Selank

Selank is a synthetic heptapeptide with the amino acid sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro, designed as an analog of the naturally occurring immunomodulatory peptide tuftsin.^[1] As a tuftsin analog, Selank acts as an anxiolytic that improves mood stability and emotional resilience without sedation.^[1] Developed at the Institute of Molecular Genetics of the Russian Academy of Sciences and the Zakusov Scientific Research Institute of Pharmacology, it serves as a regulatory peptide drug characterized by anxiolytic, nootropic, and neuroprotective effects with minimal toxicity due to its composition of natural amino acids.^[1] Approved in Russia in 2009 for the treatment of generalized anxiety disorder (GAD), Selank is administered intranasally at doses such as 2700 μg per day and demonstrates both rapid (within 1–3 days) and conventional (by day 14) symptom reduction, as measured by significant decreases in Hamilton Anxiety Rating Scale (HARS) scores (e.g., from 20.3 to 7.0 in rapid responders, p < 0.01).^[2] Pharmacologically, Selank exhibits anxiolytic effects comparable to benzodiazepines while also providing stimulatory and cognitive-enhancing benefits, such as improved learning in animals with initially poor performance after a single dose.^[3] It prolongs anti-anxiety action and supports nootropic outcomes, including enhanced memory processes potentially linked to modulation of serotonin levels and its metabolites in the brain.^[4] In clinical settings, Selank has shown efficacy in preventing and treating GAD and neurasthenia, with additional benefits in reducing anxiety under chronic stress when combined with agents like diazepam, outperforming either alone in unpredictable chronic mild stress models.^[1][5] Selank's mechanism involves allosteric modulation of GABA_A receptors, influencing GABA binding and potentially altering gene expression related to neurotransmission without direct toxicity.^[1][6] Electroencephalographic studies indicate it increases beta-rhythm activity and decreases theta/low alpha-rhythms in rapid responders after a single 900 μg dose (p < 0.05), supporting its cognitive and anxiolytic profile.^[2] Overall, Selank represents a peptide-based therapeutic with a favorable safety profile, avoiding the sedative side effects common to traditional anxiolytics.^[1]

Development

Discovery

Selank was developed in the early 1990s at the Institute of Molecular Genetics of the Russian Academy of Sciences, in collaboration with the V.V. Zakusov Research Institute of Pharmacology of the Russian Academy of Medical Sciences.^[6] The project was led by prominent researchers including I.P. Ashmarin and N.F. Myasoedov, who focused on creating novel regulatory peptides for therapeutic applications.^[7] The peptide emerged as a synthetic heptapeptide analogue of tuftsin, a natural immunomodulatory tetrapeptide (Thr-Lys-Pro-Arg) derived from the heavy chain of human immunoglobulin G, which plays a key role in enhancing phagocytic activity and immune responses.^[6] To address tuftsin's limitations, such as rapid enzymatic degradation, the original sequence was extended at the C-terminus with the tripeptide Pro-Gly-Pro, resulting in the structure Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP); this modification was intended to improve metabolic stability and prolong the duration of action.^[6] The core aim of Selank's design was to produce a compound with integrated anxiolytic and nootropic effects, avoiding the sedative side effects typical of benzodiazepines, while leveraging tuftsin's foundational immunomodulatory influences to potentially support broader neuroprotective outcomes.^[8] Early synthesis of Selank employed solid-phase peptide synthesis techniques, a standard approach for assembling short peptides during that period to ensure precise control over sequence and purity.^[9]

Approval

Selank underwent preclinical testing in the 1990s following its initial synthesis around 1990-1995 as an analogue of the natural tetrapeptide tuftsin.^[8] This phase established its potential as an anxiolytic agent, paving the way for clinical evaluation. In the 2000s, the peptide advanced through clinical trials in Russia, culminating in its registration as intranasal drops for therapeutic use.^[10] The Russian Ministry of Health approved Selank as a pharmaceutical in 2009 specifically for the treatment of generalized anxiety disorder (GAD), marking its formal entry into clinical practice.^[10] It has shown efficacy in treating GAD and neurasthenia.^[1] As of 2025, Selank remains approved in Russia for these indications and is also used for adjustment disorders.^[11] First human studies, including trials demonstrating efficacy comparable to benzodiazepines, began in the early 2000s and supported this regulatory pathway. Commercialization ensued shortly after approval, with Russian pharmaceutical company Peptogen (JSC "Peptogen") taking the lead in production and distribution of Selank nasal drops.^[12] The product became available by prescription in pharmacies across Russia and Ukraine, facilitating its integration into routine medical treatment for approved conditions.^[8]

