In vivo and in vitro toxicokinetics including metabolism, isozyme mapping, and monoamine oxidase inhibition of three (2-aminopropyl)benzo[b]thiophene (APBT) psychedelics.
Toxicology – March 01, 2026
Source: PubMed
Summary
New psychoactive substances like 5-APBT and 6-APBT strongly inhibit MAO-A (IC50s 0.4 µM and 0.6 µM), signaling potential serious drug interactions. Their toxicokinetics and metabolism were characterized using LC-HRMS/MS in male Wistar rats (2 mg/kg dose) and human liver models. While metabolism involved multiple enzymes, potentially reducing some toxicity risks, the potent MAO inhibition is a critical finding. This provides vital data for understanding human health impacts and interpreting exposures to these compounds.
Abstract
3-(2-Aminopropyl)benzo[b]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24 h after oral administration (2 mg/kg body weight) and in incubations with pooled human liver S9 fraction (25 µM after 1 and 6 h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while N-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC50 of 5-APBT 0.4 µM, 6-APBT 0.6 µM, and 3-APBT 4 µM) but only weakly MAO-B (IC50 23-49 µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.