Semax is a synthetic heptapeptide and analog of the adrenocorticotropic hormone (ACTH) fragment 4-10, with the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro, developed at the Russian Academy of Sciences in the 1970s through modification of the natural ACTH sequence by addition of the Pro-Gly-Pro tripeptide to extend the duration of its effects to 20-24 hours.[1][2] Lacking hormonal activity, Semax is approved in Russia as a nootropic and neuroprotective drug for treating ischemic stroke, dyscirculatory encephalopathy (a form of vascular cognitive impairment), optic nerve atrophy, Parkinson's disease, and neurological deficits in newborns.[1][3]Pharmacologically, Semax enhances cognitive functions such as memory, attention, and learning by upregulating brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus, modulating dopaminergic and serotonergic systems, and influencing gene expression related to immune response and vascular function in the brain.[4][5][2] It demonstrates neurotrophic effects, promoting neuronal survival and differentiation in preclinical models, and has shown efficacy in accelerating functional recovery and improving motor performance in stroke patients when administered intranasally during early rehabilitation.[6][7] Studies using functional MRI indicate that Semax alters resting-state connectivity in brain networks, including the default mode network, supporting its role in neuroprotection against ischemia and stress.[8][9]Clinically, Semax is typically administered intranasally, with common side effects limited to mild nasal irritation or discoloration in about 10% of users and transient blood glucose increases in diabetics (around 7.4%), though long-term safety data remain limited outside Russia.[1] While not approved by regulatory bodies like the FDA in the United States or EMA in Europe, ongoing research explores its potential in conditions such as attention-deficit hyperactivity disorder (ADHD), Rett syndrome, and prenatal depression, based on its ability to augment dopamine release and BDNF synthesis without the risks associated with hormonal ACTH analogs.[10][11]
Medical uses
Approved indications
Semax is approved for medical use in Russia, where it is prescribed primarily for neurological conditions involving cerebral circulation disorders and optic nerve pathologies. The 0.1% formulation is indicated for the treatment of intellectual-mnestic (cognitive and memory) disorders arising from vascular brain lesions, such as dyscirculatory encephalopathy, as well as in the recovery period following traumatic brain injury (TBI), neurosurgical interventions, and ischemic stroke.[12] It is also approved for optic nerve diseases, including atrophy and post-traumatic optic neuropathy, where clinical evaluations have demonstrated therapeutic efficacy in 70-80% of cases for vascular, toxic-allergic, and inflammatory conditions, supporting improved visual function. Additionally, the 0.1% solution serves as a nootropic agent in children aged 5 years and older for minimal brain dysfunctions, such as attention-deficit disorders. Semax is also used for Parkinson's disease and neurological deficits in newborns.[1][12]The 1% formulation of Semax is specifically approved for the acute period of ischemic stroke, aiding in neurological recovery by enhancing cerebral bloodflow and reducing neuronal damage, as evidenced by its inclusion in Russia's clinical standards for stroke management.[13]Russian clinical approvals highlight its role in improving post-stroke outcomes, with studies showing accelerated recovery of motor and cognitive functions compared to standard therapies.[14] Since 2011, Semax has been included in Russia's List of Vital and Essential Drugs, underscoring its established therapeutic value in addressing acute cerebral ischemia and related cognitive impairments.[15] This status reflects its widespread adoption in Russian clinical practice for neuroprotective applications, with approvals emphasizing benefits in encephalopathy and optic neuropathies without reliance on extensive pharmacological details.[16]
Administration and dosage
Semax is primarily administered intranasally as nasal drops or spray due to its poor oral bioavailability, a common limitation of peptide drugs that prevents effective gastrointestinal absorption.Standard formulations include 0.1% and 1% aqueous solutions, with the choice depending on the indication and required dose intensity. For adult patients recovering from stroke, a typical regimen involves 2–3 drops (300–600 mcg) of the 1% solution per nostril, administered three times daily, for a total daily dose of approximately 6 mg over 10–14 days.[7] This course may be repeated after a 20-day interval, with subsequent cycles possible after 3–6 months if clinically indicated.[7]Dosing is adjusted for specific indications and patient populations to optimize efficacy while minimizing exposure. For cognitive disorders or general nootropic use in adults, lower doses of 1–2 drops of the 0.1% solution (approximately 100–200 mcg total per administration) twice daily are commonly employed over 10–14 days. In children aged 5 years and older with minimal brain dysfunction, 1–2 drops of the 0.1% solution per nostril twice daily (total 200–400 mcg daily) are used for 30 days.[12]Although intranasal delivery is the standard route, subcutaneous or intramuscular injection has been utilized in select research protocols, particularly for precise dosing in experimental settings, though it remains less common in routine clinical practice.