Chemistry

Structure

Selank is a synthetic linear heptapeptide composed of seven amino acids with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP).^[13] Its molecular formula is C₃₃H₅₇N₁₁O₉, and the molar mass is 751.88 g/mol.^[13] Selank is structurally derived from the tetrapeptide tuftsin (Thr-Lys-Pro-Arg) through the addition of a Pro-Gly-Pro tripeptide at the C-terminus, which is designed to improve metabolic stability compared to tuftsin.^[14][9] The molecule lacks disulfide bonds or cyclic elements, maintaining a straightforward linear peptide backbone.^[13]

Properties

Selank is supplied as a sterile filtered white lyophilized (freeze-dried) powder, which is highly soluble in water and aqueous buffers such as phosphate-buffered saline (PBS).^[15][16] The powder form facilitates long-term storage and handling in laboratory settings, with solubility reaching approximately 10 mg/mL in PBS at pH 7.2.^[16] The stability of Selank is influenced by its storage conditions to minimize degradation. The lyophilized powder remains stable at room temperature for up to 3 weeks but is recommended to be stored desiccated below -18°C for extended periods.^[15] Once reconstituted in aqueous solution, it requires refrigeration at 2–8°C and maintains stability for 2–7 days under aseptic conditions, though some protocols advise limiting solution storage to one day to preserve integrity.^[15][17][16] Chemically, Selank is hydrophilic, attributed to its sequence rich in polar amino acids such as threonine, lysine, and arginine. Its calculated isoelectric point (pI) is approximately 11.5, indicating a basic character under neutral pH conditions. Compared to tuftsin, Selank demonstrates enhanced metabolic stability due to C-terminal extensions.^[14]

Pharmacology

Mechanism of Action

Selank modulates GABAergic neurotransmission primarily through allosteric enhancement of GABA receptor activity and regulation of gene expression in key brain regions. Selank affects the expression of some genes involved in GABAergic neurotransmission in the rat frontal cortex following administration, thereby promoting GABA synthesis and receptor function without cumulative effects when combined with benzodiazepines.^[18][19] Selank elevates levels of brain-derived neurotrophic factor (BDNF) in the rat hippocampus following intranasal administration. This upregulation supports neurogenesis and enhances synaptic plasticity via TrkB receptor activation, contributing to neuroprotection.^[20] By inhibiting enkephalin-degrading enzymes in human and animal plasma, Selank (with an IC50 of 15–20 µM) prolongs the half-life of endogenous enkephalins, thereby increasing opioid peptide activity and exerting anxiolytic effects comparable to classical agents but without associated addiction risk or withdrawal. This anxiolytic action contributes to improved mood stability and emotional resilience without inducing sedation.^{[21][22][6][23]} Selank influences cytokine balance by reducing pro-inflammatory markers such as IL-6, IL-1β, and TNF-α in stressed rats, restoring levels toward baseline and modulating Th1/Th2 equilibrium to mitigate inflammation. It also affects monoamine systems, altering serotonin (5-HT) and dopamine metabolism in the hippocampus and frontal cortex of mice, with decreases in 5-HT and its metabolite 5-HIAA observed in certain strains. These changes correlate with antidepressant-like effects, including reduced immobility time in the forced swim test among BALB/c mice at doses of 100–300 µg/kg.^[24][25][26] Unlike benzodiazepines, Selank exhibits no direct binding to benzodiazepine receptors on GABA-A complexes, as evidenced by its distinct modulation of [3H]GABA binding sites and lack of overlap in anxiolytic action profiles, which accounts for its absence of sedative or muscle-relaxant side effects. As a synthetic analogue of the immunomodulatory tetrapeptide tuftsin, Selank retains partial influence on immune responses.^[19][27]

