortin receptors in vitro (Bertolini 2012). The full receptor profile is not settled. Semax inhibits enkephalin-degrading enzymes from human serum at IC50 ~10 µM (Kost 2001), though the clinical significance of this property is uncertain. Genome-wide transcriptional analysis in rat focal ischemia found Semax altered hundreds of genes, with notable clusters in immune response and vascular pathways (Medvedeva 2014). A useful interpretation of the data: Semax appears most measurable when the brain is under a perturbation (stress, ischemia, fatigue, learning load) rather than as a constant baseline amplifier. This pattern fits the clinical literature too — the strongest reported effects are in stroke recovery and stress-research contexts, not in well-rested healthy volunteers.
Key research findings
- 01
Semax is a synthetic heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) structurally related to the ACTH(4-10) fragment but lacking the corticotropic (steroidogenic) activity of full ACTH; the Pro-Gly-Pro tail is reported to improve stability (in vitro).
- 02
In rodent models, Semax has been studied for neuroprotective and cognition-related endpoints, including performance in learning and memory tasks (animal model).
- 03
Preclinical studies report upregulation of BDNF and its receptor TrkB and modulation of neurotrophin signaling in rodent brain tissue (animal model / in vitro).
- 04
In vitro work has explored Semax interactions with copper-induced beta-amyloid aggregation in artificial membrane models (in vitro).
- 05
In Russia, Semax has been investigated in clinical research contexts including cerebral ischemia and cognitive endpoints; these human studies are largely region-specific and not widely replicated internationally (human study, limited).
Primary source: Human evidence (acute ischemic stroke): Gusev et al. 1997 reported improved neurological function in patients with acute hemispheric ischemic stroke after Semax administration in the acute period. The study is foundational to Russian clinical use of Semax. Human evidence (healthy cognition): Lebedeva 2018 reported effects on the brain's default mode network. Kaplan 1996 reported nootropic-like activity in healthy male participants under demanding cognitive conditions. Preclinical (BDNF/TrkB): Dolotov 2006 demonstrated single-administration BDNF and TrkB increases in rat hippocampus — the most-cited mechanistic anchor for the nootropic narrative. Preclinical (ischemia transcriptomics): Medvedeva 2014 (PMC3987924) and the 2020 PMC7350263 paper documented gene-expression changes in rat focal ischemia and ischemia-reperfusion models — important mechanism but not direct human stroke outcome data. Preclinical (depression/anxiety models): Inozemtseva 2024 reported antidepressant- and antistress-like effects in chronic unpredictable stress rat models, including BDNF normalization. Yatsenko 2013 reported similar attenuation of chronic stress effects. Evidence boundary: There is no published head-to-head Western RCT comparing Semax against modafinil, racetams, caffeine + L-theanine, or placebo for cognitive performance in healthy adults. Confidence in everyday cognitive claims should be calibrated accordingly.
Pharmacokinetic profile
Single-dose plasma curve over 24h. Shaded band = commonly-cited therapeutic window. Illustrative only.
Protocol Reference
Protocol reference
Commonly cited research range: 300–600 mcg, daily.
Reference figures reported in the research literature — not a dosing recommendation. For interactive vial math and scheduling, see the Calculator and Schedule tabs.
Cited protocol & reconstitution guide
Source-backed reference fields by phase, including any volume fields authored in the cited guide.
