Cortagen
Cortagen (Ala-Glu-Asp-Pro tetrapeptide)
A synthetic tetrapeptide (Ala-Glu-Asp-Pro) derived from Cortexin brain extract, studied primarily in preclinical models for nerve regeneration, neuroprotection, and epigenetic chromatin remodeling. No human clinical trials exist (PMID 11276314, PMID 15159690, PMID 37042594).
Last updated: 2026-03-09
Safety Summary
All side effect data comes exclusively from animal studies or vendor reports. No human adverse event data exists, and no FAERS match was returned. The Adriani et al. 2009 mouse study found that the optimal dose of 0.03 mg/kg produced motor stimulation without anxiety or emotional-affective disturbances, but sub-chronic treatment (5 days) with other Cortagen doses and the Cortexin reference produced anxiogenic-like effects in the elevated plus maze (DOI 10.2174/1876523800902010022). The Shabanov 2013 electrophysiology study on mollusk neurons found that Cortagen at very high concentrations (1000-10000 mcM) produced nonspecific depolarization effects described as potentially toxic, while 0.1-1000 mcM effects were weak and reversible (DOI 10.17816/rcf11217-25). The Kuznik 2008 study found no effect of Cortagen on immunity or hemostasis parameters in chickens (PMID 19432169). Vendor sites report no significant adverse effects, but this is not based on controlled human studies.
Known Side Effects
common
uncommon
uncommon
Who Should NOT Use This
No reproductive safety data available for Cortagen. Gene-regulatory compounds should be avoided during pregnancy and breastfeeding as a precautionary measure. This is a theoretical contraindication, not based on Cortagen-specific adverse data.
Cortagen modulates gene expression in neural tissue and promotes cell growth/neurite outgrowth (PMID 11276314, PMID 11713572). Theoretical risk of promoting tumor growth. No data exists to assess safety in this context. This is a theoretical contraindication.
Talk to Your Doctor
Before considering Cortagen, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-16]
Evidence Assessment
Tier 5: Animal and in vitro data only. No registered clinical trials on ClinicalTrials.gov. No Phase 1, 2, or 3 human data available in the accessible literature. The closest human-adjacent data consists of ex vivo studies on lymphocytes from elderly human donors (PMID 15085253, PMID 37042594), which demonstrate chromatin remodeling effects but are in vitro cell culture experiments, not in vivo human administration, and do not constitute clinical evidence. PMID 15159690 makes a brief claim of human posttraumatic recovery benefit, but no published human study supporting this claim was found in the source data. Nearly all research (approximately 14 of 15 relevant publications) originates from Khavinson's group or closely affiliated Russian institutions. One semi-independent study exists (Adriani et al. 2009, Italy, but includes a Geropharm Ltd co-author). Study sample sizes are typically small (8-16 animals per group). The evidence base does not meet criteria for Tier 4 (Phase 1 or limited human data with strong preclinical).
1Effect of Tetrapeptide Cortagen on Regeneration of Sciatic NervePMID 11276314
Turchaninova LN et al. - Bulletin of Experimental Biology and Medicine (2000) - animal study - 16 male Wistar rats (200-250g), two groups
Intramuscular injection of Cortagen (10 mcg/kg) for 10 days after sciatic nerve transection and suturing increased nerve fiber growth rate by 27% and improved conduction velocity by 40%, primarily in sensory and motor thick myelinated A-fibers. Decreased neuroma formation at suture site. Effects assessed at 5 months post-injury.
Limitations: Small sample size. Single dose tested. Single research group (Khavinson-affiliated). No blinding described. Long interval between treatment and assessment.
2Tissue-specific effects of peptidesPMID 11713572
Khavinson VKh - Bulletin of Experimental Biology and Medicine (2001) - in vitro (organotypic culture) - Organotypic tissue cultures from chick embryos / rat brain cortex
Cortexin and Cortagen induced intensive neurite outgrowth in cortex tissue cultures while inhibiting growth in subcortical structure cultures, demonstrating tissue specificity. Peptide panel showed tissue-specific growth effects matching the tissue of origin.
Limitations: In vitro only. No dose-response details or human validation in abstract. Single research group.
3Tissue-specific action of synthetic peptides in tissue culture of rats of various agesPMID 12096446
Not specified in available data - Advances in Gerontology (Uspekhi Gerontologii) (2002) - in vitro - Rat tissue cultures from animals of various ages
Studied tissue-specific action of synthetic peptides including Cortagen in tissue cultures from rats of different ages. Full findings not available from English abstract.