Pharmacokinetics

Selank is primarily administered via the intranasal route, which allows for rapid absorption through the nasal mucosa, with intravenous administration used in research settings.^[28] The intranasal method provides efficient delivery to the central nervous system, bypassing first-pass metabolism.^[28] Following intranasal administration, Selank is absorbed quickly and has a short plasma half-life due to rapid enzymatic breakdown.^[29] Selank crosses the blood-brain barrier efficiently, particularly when administered intranasally, achieving higher concentrations in brain regions such as the hippocampus and cortex compared to peripheral tissues.^[28] This distribution pattern supports its targeted effects in the central nervous system. The peptide's structural stability contributes to its ability to penetrate the blood-brain barrier effectively.^[28] Metabolism of Selank occurs primarily through degradation by peptidases, yielding shorter peptide fragments such as pentapeptides, tripeptides, and dipeptides; no active metabolites have been identified.^[29] Excretion is mainly renal, with metabolic fragments cleared from the body within hours, and the short half-life prevents accumulation even with repeated dosing.^[29]

Medical Use

Indications

Selank is approved in Russia for the treatment of generalized anxiety disorder (GAD) and neurasthenia in adults, particularly for mild-to-moderate cases where non-sedating anxiolytic effects, including improvements in mood stability and emotional resilience, are preferred over traditional benzodiazepines.^{[30][31][32][6][23]} Beyond its primary approval, Selank has been investigated for off-label uses including anxiety-asthenic disorders, where it demonstrates efficacy in alleviating asthenic symptoms without impairing cognitive function.^[33][23] It is also researched for adjustment disorders, showing potential in maintaining psychoemotional stability during stressful life transitions.^[34] Additionally, Selank serves as an adjunct therapy in depression, particularly in stress-related depressive states, by enhancing mood regulation alongside standard antidepressants.^[35] In terms of cognitive enhancement, Selank is explored for improving attention, memory, and learning in individuals with stress-induced cognitive impairments, leveraging its nootropic properties to support mental clarity without sedation.^[6] Potential neuroprotective applications include its investigation for posttraumatic stress disorder (PTSD), where it may aid in reducing hyperarousal and emotional dysregulation.^[36] Furthermore, Selank shows promise in alleviating symptoms of alcohol withdrawal syndrome, particularly in reducing anxiety during acute abstinence phases.^[37] These uses target patient populations experiencing chronic stress or neurological insult, emphasizing its role in non-sedative, immunomodulatory support.^[35] Short-term benefits of Selank are observed within days to weeks in responsive individuals, based on clinical observations. It provides anxiolytic effects that reduce anxiety symptoms comparably to low-dose benzodiazepines such as diazepam or phenazepam, but without sedation, muscle relaxation, or cognitive impairment. These effects are effective for GAD, neurasthenia, and stress-related anxiety. Selank improves mood and stress response by enhancing emotional resilience, reducing irritability, and promoting calmness through modulation of serotonin and dopamine systems. It also offers cognitive enhancements, including improved focus, memory, learning, and mental clarity, with stimulating effects in some patients. Additionally, mild immunomodulation, such as regulation of cytokines, has been noted, along with protection against stress-induced issues in animal models. These benefits may be enhanced when Selank is combined with traditional treatments.^[6][5]

Administration

Selank is primarily administered intranasally as a 0.15% aqueous solution in the form of nasal drops, supplied in 3 ml bottles with a dropper for precise delivery.^[30] The drug is instilled in a sitting position with the head slightly tilted back, after clearing the nasal passages if necessary; following instillation, each nostril is gently pinched for a short time to facilitate absorption.^[38] The recommended dosage is 2-3 drops per nostril, equivalent to 200-300 μg per administration, given 2-3 times daily, resulting in a total daily dose of 600-900 μg for anxiety-related applications.^[38] Treatment courses typically last 10-14 days, with the option to repeat after a 1-3 month break under medical guidance to prevent tolerance development.^[38] In research or non-commercial settings, lyophilized Selank powder is reconstituted by dissolving it in sterile water or saline to prepare the 0.15% solution, after which it must be stored refrigerated at 2-8°C to maintain stability.^[39] The intranasal route enhances brain targeting by bypassing the blood-brain barrier through olfactory pathways.^[6] No routine blood monitoring is required due to Selank's favorable safety profile, and self-administration is possible with initial medical supervision to ensure proper technique and dosing adherence.^[30]

