The toxicity of psychedelic LSD derivatives: 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), 1-valeryl-LSD (1V-LSD) and 1-cyclopropylmethanoyl-LSD (1cP-LSD)-prediction of toxicological parameters relevant to clinical and forensic toxicology using multi-in silico approach.

Lysergamide analogs such as ALD-52, 1P-LSD, 1B-LSD, 1 V-LSD, and 1cP-LSD have emerged as new psychoactive substances (NPS) with hallucinogenic potential, yet their toxicological profiles remain largely unexplored. In this study, a comprehensive in silico assessment was conducted using multiple platforms (e.g., ADMETlab 3.0, Percepta, STopTox, ProTox 3.0, VEGA, TEST 5.1.2) to predict critical toxicological parameters relevant to clinical and forensic toxicology. Acute toxicity was predicted for all compounds, with LD50 values in rats ranging from 49 to 85 mg/kg (Percepta) and oral/inhalation exposure identified as the most concerning routes. Organ-specific toxicity highlighted elevated pulmonary risk for 1 V-LSD (92%) and 1cP-LSD (81%), and highest predicted hematotoxicity for 1P-LSD (76%) and 1B-LSD (75%). Genotoxicity alerts were consistently identified for ALD-52 and 1cP-LSD (up to 90% predicted probability, Percepta), while OCHEM classified all compounds as non-mutagenic. Cardiotoxicity assessment revealed the strongest hERG channel inhibition for 1 V-LSD (IC50 = 1.4 µM, Percepta), suggesting elevated proarrhythmic potential. Dermal and ocular irritation risks were uniformly low across platforms. The results support that structural modifications at the N-1-acyl position influence toxicity patterns, particularly affecting cardiopulmonary and genotoxic endpoints. These findings underscore the utility of in silico methods for early risk assessment and prioritization of lysergamide-based NPS for further toxicological evaluation.