Limitations: Published in Russian. Limited abstract information available. Single research group.
4The delayed effect of cortagen on the restoration of injured nerve functionPMID 12134478
Kolosova LI et al. - Doklady Biological Sciences (2002) - animal study - Not available (no abstract)
Examined delayed effects of Cortagen on nerve function restoration. No abstract available to assess specific findings.
Limitations: No abstract available in PubMed. Full text not accessible. Cannot evaluate methodology or results.
5Effects of short peptides on thymocyte blast transformation and signal transduction along the sphingomyelin pathwayPMID 12420072
Khavinson VKh et al. - Bulletin of Experimental Biology and Medicine (2002) - in vitro - Mouse thymocytes
NEGATIVE RESULT for Cortagen: Cortagen produced no comitogenic effect on thymocyte proliferation, unlike Vilon (most potent) and Epithalon (less potent). Cortagen also produced less stimulatory effect on sphingomyelinase activity compared to Vilon and Epithalon.
Limitations: In vitro only. The negative result is informative -- suggests tissue specificity (brain not thymus) rather than lack of bioactivity. Single research group.
6In vitro effect of short peptides on expression of interleukin-2 gene in splenocytesPMID 12447482
Kazakova TB et al. - Bulletin of Experimental Biology and Medicine (2002) - in vitro - CBA mouse splenocytes
Cortagen activated IL-2 mRNA synthesis in splenocytes in the absence of specific inductors. Effect was concentration- and duration-dependent. However, Cortagen produced a less pronounced effect compared to Vilon and Epithalon.
Limitations: In vitro only. Comparative weakness relative to other peptides. Single research group.
7Effects of short peptides on lymphocyte chromatin in senile subjectsPMID 15085253
Khavinson VKh, Lezhava TA, Malinin VV - Bulletin of Experimental Biology and Medicine (2004) - ex vivo human cell study - Leukocytes from subjects aged 75-88 years (donor count not specified)
Cortagen (along with Vilon, Epithalon, Livagen, Prostamax) induced activation of ribosome genes, decondensation of densely packed chromatin fibrils, and release of age-repressed genes (deheterochromatinization). Unlike Epithalon and Livagen, Cortagen did not affect pericentromeric structural heterochromatin of chromosomes 1, 9, or 16.
Limitations: Ex vivo study -- human cells cultured in vitro, not in vivo human treatment. Number of donors not specified. Single research group.
8Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarrayPMID 15159690
Anisimov SV, Khavinson VKh, Anisimov VN - Neuro Endocrinology Letters (2004) - animal study (transcriptomics) - Female 6-month CBA mice, control vs Cortagen-treated groups (n not stated); 15,247 transcripts analyzed
Microarray analysis of 15,247 transcripts in mouse heart revealed 234 clones (1.53%) with significant expression changes matching 110 known genes across diverse functional categories. Maximum upregulation +5.42-fold, downregulation -2.86-fold. Comparison with Vilon, Epithalon, and melatonin showed both common and Cortagen-specific effects. Paper also states 'In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue' but the specific human study is not cited and was not found in source data.
Limitations: Animal model (mouse heart, not brain). The claim of human therapeutic effects is not substantiated by a cited study. n not stated. Single research group.
9Synthesis of IL-2 mRNA in cells of rat hypothalamic structures after injection of short peptidesPMID 16224591
Kazakova TB et al. - Bulletin of Experimental Biology and Medicine (2005) - animal study - Rats (number not specified)
In situ hybridization showed that Vilon, Epithalon, and Cortagen modulated IL-2 gene expression in vivo in rat hypothalamic cells, with effects depending on timing and route of administration.
Limitations: Brief abstract with limited detail. Sample size not specified. Single research group.
10Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptidesPMID 17426849
Gumen AV et al. - Bulletin of Experimental Biology and Medicine (2006) - in vitro/animal study - Young and old mouse peritoneal macrophages
LPS-stimulated macrophage production of lymphocyte-activating factors was lower in old animals. Short peptides including Cortagen showed opposite modulating effects on macrophage production in young vs old mice, suggesting a possible mechanism of age-related immune correction.
Limitations: In vitro with some in vivo elements. Specific quantitative data for Cortagen not detailed. Single research group.