Clinical Studies

Preclinical Research

Preclinical studies have established Selank's anxiolytic potential through behavioral assays in rodents. In rats subjected to the elevated plus-maze test, intranasal administration of Selank at 300 μg/kg increased the time spent in open arms and reduced anxiety-like behaviors, with efficacy comparable to oral diazepam (1 mg/kg) but without impairing locomotor activity, indicating an absence of sedation. These anxiolytic effects were observed rapidly, within hours of administration, demonstrating short-term benefits in reducing stress-induced anxiety without sedative side effects.^[5] Regarding neuroprotection, Selank mitigated ethanol-induced cognitive impairments in aged rats. Chronic ethanol exposure (10% solution for 30 weeks) led to memory and attention deficits during withdrawal, which Selank (0.3 mg/kg/day, intraperitoneal for 7 days) reversed, improving performance in recognition memory tasks. This intervention provided short-term protective effects against stress-induced neuronal damage, with benefits emerging within days of treatment.^[40] Additionally, intranasal Selank (250–500 μg/kg) upregulated brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus, increasing BDNF mRNA levels by 1.5–2-fold at 3 hours and protein levels by 30% at 24 hours post-administration, supporting its role in countering stress-related neuronal damage on a short-term basis.^[20] Selank exhibited immunomodulatory effects in rodent models of inflammation and stress. In rats under social stress conditions, intraperitoneal Selank (100 μg/kg/day for 20 days) downregulated pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, while restoring anti-inflammatory IL-4 levels to baseline, thereby attenuating the inflammatory response with rapid onset in responsive models, offering short-term protection against stress-induced immune dysregulation.^[24] In mouse spleen tissue, Selank (100 μg/kg, intraperitoneal) altered the expression of multiple inflammation-related genes, including those encoding cytokines and chemokines, demonstrating broad regulatory influence on immune signaling pathways within days of administration.^[41] Toxicity assessments in preclinical models revealed a favorable safety profile for Selank. Selank's anxiolytic effects may involve brief modulation of GABA-related gene expression in the brain.^[6]

Human Trials

Human clinical trials on Selank have primarily evaluated its anxiolytic efficacy in patients with generalized anxiety disorder (GAD) and related anxiety-spectrum conditions, often using standardized scales such as the Hamilton Anxiety Rating Scale (HAM-A). These studies, conducted mainly in Russia, have demonstrated Selank's potential to reduce anxiety symptoms comparably to traditional benzodiazepines while offering additional cognitive benefits, with short-term effects appearing within days to weeks in responsive individuals. A seminal 2008 randomized controlled trial enrolled 62 patients diagnosed with GAD or neurasthenia, assigning 30 to intranasal Selank (2700 μg/day for 14 days) and 32 to medazepam (30 mg/day orally). Both treatments significantly reduced anxiety scores on the HAM-A, with Selank achieving similar anxiolytic effects to medazepam but exhibiting superior psychostimulant properties that enhanced attention and cognitive performance in stressed participants, as measured by the Clinical Global Impression (CGI) scale and Zung Self-Rating Anxiety Scale. These benefits, including reduced anxiety without sedation, muscle relaxation, or cognitive impairment, were noted within days in many participants. No significant differences in overall response were noted between groups, but Selank was better tolerated without sedation or withdrawal issues.^[42] In a 2015 comparative trial involving 70 patients with anxiety-phobic, hypochondriac, and somatoform disorders (ICD-10 codes F40.2–F40.9, F41.1–F41.9, F45.0–F45.2), researchers assessed phenazepam monotherapy (n=30) against combined Selank (2700 μg/day intranasally) plus reduced-dose phenazepam (n=40) over 21 days. The combination therapy yielded superior outcomes, including faster reductions in depressive symptoms on the Hamilton Depression Rating Scale (HDRS) and improved quality of life on the SF-36 scale, alongside fewer cognitive side effects like memory and attention deficits (evaluated via Stroop test and verbal fluency tasks). Patients on the combination reported 70–80% greater tolerability during withdrawal, highlighting Selank's role in mitigating benzodiazepine-related impairments and providing rapid benefits, such as enhanced emotional resilience and calmness, when combined with traditional treatments.^[43] Subsequent investigations have explored responder variability and neuroimaging correlates. A 2012 analysis of 20 GAD patients treated with Selank identified rapid responders (40% of cohort) who showed symptom relief within 3 days on HAM-A, contrasted with slower responders requiring 7–14 days, accompanied by distinct EEG changes indicating enhanced neural synchronization. These rapid effects included anxiolytic benefits comparable to low-dose benzodiazepines, mood improvements via serotonin and dopamine modulation, and cognitive enhancements like improved focus and memory, without sedative effects. A 2020 resting-state fMRI study in healthy subjects (n=20 per group) demonstrated that acute Selank administration altered functional connectivity in the default mode network and limbic regions, patterns linked to reduced anxiety processing. Across these trials, stressed cohorts exhibited consistent cognitive enhancements, including improved short-term memory and attentional focus, without the dulling effects of sedatives. However, most research originates from Russian institutions with sample sizes of 20–100, lacking large-scale, multinational Phase III validation to confirm generalizability.^[44][45]