Safety and tolerability
Adverse effects
Semax is generally well-tolerated in clinical settings, with no serious adverse effects reported across multiple studies involving patients with cerebrovascular insufficiency and motor neuron disease. In a trial of 187 patients treated intranasally with Semax for cerebrovascular insufficiency, the medication demonstrated excellent tolerability, including in older individuals, with only a minor percentage of side effects observed and no impact on disease complications. Similarly, an open-label study of 27 patients with motor neuron disease receiving two 10-day courses of intranasal Semax (12 mg daily) reported no adverse effects, alongside improvements in quality of life.[17][18]The most commonly reported issues are mild and transient, primarily local reactions from intranasal administration, such as nasal irritation, dryness, or a mild burning sensation, affecting about 10% of patients including nasal cavity discoloration.[1] These effects are typically self-limiting and resolve without intervention. Transient increases in blood glucose have been observed in about 7.4% of diabetic patients. In controlled settings, systemic side effects are rare, though one study in healthy subjects noted a potential increase in anxiety-like responses (e.g., heightened vigilance) at a 1 mg intranasal dose.[1][19]Long-term data from available clinical trials, spanning up to 30 days of use, show no evidence of dependency, tolerance development, or withdrawal symptoms upon discontinuation. Minimal systemic absorption contributes to the low incidence of broader effects, supporting its targeted central nervous system action.[20]Routine monitoring for allergic reactions is advised in sensitive patients, particularly those with a history of nasal sensitivities, to ensure early detection of any localized hypersensitivity.
Contraindications and precautions
Semax is contraindicated in patients with known hypersensitivity to the active substance or any excipients in the formulation.[21] It is also absolutely contraindicated during pregnancy and lactation due to insufficient clinical data regarding safety in these populations.[22] Acute psychotic states, anxiety disorders, and a history of seizures further represent absolute contraindications to its use.[21]Relative precautions are advised in certain conditions where the risk-benefit profile requires careful consideration. Patients with epilepsy should use Semax with caution, given the contraindication for those with a seizure history, and monitoring for neurological effects is recommended.[22] For patients with autoimmune disorders, caution is suggested due to Semax's potential immunomodulatory effects, though specific data remain limited.[2] Use in children is approved for specific neurological deficits including in newborns, but the 0.1% formulation is contraindicated in children under 5 years per some guidelines, with close monitoring required for pediatric use in neurology contexts.[21][1]Regarding drug interactions, no major pharmacokinetic interactions involving cytochrome P450 enzymes have been reported, consistent with Semax's peptide nature and intranasal route of administration.[21] However, potential enhancement of central nervous system effects may occur when combined with antidepressants or other nootropics, necessitating cautious co-administration and clinical oversight.[23] Intranasal vasoconstrictors should be avoided to prevent additive irritation.[22]In special populations, data on dose adjustments for the elderly or those with renal or hepatic impairment are limited, but monitoring is advised given the lack of extensive studies in these groups.[20]
Pharmacology
Pharmacodynamics
Semax exerts its pharmacological effects primarily through the upregulation of neurotrophic factors, notably brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in key brain regions such as the hippocampus and cerebral cortex. In rat models, intranasal administration of Semax at doses of 50–100 μg/kg rapidly induces BDNF protein levels in the basal forebrain, with peak elevations observed within hours, supporting enhanced neuronal survival and synaptic plasticity.[24] Similarly, Semax stimulates NGF gene expression in the hippocampus and frontal cortex, with mRNA levels increasing significantly 20 minutes post-administration in some studies, though transient decreases occur initially in certain regions like the retina.[25] These neurotrophic actions contribute to Semax's role in promoting neurogenesis and cognitive enhancement.[26]Semax also modulates neurotransmitter systems, particularly serotonergic and dopaminergic pathways, by enhancing their activity and release. In rodent striatum, Semax (0.15 mg/kg intraperitoneally) increases extracellular levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) by up to 180% within 1–4 hours, indicating boosted serotonergic transmission without directly altering serotonin tissue content.