11Effects of bioactive tetrapeptides on free-radical processesPMID 18239817
Kozina LS - Bulletin of Experimental Biology and Medicine (2007) - animal study - Rats (number and dose not specified in abstract)
Injections of Epithalon and Cortagen to rats decreased lipid peroxidation products and reduced oxidative modification of proteins, paralleled by suppression of antioxidant activity in rat serum and cerebral cortex.
Limitations: Very brief abstract. No sample size or dose specified. Antioxidant activity was 'suppressed' alongside LPO reduction -- ambiguous finding. Combined Epithalon/Cortagen design limits isolation of Cortagen-specific effects.
12Effects of epithalon and cortagene on immunity and hemostasis in neonatally hypophysectomized chicken and old birdsPMID 19432169
Kuznik BI et al. - Advances in Gerontology (Uspekhi Gerontologii) (2008) - animal study - Neonatally hypophysectomized chickens and old birds
NEGATIVE RESULT for Cortagen: 40-day injections of Epithalon completely eliminated anemia, immune deficiency, hypercoagulation, and inhibited fibrinolysis in hypophysectomized chickens. Cortagen (which differs from Epithalon only by terminal amino acid: Pro vs Gly) did not affect any of these parameters.
Limitations: Avian model (chickens). Published in Russian-language journal. Negative result for Cortagen demonstrates that single amino acid substitution drastically changes biological activity.
13Modulatory Effects of Cortexin and Cortagen on Locomotor Activity and Anxiety-Related Behavior in Mice
Adriani W, Granstrem O, Romano E, Koroleva S, Laviola G - The Open Neuropsychopharmacology Journal (2009) - animal study (behavioral pharmacology) - CD-1 mice, groups of ~8 per dose condition
Semi-independent (lead author from ISS Rome, but includes Geropharm Ltd co-author). Cortagen at 0.03 mg/kg i.p. enhanced locomotion both acutely and after sub-chronic treatment (5 days) with few effects on anxiety-related behavior. Other Cortagen doses and sub-chronic Cortexin reference produced anxiogenic-like effects in the elevated plus maze. Concluded that cortagen leads to motor stimulation with no side effects on emotional-affective profiles at optimal dose.
Limitations: Animal model (mice). Small group sizes (~8). Non-standard significance threshold (p < 0.10). Includes Geropharm Ltd co-author. Only semi-independent behavioral study available.
14Cortexin and cortagen as correcting agents in functional and metabolic disorders in the brain in chronic ischemiaPMID 21476278
Zarubina IV, Shabanov PD - Experimental and Clinical Pharmacology (2011) - animal study - Ischemic rats with high and low hypoxia resistance (n not stated)
Cortexin and Cortagen accelerated recovery of disturbed behavior in ischemic rats and prevented excessive lipid peroxidation and decreased antioxidant activity in brain tissue.
Limitations: Abstract-only Russian study. Combines Cortexin and Cortagen, so Cortagen-specific contribution not fully separable. n not stated.
15Neuroprotective action of Cortexin and Cortagen
Shabanov PD, Vislobokov AI - Reviews on Clinical Pharmacology and Drug Therapy (2013) - in vitro (electrophysiology) - Neurons from mollusk Planorbarius corneus ganglia
Cortagen at 0.1-100 mcM caused hyperpolarization of neurons (2-3 mV) and decreased spontaneous impulse activity, interpreted as activating/neuroprotective action. At 1000 mcM, slight depolarization occurred. At 10 mM, strong reversible depolarization with suppressed action potentials (considered nonspecific/toxic). Sodium current suppression was stronger than calcium current suppression at high concentrations.
Limitations: Mollusk (invertebrate) model -- limited translational relevance to mammals. Published in Russian. High concentrations showing toxicity far above proposed therapeutic range.
16Epigenetic modification under the influence of peptide bioregulators on the 'old' chromatinPMID 37042594
Lezhava T et al. - Georgian Medical News (2023) - ex vivo human cell study - Lymphocytes from individuals aged 75-88 years (donor count not specified)
Cortagen (along with Epithalon, Livagen, and Vilon) induced deheterochromatinization of total heterochromatin, activated ribosomal gene synthesis in acrocentric chromosome satellite stalks, but did not cause decondensation of pericentromeric structural heterochromatin. Each peptide bioregulator had selective effects on specific chromosome regions.
Limitations: Ex vivo study, not in vivo human treatment. Lead author (Lezhava) has co-published with Khavinson. Number of donors not specified.