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<p>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<i> in silico</i> assessment of key toxicological endpoints for six tryptamines of clinical and forensic interest: tryptamine, psilocin, psilocybin (4-PO-DMT),</p><p>N, N-dimethyltryptamine (DMT), 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT),</p><p>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 (LD<sub>50</sub>), 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 LD<sub>50</sub> values were in the 100–500&#xa0;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 &lt; IC<sub>50</sub> &lt; 45 µM), suggesting possible cardiotoxic potential, while psilocybin demonstrated lower risk (IC<sub>50</sub> ≈ 760 µM). Most tryptamines were predicted to be non-mutagenic and non-endocrine active (LogRBA &lt; − 3).</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月31日

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  • Kamil Jurowski,
  • Damian Kobylarz,
  • Maciej Noga

摘要

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).