Weeks 1–2
200 mcg
Weeks 3–4
300 mcg
Weeks 5–6
400 mcg
Weeks 7–12
500 mcg
| Phase | Reference amount | Units / volume |
|---|---|---|
| Weeks 1–2 | 200 mcg | 12 units (0.12 mL) |
| Weeks 3–4 | 300 mcg | 18 units (0.18 mL) |
| Weeks 5–6 | 400 mcg | 24 units (0.24 mL) |
| Weeks 7–12 | 500 mcg | 30 units (0.30 mL) |
Titration protocol
- Animal pharmacology (rodent)StartUp to ~1 mg/kg
Not human-applicable; for context only — Animal pharmacology summaries
- Human research-community planning (subQ)BuildSub-milligram per administration
Sparse direct human data — Community research planning, not formal trials
- Cognitive / nootropic research planning Split into 2 administrations (morning + early afternoon)BuildAbout 0.6 to 1.5 mg/day
Russian clinical literature (Voronina 2023; Kaplan 1996)
- Acute ischemic stroke (clinical, Russia) Multiple daily administrations during acute periodBuildHigher daily amounts under hospital supervision
Gusev 1997 acute-stroke clinical study
- Healthy-volunteer cognitive-attention study One-time research administrationMaintenanceSingle intranasal administration of about 1.2 mg
ADDF Cognitive Vitality summary
Storage & Handling
Storage requirements(typical for most peptides)
Can be stored for extended periods. Protect from moisture.
Store in refrigerator door. Never freeze after reconstitution.
Label vials with reconstitution date. Discard if cloudy.
Reconstitution steps
- 01🌡️Draw 3.0 mL bacteriostatic water with a sterile syringe.
- 02🧴Inject slowly down the vial wall; avoid foaming.
- 03💉Gently swirl/roll until dissolved (do not shake).
- 04💧Label and refrigerate at 2–8 °C (35.6–46.4 °F), protected from light.
- 05🔄Important: This guide is for educational purposes only and is not medical advice. For research use only. Not for human consumption.
- 06🏷️Intranasal (IN) Research Summary
- 07❄️Semax has been studied extensively via the intranasal route in human clinical and preclinical settings. The following bullets summarize reported findings from the literature. All stated amounts are reported in studies unless otherwise noted.
- 08💉Primary studied route: Intranasal delivery (nasal drops or spray) is the predominant administration route in published human research for Semax; oral bioavailability is poor due to rapid enzymatic degradation[1][14]. (Reported in studies.)
- 09💉Approved formulation (Russia): Semax is registered as a 0.1% intranasal solution (equivalent to 1,000 mcg/mL or 1.0 mg/mL) dispensed via dropper bottle; each standard drop is reported to deliver approximately 50 mcg of peptide[2]. (Reported in studies.)
- 10💉Higher‑concentration formulation: A 1% Semax intranasal solution (10,000 mcg/mL or 10.0 mg/mL) has been used in acute neurological settings (e.g., ischemic stroke) to deliver larger amounts per actuation without excessive volume[3][2]. (Reported in studies.)
- 11💉Delivery device: Published clinical protocols describe a dropper bottle with a cap‑pipette; some formulations reference a metered nasal spray. Specific per‑actuation delivered volume for spray devices was not consistently reported across studies[2][11]. (Reported in studies; device output not standardized across sources.)
- 12💉Cognitive/neuroprotective studies (human): In adult cerebrovascular patients, total daily intranasal amounts of 200–6,000 mcg (divided into 3–4 administrations) were reported over courses of 5–14 days, with lower ranges (200–900 mcg/day) used for milder cognitive indications over shorter durations[2][3]. (Reported in studies.)
- 13💉Pediatric study (human): In children ages 7–18 with minimal brain dysfunction, daily intranasal amounts of 200–400 mcg (approximately 5–6 mcg/kg) divided into two administrations were reported over a 30‑day course[2]. (Reported in studies.)
- 14💉Optic neuropathy study (human): In 36 patients with glaucomatous optic neuropathy, daily intranasal Semax was administered for approximately one month; no significant adverse effects were reported[6]. (Reported in studies.)
- 15💉Pharmacokinetic notes: Intranasal Semax is reported to have a short duration of action, necessitating multiple daily administrations in clinical protocols. Preclinical comparison of intranasal versus injection routes showed differences in onset and duration profiles, with injection providing more sustained systemic levels[4][5]. (Reported in studies.)