[27] For dopamine, Semax alone does not significantly change basal levels but potentiates the release induced by psychostimulants like d-amphetamine, amplifying extracellular dopamine and locomotor responses.[27] Additionally, Semax inhibits enkephalin-degrading enzymes in human serum with an IC50 of 10 μM, thereby prolonging the activity of endogenous opioids and related regulatory peptides.[28]The neuroprotective profile of Semax involves multiple pathways, including the promotion of neurogenesis and reduction of inflammation. Transcriptome analyses in rat models of cerebral ischemia-reperfusion reveal that Semax upregulates genes associated with neurogenesis, such as Hes5 and Neurod6, facilitating neuronal repair and differentiation in the affected brain regions.[26] It also attenuates inflammation by suppressing pro-inflammatory cytokine genes (e.g., Ccl6, Ccl9) and heat shock proteins (e.g., Hspa1a/b), counteracting ischemia-induced immune activation at 24 hours post-injury.[26] Furthermore, Semax enhances cerebral blood flow by modulating vascular endothelial growth factor (VEGF) family genes; in rat focal ischemia models, it normalizes Vegf-b and Vegf-d mRNA expression, opposing ischemic downregulation and promoting endothelial proliferation.[29] Recent studies (as of 2025) have identified additional mechanisms, such as targeting the μ-opioid receptor gene (Oprm1) to inhibit lysosome-mediated pyroptosis and neuroinflammation, promoting functional recovery in spinal cord injury models.[30]Beyond neuroprotection, Semax influences immune-related gene expression and exhibits potential antidepressant effects via hypothalamic-pituitary-adrenal (HPA) axis regulation. In ischemic rat brains, Semax alters the transcription of immune genes, including those for immunoglobulins and chemokines, to bolster adaptive responses without exacerbating inflammation.[26] Its antidepressant-like actions, observed in chronic unpredictable stress paradigms, involve restoring hippocampal BDNF levels and mitigating anhedonia, likely through melanocortin-mediated HPA modulation that attenuates stress markers.[11]
Pharmacokinetics
Semax exhibits rapid absorption following intranasal administration, with detectable levels in ratblood and brain achieved within 2 minutes post-dose at 50 μg/kg.[31] Approximately 0.5% of the administered dose reaches the blood and 0.093% penetrates the brain per gram of tissue at this early time point, indicating efficient uptake via the nasal route.[31] Oral bioavailability is negligible, typically less than 1%, owing to rapid enzymatic degradation of the peptide in the gastrointestinal tract.[1]The drug demonstrates preferential distribution to the central nervous system, crossing the blood-brain barrier more effectively via intranasal delivery compared to intravenous administration, achieving 10- to 15-fold higher brain concentrations.[31] This results in substantial central nervous system penetration while showing limited accumulation in peripheral tissues.[31]Metabolism occurs primarily through enzymatic degradation by peptidases in plasma and tissues, yielding metabolites such as Pro-Gly-Pro, Phe-Pro-Gly-Pro, and longer fragments like Glu-His-Phe-Pro-Gly-Pro.[31] No active metabolites have been identified, as the breakdown products lack the biological activity of intact Semax.[31]Excretion is predominantly renal, consistent with the clearance of small peptides.[1] Semax has a short plasma half-life of several minutes, leading to complete clearance from the body within hours.[32]Pharmacokinetic parameters are minimally affected by age or disease states, though nasal congestion can impair intranasal absorption by obstructing mucosal contact.[1]
Chemistry
Structure and properties
Semax is a synthetic heptapeptide and analog of the adrenocorticotropic hormone (ACTH) fragment ACTH(4-10), characterized by the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP). This structure replaces the C-terminal Arg-Trp-Gly sequence of the native ACTH(4-10) (MEHFRWG) with Pro-Gly-Pro to enhance proteolytic stability and central nervous system penetration. Its molecular formula is C_{37}H_{51}N_{9}O_{10}S, with a molecular weight of 813.9 g/mol.[33][34]As a linear peptide lacking disulfide bonds, Semax exhibits key structural features that confer resistance to enzymatic degradation: the C-terminal Pro-Gly-Pro motif creates steric hindrance to carboxypeptidase and endopeptidase attack. These modifications result in greater stability compared to the parent ACTH fragment, enabling prolonged activity in biological environments.[35]Physically, Semax is supplied as a sterile-filtered white lyophilized powder, highly soluble in water (>2 mg/mL) and physiological saline, facilitating reconstitution for intranasal or injectable administration. For optimal stability, the lyophilized form should be stored below -18°C in a desiccated environment, while reconstituted solutions are stable at 4°C for up to 7 days.[36][37]
