Salvinorin A, the main psychoactive compound in Salvia divinorum, breaks down rapidly in rat plasma. At 37 degrees Celsius, its degradation rate constant was 3.8 x 10^(-1) per hour, much faster than at 4 degrees Celsius, where it was less than 6.0 x 10^(-3) per hour. The enzyme carboxylesterase primarily drives this breakdown, as inhibitors of that enzyme strongly suppressed degradation, while inhibitors of other esterases had little effect. The degradation products include salvinorin B (the deacetylated form) and lactone-ring-open forms of both salvinorin A and salvinorin B, with the ring-opening reactions involving a calcium-dependent lactonase.
The psychedelic compound DMT is metabolized primarily by monoamine oxidase A, but other pathways are poorly understood. This work investigated cytochrome P450 (CYP) enzymes in DMT metabolism by incubating DMT with recombinant human CYP enzymes and human liver microsomes, then analyzing metabolites with high-resolution mass spectrometry. DMT was rapidly metabolized by CYP2D6, while stable with all other tested CYP enzymes. Metabolism in human liver microsomes was reduced by harmine and SKF-525A but not quinidine, likely due to residual MAO-A activity. CYP2D6 incubations produced mono-, di-, and tri-oxygenated metabolites, probably from hydroxylation on the indole core. The findings may affect safety for ayahuasca use in slow CYP2D6 metabolizers or with CYP2D6 inhibitors.