Indolethylamine <i>N</i>-Methyltransferase Deletion Impacts Mouse Behavior without Disrupting Endogenous Psychedelic Tryptamine Production

Exogenously administered psychedelics produce both rapid and long-lasting effects on neuroplasticity and behavior, but it is currently unclear if endogenously produced psychedelics can elicit similar effects. There have been relatively few studies on the role of endogenous psychedelics in health and disease, perhaps owing to the difficulty in quantifying their levels and manipulating their production. Here, we describe highly sensitive mass spectrometry-based analytical methods for quantifying endogenous psychedelics in mice, and we disclose a genetic mouse model lacking indolethylamine <i>N</i>-methyltransferase (INMT), an enzyme believed to play a critical role in the production of endogenous psychedelics and previously characterized as a thioether <i>S</i>-methyltransferase. We found that INMT knockout (KO) does not produce any major abnormalities in reproduction or growth, but it does impact a range of mouse behaviors across several distinct domains. However, INMT KO did not result in an obvious decrease in endogenous psychedelic levels, suggesting that psychedelics might be produced by alternative biosynthetic pathways in rodents.