In-silico toxicity study of tryptamine, psilocin, psilocybin, N,N-dimethyltryptamine, 5'-methoxy-N,N-dimethyltryptamine and O-acetylpsilocin.

Serotonergic tryptamines, including psilocin, psilocybin, DMT, and 5-MeO-DMT, are increasingly used medically and recreationally, but experimental toxicity data are scarce. A comprehensive computational assessment using nine validated QSAR models evaluated six tryptamines for acute toxicity, organ effects, cardiotoxicity, genotoxicity, irritation, and estrogenic activity. All compounds were classified as high toxicological concern (Cramer Class III). Predicted oral LD50 values ranged from 100 to 500 mg/kg, indicating moderate to high acute toxicity. Cardiovascular and gastrointestinal systems were primary targets (≥90% predicted effect). DMT and 5-MeO-DMT showed the highest predicted hERG inhibition (IC50 20–45 µM), suggesting cardiotoxic potential, while psilocybin showed lower risk (IC50 ≈760 µM). Most tryptamines were predicted non-mutagenic and non-endocrine active.

Study at a glance

Abstract

Understanding the toxicity of serotonergic tryptamines is becoming increasingly important from both clinical and forensic perspectives, yet experimental data for these compounds remain extremely limited. Despite their growing medical relevance and widespread non-medical use, there is still no systematic evaluation of their toxicological risks. This study presents the first comprehensive in silico assessment of key toxicological endpoints for six tryptamines of clinical and forensic interest: tryptamine, psilocin, psilocybin (4-PO-DMT),N, N-dimethyltryptamine (DMT), 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT),and O-acetylpsilocin (4-AcO-DMT). A multi-model computational approach was applied using STopTox, admetSAR 3.0, ADMETlab 3.0, ACD/Labs Percepta, Toxtree, ProTox 3.0, OCHEM, TEST, and VEGA QSAR, following OECD principles for QSAR model validation. The study covered acute systemic toxicity (LD50), organ-specific effects, cardiotoxicity (hERG inhibition), genotoxicity (Ames test), irritation potential, and estrogenic activity (ER-α binding). All compounds were classified as Cramer Class III (high toxicological concern). Predicted oral LD50 values were in the 100-500 mg/kg range, indicating moderate to high acute toxicity. Cardiovascular and gastrointestinal systems were consistently identified as primary targets (predicted effect ≥ 90%). DMT and 5-MeO-DMT showed the highest predicted hERG inhibition (20 < IC50 < 45 µM), suggesting possible cardiotoxic potential, while psilocybin demonstrated lower risk (IC50 ≈ 760 µM). Most tryptamines were predicted to be non-mutagenic and non-endocrine active (LogRBA < - 3).