- 16💉Variability and limitations: Intranasal bioavailability is subject to individual anatomical variation, mucosal condition, and device‑specific delivery volumes. Most published human data originate from Russian clinical registries and journals; large‑scale Western randomized controlled trials are lacking[14][12]. (Inference based on available evidence.)
- 17💉Nasal Spray Device Output & Conversion Math
- 18💉Important: Nasal spray pumps vary significantly in delivered volume per actuation depending on manufacturer, pump mechanism, and priming. The mcg delivered per spray depends entirely on the specific device used. Always use manufacturer specifications or direct gravimetric measurement to determine delivered volume per actuation.
- 19💉Parameterized Framework
- 20💉Given two known inputs, the amount per actuation can be calculated:
- 21💉Input 1: concentration_mcg_per_mL (or convert from mg/mL × 1,000)
- 22💉Input 2: pump_output_mL_per_actuation (from device specs or measurement)
- 23💉Output: amount_mcg_per_actuation = concentration_mcg_per_mL × pump_output_mL_per_actuation
- 24💉Optional volume mapping (U‑100 convention): If a “units” convention is used as a volume measure, 100 units = 1.0 mL. Therefore: pump_output_mL_per_actuation = units_per_actuation ÷ 100, and amount_mcg_per_actuation = concentration_mcg_per_mL × (units_per_actuation ÷ 100).
- 25💉Nasal Actuation Calculation Table (Placeholders)
- 26💉CONCENTRATION (MCG/ML) PUMP OUTPUT (ML/ACTUATION) AMOUNT PER ACTUATION (MCG) ACTUATIONS PER ML (1 ÷ PUMP OUTPUT) TOTAL ACTUATIONS IN RECONSTITUTED VOLUME
Additional storage notes
-4°F (-20°C) long-term; refrigerator (35.6-46.4°F / 2-8°C) short-term — Keep sealed and away from light. Verify supplier label.
35.6-46.4°F (2-8°C) — Use within several weeks per supplier label and bacteriostatic water beyond-use guidance.
Most labels: refrigerator (35.6-46.4°F / 2-8°C) recommended; some manufacturers tolerate cool, dry storage below 50°F (10°C) — UK NIBSC reference recommends ~39°F (4°C). Verify the specific bottle label.
Out of direct sunlight; avoid temperature cycling — Repeated freeze-thaw or heat exposure increases aggregation risk.
Clinical Evidence
Clinical evidence
Studies show improved attention, memory, mental clarity, and stress resilience. Neuroprotective in stroke models.
Human evidence (acute ischemic stroke): Gusev et al. 1997 reported improved neurological function in patients with acute hemispheric ischemic stroke after Semax administration in the acute period. The study is foundational to Russian clinical use of Semax. Human evidence (healthy cognition): Lebedeva 2018 reported effects on the brain's default mode network. Kaplan 1996 reported nootropic-like activity in healthy male participants under demanding cognitive conditions. Preclinical (BDNF/TrkB): Dolotov 2006 demonstrated single-administration BDNF and TrkB increases in rat hippocampus — the most-cited mechanistic anchor for the nootropic narrative. Preclinical (ischemia transcriptomics): Medvedeva 2014 (PMC3987924) and the 2020 PMC7350263 paper documented gene-expression changes in rat focal ischemia and ischemia-reperfusion models — important mechanism but not direct human stroke outcome data. Preclinical (depression/anxiety models): Inozemtseva 2024 reported antidepressant- and antistress-like effects in chronic unpredictable stress rat models, including BDNF normalization. Yatsenko 2013 reported similar attenuation of chronic stress effects. Evidence boundary: There is no published head-to-head Western RCT comparing Semax against modafinil, racetams, caffeine + L-theanine, or placebo for cognitive performance in healthy adults. Confidence in everyday cognitive claims should be calibrated accordingly.