Synthesis and formulation
Semax is synthesized via solid-phase peptide synthesis (SPPS) using the Fmoc (9-fluorenylmethyloxycarbonyl) protection strategy, a standard approach for producing synthetic peptides like this heptapeptide analogue of ACTH(4-10). The process begins with the C-terminal amino acid attached to a solid support resin, followed by sequential addition of the remaining six amino acids (Met-Glu-His-Phe-Pro-Gly-Pro) through iterative cycles of coupling and deprotection.[38]During synthesis, each Fmoc-protected amino acid is activated using coupling agents such as HBTU in conjunction with a base like diisopropylethylamine, enabling amidebond formation with the resin-bound peptide chain. The Fmoc protecting group is then removed with 20% piperidine in dimethylformamide (DMF). Upon completion of the chain assembly, the peptide is cleaved from the resin and deprotected using a mixture containing trifluoroacetic acid (TFA), often with scavengers like triisopropylsilane and water. The resulting crude product undergoes purification by reverse-phase high-performance liquid chromatography (HPLC), followed by lyophilization to yield the pure peptide. This method ensures high purity and yield for laboratory-scale production of Semax.[38]Pharmaceutically, Semax is formulated primarily as sterile aqueous nasal drops at concentrations ranging from 0.1% to 1% w/v, dissolved in isotonic saline with preservatives such as methylparahydroxybenzoate (1 g/L) to prevent microbial growth. The solution is prepared under aseptic conditions and packaged in multidose vials, typically 3 mL, for intranasal administration. Alternatively, Semax is supplied as a lyophilized powder in vials for reconstitution with sterile water or saline prior to subcutaneous or intramuscular injection.[39]Lyophilized Semax demonstrates excellent stability, maintaining potency for 2-3 years when stored refrigerated at 2-8°C and protected from light and excessive heat, which could otherwise promote oxidation of the methionine residue. Reconstituted formulations should be refrigerated and used within 2-7 days to avoid degradation.[36]
History and development
Discovery and early research
Semax was developed in the 1970s at the Institute of Molecular Genetics of the Russian Academy of Sciences in Moscow as part of broader research into synthetic regulatory peptides derived from natural hormones.[23] The work was led by researchers including I.P. Ashmarin, focusing on analogs of adrenocorticotropic hormone (ACTH) fragments to improve metabolic stability and therapeutic potential.[40]The peptide is a heptapeptide analog of the ACTH(4-10) fragment (Met-Glu-His-Phe-Pro-Gly-Pro), incorporating a Pro-Gly-Pro C-terminal extension to confer resistance to enzymatic degradation while preserving neuromodulatory properties.[41] This modification addressed limitations of the native ACTH fragment, which was known since the 1950s for exhibiting cognitive and neuroprotective effects independent of its hormonal activity.[1]Initial preclinical studies in the early 1990s revealed Semax's nootropic effects in rodent models exposed to hypoxia and cerebral ischemia, where it facilitated recovery of cognitive functions without hormonal side effects.[42] A seminal 1991 publication in Russian scientific literature demonstrated that intranasal administration of Semax enhanced learning and memory retention in rats during active avoidance tasks, outperforming the parent ACTH fragment in duration and efficacy.[41]Further early investigations explored Semax's neuroprotective potential in models of brain injury, such as global ischemia, showing reduced neuronal damage and improved behavioral outcomes in rats, building directly on the neuromodulatory foundation of natural ACTH-derived peptides identified in prior decades.[43]
Clinical development and approval
Semax's clinical development began in Russia during the 1990s, with early Phase I and II trials focusing on its potential for stroke recovery and cognitive impairment. Initial studies in the late 1990s evaluated its neuroprotective effects in acute ischemic stroke patients, demonstrating accelerated neurological restoration when added to standard therapy. For instance, a 1999 clinical trial investigated Semax's immunobiochemical mechanisms in the acute phase of ischemic stroke, showing positive impacts on neuroprotection. By the early 2000s, further trials confirmed its efficacy; a 2001 study involving 30 patients with hemispheric ischemic stroke reported that Semax influenced the rate of functional recovery during intensive therapy.