IN VITRO INHIBITORY POTENTIAL OF CLASSIC HALLUCINOGENS LSD, 5-MEO-DMT AND MESCALINE OVER CYTOCHROME P450 ENZYMES

Background: Lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and mescaline are classic hallucinogens known for their recreational use, whose consumption increased in the last decades. Despite some available data on the metabolism of these drugs, little is known about their CYP450 metabolism [1,2,3]. Nevertheless, this information is of crucial relevance to predict drug-drug interactions and understand toxicological phenomena, in particular interindividual variability. This study intended to evaluate the potential inhibition of LSD, 5-MeO-DMT, and mescaline over CYP450 isoenzymes CYP3A4, CYP2D6, CYP2B6, CYP2A6, and CYP2E1.
Methods: The Vivid® CYP450 screening kits were used following the manufacturer’s instructions. Concentration ranges tested for each drug were 3.9x10-5–0.7 mM (n=20), 1.9x10-4–4.0 mM (n=18) and 9.8x10-5–1.6 mM (n=20) for CYP3A4; 5.7x10-8–0.6 mM (n=24), 9.5x10-7–4.0 mM (n=19) and 9.8x10-5–6.2 mM (n=23) for CYP2D6; 1.7x10-5–1.4 mM (n=32), 2.4x10-4–6.0 mM (n=32) and 9.8x10-5–6.0 mM (n=32) for CYP2B6; 1.2x10-6–2.6 mM (n=28), 2.9x10-6–6.0 mM (n=28) and 4.4x10-6–10.4 mM (n=32) for CYP2A6; and 3.9x10-5–1.3 mM (n=32), 2.4x10-4–5.0 mM (n=31) and 9.8x10-5–6.0 mM (n=31) for CYP2E1, for LSD, 5-MeO-DMT and mescaline, respectively. A solvent control and a positive control of inhibition (10 mM ketononazole for CYP3A4, 10 mM quinidine for CYP2D6, 30 mM miconazole for CYP2B6, and 100 mM tranylcypromine for CYP2A6, and 1 mM tranylcypromine for CYP2E1) were used. Fluorescence was measured for 60 minutes at excitation and emission wavelengths of 415/20 and 460/20 nm, respectively, using the Biotek® Synergy Mx monochromator-based microplate reader. The half-maximal inhibitory concentration (IC50) was calculated using GraphPad prism 9.3.0. For CYP2A6 and CYP3A4 a minimum of five independent experiments were performed, four independent experiments for CYP2B6 and CYP2E1, and three independent experiments for CYP2D6.
Results: IC50 values of 45.78 mM/ 208.21 mM/ 142.35 mM for CYP3A4; 0.35 mM/ 3.47 mM/ 863.46 mM for CYP2D6; 439.51 mM/ 898.06 mM/ 458.43 mM for CYP2B6; 90.39 mM/ 389.50 mM/ 425.84 mM for CYP2A6; and 284.05 mM/ 1040.02 mM/ 444.11 mM for CYP2E1 were obtained for LSD, 5-MeO-DMT and mescaline, respectively.
Conclusions: The results demonstrate that both LSD and 5-MeO-DMT have strong potential to be CYP2D6 inhibitors. Since this enzyme is highly polymorphic and critically involved in the metabolism of many drugs, these results hold great toxicological relevance.