- 01Semax is a synthetic heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) structurally related to the ACTH(4-10) fragment but lacking the corticotropic (steroidogenic) activity of full ACTH; the Pro-Gly-Pro tail is reported to improve stability (in vitro).
- 02In rodent models, Semax has been studied for neuroprotective and cognition-related endpoints, including performance in learning and memory tasks (animal model).
- 03Preclinical studies report upregulation of BDNF and its receptor TrkB and modulation of neurotrophin signaling in rodent brain tissue (animal model / in vitro).
- 04In vitro work has explored Semax interactions with copper-induced beta-amyloid aggregation in artificial membrane models (in vitro).
- 05In Russia, Semax has been investigated in clinical research contexts including cerebral ischemia and cognitive endpoints; these human studies are largely region-specific and not widely replicated internationally (human study, limited).
Evidence maturity varies by compound; much peptide research is preclinical (in vitro or animal-model). Where human data are limited, findings should be read as research observations, not clinical conclusions.
References
Literature references
Published research articles and sources related to Semax.
- 01U.S. Food and Drug Administration Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (503A Category 2 list). FDA.gov (2025)et al. (2025)
- 02U.S. Food and Drug Administration July 23-24, 2026: Meeting of the Pharmacy Compounding Advisory Committee — Semax (free base / acetate) for cerebral ischemia and trigeminal neuralgia. FDA.gov / Federal Register Docket FDA-2026-N-2979 (2026)et al. (2026)
- 03Federal Register / FDA Pharmacy Compounding Advisory Committee Notice of Meeting and Establishment of Public Docket — peptide nominations for 503A Bulk Drug Substances List. Federal Register (2026)et al. (2026)
- 04Voronina TA Cognitive Impairment and Nootropic Drugs: Mechanism of Action and Spectrum of Effects. Neurochemical Journal (2023)et al. (2023)
- 05Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research (2006)et al. (2006)
- 06Eremin KO, Kudrin VS, Saransaari P, et al. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochemical Research (2005)et al. (2005)
- 07Bertolini A Drug-induced activation of the nervous control of inflammation: a novel possibility for the treatment of hypoxic damage. European Journal of Pharmacology (2012)et al. (2012)
- 08Kost NV, Sokolov OI, Gabaeva MV, et al. Semax and selank inhibit the enkephalin-degrading enzymes from human serum. Bioorganicheskaia Khimiia (2001)et al. (2001)
- 09Medvedeva EV, Dmitrieva VG, Povarova OV, et al. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics (PMC3987924) (2014)et al. (2014)
- 10Filippenkov IB, Stavchansky VV, Glazova NY, et al. Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats. Genes (PMC7350263) (2020)et al. (2020)
- 11Inozemtseva LS, Karpenko EA, Dolotov OV, et al. Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. European Journal of Pharmacology (2024)et al. (2024)
- 12Gusev EI, Skvortsova VI, Miasoedov NF, et al. Effectiveness of Semax in the acute period of hemispheric ischemic stroke (a clinical and electrophysiological study). Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova (1997)et al. (1997)
- 13Deigin VI, Poluektova EA, Beniashvili AG, et al. Development of Peptide Biopharmaceuticals in Russia. Pharmaceutics (PMC9030433) (2022)et al. (2022)
- 14Alzheimer's Drug Discovery Foundation Semax — Cognitive Vitality for Researchers (safety and evidence summary). ADDF (2020)et al. (2020)
Observed Effects
Observed effects in cited research
Nasal cavity discoloration (intranasal route)
- ADDF reports approximately 10% of intranasal users experience nasal cavity discoloration.
Increased blood glucose
- Reported specifically in people with diabetes.
Anxiety / overstimulation
- Some users describe a 'too activated' feeling, especially when stacked with caffeine, stimulants, or used late in the day.
Nasal irritation, sneezing, dryness (intranasal route)
- Local effects from nasal solution are common with frequent use.
