First toxicity profile prediction for mesembrine - archetypal psychoactive Sceletium alkaloid: prediction of key toxicological endpoints important to clinical and forensic toxicology using a multi-faceted in silico approach.

This study aims to perform a comprehensive in silico toxicological assessment of mesembrine using multiple computational tools to evaluate its safety profile, with relevance for both clinical and forensic toxicology. A canonical SMILES representation of mesembrine was analyzed using a suite of qualitative and quantitative prediction platforms: ADMETlab 3.0, admetSAR 3.0, Deep-PK, ProTox 3.0, STopTox, TEST 5.1.2, ACD/Percepta, and VEGA QSAR 1.2.3. These tools were used to predict acute toxicity (LD₅₀), organ-specific toxicity, genotoxicity, cardiotoxicity (hERG inhibition), and skin/eye irritation. Mesembrine was predicted to have moderate acute toxicity, with estimated oral LD₅₀ values in rats ranging between 340 and 370 mg/kg, corresponding to GHS Category 4. Organ-specific toxicity models indicated a high probability of adverse effects on the respiratory and renal systems, with conflicting predictions for hepatotoxicity. A low-to-moderate probability of hERG channel inhibition suggests potential cardiotoxicity at elevated concentrations. Genotoxicity (Ames test) predictions consistently placed mesembrine in the non-mutagenic category. However, predictions for dermal and ocular irritation were inconclusive, with results varying between platforms. This study presents the first integrative in silico toxicological profile of mesembrine. While it supports a moderate toxicity classification, the results highlight specific concerns regarding respiratory, renal, and potential cardiac toxicity. Given the compound's psychoactive properties and growing commercial availability, further in vitro and in vivo studies are essential for comprehensive risk assessment and regulatory guidance, particularly in forensic toxicology contexts.