N, N-dimethyltryptamine forms oxygenated metabolites via CYP2D6-an in vitro investigation

N, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT. This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high-resolution mass spectrometry for metabolite identification.DMT was rapidly metabolised by CYP2D6, while stable with all other investigated CYP enzymes. The metabolism of DMT in HLM was reduced after inclusion of harmine and SKF-525A whereas quinidine did not affect the metabolic rate, likely due to MAO-A residues present in HLM. Analysis of the CYP2D6 incubates showed formation of mono-, di- and tri-oxygenated metabolites, likely as a result of hydroxylation on the indole core. More research is needed to investigate the role of this metabolic pathway in vivo and any pharmacological activity of the proposed metabolites. Our findings may impact on safety issues following intake of ayahuasca in slow CYP2D6 metabolizers or with concomitant use of CYP2D6 inhibitors.

Automated summary

The study investigated the metabolic pathways of N, N-dimethyltryptamine (DMT) to ensure its safe and effective use. It found that CYP2D6 plays a major role in the metabolism of DMT, while other CYP enzymes do not affect its metabolism. Analysis of incubates with CYP2D6 showed the formation of various metabolites, possibly through hydroxylation on the indole core. Further research is needed to understand the in vivo role and pharmacological activity of these metabolites.