Sleep disruption
- Late-day use can interfere with sleep onset, especially at the upper end of research-context ranges.
Theoretical and product-level risks
- FDA's 503A Category 2 listing (active September 29, 2023 to April 23, 2026) flagged Semax for immunogenicity risk for certain routes of administration due to potential for aggregation and peptide-related impurities . That risk is about how the molecule is manufactured, handled, and stored — not the molecule itself. Removal from Category 2 in April 2026 was a procedural withdrawal of nominations, not a safety clearance.
Quality matters more than dose
- For a peptide used at sub-milligram amounts, batch contamination or aggregation can matter more than a 10-20% dose change. Documentation (HPLC purity, identity confirmation, endotoxin testing, batch-specific COA) should be the first sourcing checkpoint, not the last.
Research Considerations
Research considerations
Research peptide. Can be stimulating. Start low dose. Consult healthcare provider.
- Semax is not a universal nootropic. The published research clusters around specific neurological and cognitive contexts, and several populations should not be treated as candidates outside formal medical care.
- Semax research interest concentrates in cerebral ischemia and stroke recovery, post-traumatic cognitive impairment, attention/memory under cognitive load, and stress-related conditions. The July 24, 2026 FDA PCAC review will specifically discuss Semax for cerebral ischemia and trigeminal neuralgia .
- ADDF and Russian-language safety summaries note Semax may raise blood glucose levels in people with diabetes.
- There is not enough human research to evaluate fetal or infant safety. ADDF lists pregnancy and lactation as contraindications.
- A 1996 study described an anxiogenic component in some research subjects, suggesting Semax can amplify anxiety in already-anxious individuals. Calmer-feel goals are usually a better fit for Selank than Semax.
- Semax interacts with monoaminergic systems in animal models. Combining with SSRIs, SNRIs, MAOIs, stimulants, or sleep-affecting drugs deserves clinician oversight.
- FDA's compounding-risk language specifically calls out aggregation and peptide-related impurities for Semax. Product quality and immunogenicity risk can exceed molecule risk.
Factors noted in the research literature; not patient-specific medical advice.
Regulatory Status
Regulatory status
RUO
Comparisons
Comparisons
| Compound | Mechanism | Route | Status |
|---|---|---|---|
| Semaxthis | Increases BDNF expression, enhances dopamine and serotonin metabolism. Provides neuroprotection and cognitive enhancement. | nasal, subcutaneous | Investigational / RUO |
| Cerebrolysin | A porcine brain-derived preparation of low-molecular-weight neuropeptides and free amino acids studied for neurotrophic activity supporting neuronal survival, synaptic plasticity, and modulation of neuroinflammation. | subcutaneous | Investigational / RUO |
| DSIP | A naturally occurring nonapeptide studied for influence on sleep architecture and hypothalamic-pituitary-adrenal (stress-axis) modulation; its precise receptor targets remain incompletely characterized. | subcutaneous | Investigational / RUO |
| PE-22-28 | A synthetic heptapeptide (GVSWGLR) derived from the sortilin propeptide that acts as a selective antagonist of TREK-1 potassium channels, a mechanism studied for mood regulation and neuroplasticity. | subcutaneous | Investigational / RUO |
| Pinealon | A synthetic tripeptide bioregulator (Glu-Asp-Arg) studied for cell-penetrating, gene-regulatory activity in neural tissue, with proposed antioxidant and neuroprotective effects. | subcutaneous | Investigational / RUO |
| Sermorelin | Binds to GHRH receptors to stimulate pulsatile GH release, mimicking natural patterns. Preserves feedback mechanisms. | subcutaneous | Investigational / RUO |
| SLU-PP-332 | A synthetic pan-agonist of estrogen-related receptors (ERR alpha/beta/gamma) studied for activation of an aerobic-exercise-like gene program and increased oxidative metabolism. | — | Investigational / RUO |
Attributes shown for research comparison only; not a statement of efficacy or therapeutic equivalence.