[44][45]These Russian-led studies established Semax's role in enhancing brain-derived neurotrophic factor (BDNF) levels, which correlated with faster motor and functional recovery in stroke survivors. A 2018 trial with 110 ischemic stroke patients further validated this, showing that intranasal Semax (6000 μg/day for 10 days, repeated after a 20-day interval) increased plasma BDNF, expedited rehabilitation, and improved motor performance when combined with early rehabilitation.[7]Semax was first registered in Russia in 1994 for limited use in neurological conditions, primarily as a nootropic agent for emergency medical kits. Full regulatory approval followed on December 7, 2011, by the Russian Federation government, expanding its indications to include stroke, transient ischemic attack, cognitive disorders, optic nerve diseases, and peptic ulcers. As of 2025, Semax remains approved only in Russia and select Eastern European countries, with no major international regulatory approvals from bodies like the FDA or EMA.Recent developments from 2024 to 2025 have explored Semax's applications beyond traditional indications, including preclinical trials on spinal cord injury where it modulated the Oprm1 gene to promote deubiquitination, reduce pyroptosis, and enhance functional recovery in models of neuroinflammation. Mechanistic studies have also highlighted its antidepressant potential in chronic unpredictable stress models and neuroprotective effects in Alzheimer's disease pathways, alongside improvements in memory during chronic brain ischemia. Ongoing research in Russia investigates Semax for ADHD, anxiety disorders, and neurodegeneration, with over 50 trials conducted domestically but limited Western clinical data available, emphasizing the need for larger international Phase III studies.[30]
Society and culture
Legal status
In Russia and other Commonwealth of Independent States (CIS) countries, including Ukraine, Semax is classified as a prescription medication and recognized as a nootropic and neuroprotective agent, primarily used for treating conditions such as stroke, cognitive disorders, and brain trauma.[14] It is included on the Russian List of Vital and Essential Drugs, a government-approved reference of key medications that ensures its availability in the national healthcare system.[15]Internationally, Semax has not been approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as of 2025, and it lacks equivalent regulatory authorization in most other countries.[46][47] In the United States, the FDA has identified Semax as a bulk drug substance that may present significant safety risks in compounding due to potential immunogenicity, aggregation, and impurities.[46] It is typically regarded as a research chemical rather than a pharmaceutical or dietary supplement, with restrictions on importation for personal use due to its unapproved status.[48]Semax is not classified as a controlled substance under United Nations conventions on narcotic drugs or psychotropic substances, nor is it scheduled in the U.S. Controlled Substances Act.[49] However, its availability outside approved regions often occurs through unregulated gray-market online sales, where it is marketed for research purposes but lacks oversight on quality or purity.[50] As of 2025, no major global regulatory approvals for Semax are pending, though ongoing research continues to explore its applications.[51]
Etymology and availability
The name Semax derives from the Russian phrase "семь аминокислот" (sem' aminokislot), translating to "seven amino acids," a reference to its heptapeptide composition consisting of seven amino acid residues.[15]Semax is manufactured by Peptogen, a Russian pharmaceutical company established in collaboration with the Institute of Molecular Genetics of the Russian Academy of Sciences, and is commercially available as intranasal drops in formulations such as 0.1% and 1% concentrations. In approved markets like Russia, it is marketed for supporting cognitive health and neuroprotection.[52][53][14]Within Russia, Semax requires a prescription and is dispensed through pharmacies, and has been included on the country's List of Vital and Essential Drugs since 2011.[15][14] Outside Russia, it lacks regulatory approval for medical use in most jurisdictions and is not available over-the-counter; however, it can be obtained globally via online vendors, particularly in China and Europe, where it is sold as a research chemical or peptide, frequently without rigorous quality assurance or standardization.[15][14][54][55]In non-medical contexts, Semax has become popular among nootropic enthusiasts for purported cognitive enhancement benefits, including improved focus and memory, as well as potential anxiety reduction, with users commonly self-administering it through nasal spray formulations despite limited clinical evidence for these applications beyond research settings.[23][56]