Safety and Regulation

Adverse Effects

Selank exhibits a favorable safety profile in clinical studies, characterized by high tolerability and the absence of typical adverse effects associated with traditional anxiolytics. Unlike benzodiazepine tranquilizers, its anxiolytic effects occur without accompanying sedation, myorelaxation, amnesia, dependence, or withdrawal symptoms.^[6] In comparative clinical trials involving patients with anxiety disorders, Selank demonstrated pronounced anxiolytic efficacy alongside excellent tolerability, with no significant side effects reported relative to phenazepam.^[46] Similarly, in a study of patients with adjustment and posttraumatic stress disorders treated with intranasal Selank for 14 days, no adverse reactions were observed, underscoring its good clinical tolerability and safety in stress-related conditions.^[47] No serious risks, such as cardiovascular events, have been documented in clinical use; while immunogenicity risks have been raised by regulatory bodies like the FDA, none have been observed in approved Russian trials, attributable to its synthetic peptide structure and targeted mechanism.^[6] Long-term safety data remain limited, but available evidence from short- to medium-term trials shows no evidence of tolerance development or cognitive impairment, even in elderly patients with nervous system disorders.^[48] Overdose cases have not been reported, with preclinical data suggesting only transient, mild symptoms like nausea at supratherapeutic doses exceeding 5 mg.^[49] However, Selank is considered experimental outside of Russia, with limited high-quality, large-scale human trials, primarily consisting of small-scale studies (typically 20-100 participants) conducted in Russian institutions.^[48][49] Potential interactions with other medications have been noted, including synergistic effects with benzodiazepines such as phenazepam, where Selank may enhance anxiolytic efficacy while reducing associated adverse effects.^[43] Common side effects, particularly with intranasal administration, include nasal irritation, sinus pain, headache, fatigue, and dizziness.^[49][48] Due to its unregulated status in many jurisdictions, variations in product purity can occur, potentially increasing risks from contaminants or inconsistent dosing.^[50] Individuals considering Selank use are advised to consult a healthcare professional beforehand, especially those with underlying medical conditions, given the limited long-term data and potential for interactions.^[49][48]

Legal Status

In Russia, Selank has been approved as a prescription medication for the treatment of generalized anxiety disorder since 2009, with certain formulations available over-the-counter for anxiety management.^[51][8] In the United States, Selank is not approved by the Food and Drug Administration (FDA) for any medical use. It was placed on the agency's Category 2 list of bulk drug substances that may present significant safety risks for compounding in 2023 but was removed in September 2024 following additional information from the nominator. As of 2025, it remains available solely as a research chemical for non-human use or potentially through accredited compounding pharmacies, subject to ongoing evaluation.^{[52][48][53][14]} In the European Union and various other countries, Selank is unscheduled and lacks regulatory approval for human therapeutic applications, rendering it unregulated for clinical or consumer use beyond research purposes.^[14] In jurisdictions such as New Zealand, it is classified as an unscheduled peptide with imports subject to monitoring by Medsafe due to unverified therapeutic claims.^[54] Internationally, Selank is not included on the World Health Organization's list of essential medicines or prohibited substances, permitting its use in research settings worldwide while prohibiting unsubstantiated therapeutic marketing outside of Russia. As of 2025, countries including Canada and Australia maintain border controls on peptide imports, often requiring prescriptions or approvals that Selank does not meet for personal importation.^[55][56]