FAQ
Frequently asked questions
Semax is a synthetic seven-amino-acid peptide (a heptapeptide) with the sequence Met-Glu-His-Phe-Pro-Gly-Pro. It is derived from a fragment of adrenocorticotropic hormone (ACTH) with an added Pro-Gly-Pro tail for stability, and is most commonly studied as an intranasal nootropic and neuroprotective peptide.
Semax is reported to nudge brain plasticity programs and stress-response biology rather than acting as a classical stimulant. It has been associated with increased BDNF and TrkB signaling in rodent brain studies, modulation of dopamine and serotonin systems, and gene-expression changes in ischemia models. Effects are most measurable when the brain is under load.
No. Semax is not an FDA-approved drug in the United States. It was placed on FDA's 503A Category 2 list of bulk substances flagged for compounding safety risks in September 2023 and removed from that list on April 23, 2026 after the underlying nominations were withdrawn. Removal from Category 2 does not authorize compounding. The Pharmacy Compounding Advisory Committee will discuss Semax for possible inclusion on the 503A Bulks List on July 24, 2026, specifically for cerebral ischemia and trigeminal neuralgia.
Total daily intranasal amounts in the cognitive research literature commonly fall around 0.6 to 1.5 mg per day, divided across two administrations. Acute-stroke clinical research used higher amounts under hospital supervision. Subcutaneous research-context amounts are sub-milligram per administration. These are reported trial-context ranges, not a dosing recommendation. PDP does not publish personalized Semax dosing protocols.
Both are short Russian-origin synthetic peptides with a Pro-Gly-Pro stabilizing tail, and both are most commonly discussed as intranasal solutions. Semax is associated with cognitive activation, focus, and neuroprotection (ACTH-derived). Selank is associated with anxiolytic and stress-modulating effects (tuftsin-derived, GABAergic gene-expression involvement). The simplest framing is: Semax for cognitive push, Selank for calm focus.
Semax is not authorized as a medicine by the UK Medicines and Healthcare products Regulatory Agency (MHRA). Sales of Semax nasal solution to UK consumers as a 'research chemical' do not constitute medical authorization or approval for human use.
Combining Semax and Selank is a research-community planning concept sometimes called the Russian Nootropic Stack. The logic is to pair cognitive activation (Semax) with calmer stress handling (Selank). The combination is not a clinically validated protocol, and FDA has flagged compounding-related risks for both peptides.
Intranasal Semax is described as fast-onset, with same-day effects on attention or task initiation reported by some users. Neuroprotective and immunomodulatory signals in the literature take longer (typically 2-4 weeks of consistent administration). Subjective reports vary widely, and a single session is not sufficient to evaluate the molecule.
Reported observed effects include nasal cavity discoloration in approximately 10% of intranasal users (per the Alzheimer's Drug Discovery Foundation summary), increased blood glucose in people with diabetes, overstimulation or anxiety in sensitive users, nasal irritation with frequent intranasal use, and sleep disruption with late-day administration. FDA's compounding-risk language additionally flags potential immunogenicity from aggregation and peptide-related impurities for certain routes.
No. Material sold as 'research grade' or 'research use only' is not authorized for human use and is the specific category FDA flagged for immunogenicity risk from aggregation and peptide-related impurities. Quality, identity, and purity documentation can vary widely between sellers, and product-level risk can exceed molecule-level risk for a peptide used at sub-milligram amounts.
No. This page is an educational research reference for Semax (heptapeptide) and is not medical advice, a prescription, or a recommendation to use the substance. Semax is not FDA-approved in the United States. Consult a qualified clinician for any health decision involving Semax or related peptides.
Research-use notice
Research Use Only. This educational content and calculation support is intended for private research documentation. It does not provide medical advice, human-use directions, or claims of safety or effectiveness.