Potent and Irreversible? Evaluating the In Vitro Monoamine Oxidase Inhibition Potential of Eight Psychedelics of the Cyclopropylamine Type

Background/Objectives: 2,5-Dimethoxy-4-methylphenylcyclopropylamine (25D-CPA or DMCPA) is a psychedelic which is closely related to the non-selective and irreversible monoamine oxidase (MAO) inhibitor tranylcypromine. MAO inhibition (MAOI) might be associated with monoaminergic toxicity due to elevated neurotransmitter levels. This study aimed to assess the risk of intoxication due to MAOI for eight cyclopropylamines (CPA) including 25D-CPA. Methods: A previously validated in vitro inhibition assay using recombinant human MAO isoforms A or B and substrate kynuramine followed by hydrophilic interaction liquid chromatography–high-resolution tandem mass spectrometry analysis was applied. Following statistically significant MAOI during prescreening (10 µM inhibitor concentration), IC50 values were determined by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration (10 concentrations levels, each). Tranylcypromine was used as positive control and for comparison. Additionally, the effect of a preincubation (inhibitor + MAO, 30 min) before kynuramine addition was assessed. Results: All CPAs and tranylcypromine significantly inhibited both MAO isoforms. MAO-A activity decrease ranged from 46% (25D-CPA) to 98% (2,4,6-trimethoxyphenylcyclopropylamine), and MAO-B activity decreased from 37% (25D-CPA and 4-bromo-2,5-dimethoxyphenylcyclopropylamine) to 97% (2,4,6-trimethoxyphenylcyclopropylamine). Tranylcypromine decreased MAO activities by 87% (MAO-A) and 98% (MAO-B). The lowest MAO-A and MAO-B IC50 values were determined for 2,4,6-trimethoxyphenylcyclopropylamine (0.16 µM and 0.26 µM, respectively), 4-fluoro-2,6-dimethoxyphenylcyclopropylamine (0.69 µM and 1.2 µM, respectively), and tranylcypromine (0.78 µM and 0.15 µM, respectively). Preincubation fortified MAOI, indicating potentially irreversible inhibition. Conclusions: The dual MAOI of all CPA might suggest a risk of clinical effects including hypertensive crisis and serotonin syndrome. Despite these considerations, the present findings are based exclusively on in vitro experiments, and further studies are needed for final evaluation.