Qualitative and quantitative in silico toxicity profiling of "angel dust": phencyclidine (PCP) analogues as new psychoactive substances (3-HO-PCP, 3-MeO-PCP, 4-MeO-PCP, 3-HO-PCE, 3-MeO-PCE, 4-MeO-PCE).

Phencyclidine (PCP) and its analogues (3-HO-PCP, 3-MeO-PCP, 4-MeO-PCP, 3-HO-PCE, 3-MeO-PCE, 4-MeO-PCE) are dissociative new psychoactive substances with high abuse potential and limited safety data. An integrated in silico workflow using multiple computational tools predicted moderate acute toxicity for all analogues, with rat oral LD50 values consistently in the 200-630 mg/kg range across platforms, and substantially lower intravenous LD50 values in mice (25-59 mg/kg). Organ-specific predictions highlighted the lungs, liver, and blood as prominent targets, and cardiotoxicity signals included potential hERG inhibition and QT-prolongation risk. Genotoxicity predictions were consistently negative, while eye and skin irritation potential was notable for phenolic analogues. Endocrine screening suggested at most weak-to-moderate estrogen receptor alpha interactions.

Study at a glance

Abstract

Phencyclidine (PCP), historically known as "angel dust," and its analogues (3-HO-PCP, 3-MeO-PCP, 4-MeO-PCP, 3-HO-PCE, 3-MeO-PCE, 4-MeO-PCE) are dissociative new psychoactive substances with high abuse potential and limited experimental safety data. An integrated in silico workflow (STopTox, admetSAR 3.0, ADMETlab 3.0, ACD/Labs Percepta, Toxtree, ProTox 3.0, OCHEM, TEST, VEGA QSAR) was applied to profile acute toxicity and key hazard domains. Across platforms, rat oral LD50 values for PCP-type analogues were consistently in the ~ 200-630 mg/kg range (Percepta 210-800 mg/kg, TEST 197-628 mg/kg, VEGA 278-368 mg/kg, ProTox ~ 348-404 mg/kg), indicating moderate acute toxicity by the oral route; substantially lower LD50 values were predicted for intravenous exposure in mice (~ 25-59 mg/kg). Qualitative models (STopTox, ADMETlab, admetSAR) classified all compounds as acutely toxic by the oral route (e.g., STopTox oral toxicity confidence ~ 77-92%) and commonly predicted inhalation/dermal risks depending on the analogue; admetSAR assigned EPA Category III for acute oral toxicity. Organ-specific effects (Percepta; ADMETlab) highlighted the lungs, liver, and blood as prominent targets (e.g., lungs 0.89-0.93, liver up to 0.91, blood up to 0.85), with gastrointestinal involvement (up to 0.82) and generally lower kidney probabilities (~ 0.09-0.70). Cardiotoxicity signals included predicted hERG inhibition with Percepta IC50 ~ 4.9-12.3 µM and high probabilities of hERG blockade in ADMETlab/admetSAR, supporting potential QT-prolongation risk. Genotoxicity predictions were consistently negative across Percepta, OCHEM, ADMETlab, admetSAR, and VEGA. Eye/skin irritation potential was notable for phenolic analogues, with Percepta indicating high probabilities for 3-HO-PCP and 3-HO-PCE (eye ~ 88-90%, skin ~ 96%), while other tools showed model-dependent variability. Endocrine screening suggested at most weak-to-moderate ER-α interactions, with the highest probability for 3-HO-PCP (LogRBA > - 3). Overall, convergent multi-tool evidence indicates moderate acute toxicity, cardiotoxicity signals, and multi-organ risk for PCP analogues, while mutagenicity appears unlikely. These results provide mechanistic and quantitative context to inform clinical management, forensic interpretation, and risk assessment of this NPS class.