DMT, a psychedelic compound being developed for major depressive disorder, is rapidly cleared from the body with a mean elimination half-life of 9 to 12 minutes. In vitro experiments showed that blocking monoamine oxidase A and certain cytochrome P450 enzymes (CYP2D6 and, to a lesser extent, CYP2C19) slowed DMT's clearance. The drug has low lipophilicity and low plasma protein binding, meaning a high proportion is available for distribution and metabolism, consistent with its very fast clinical pharmacokinetics. In a phase I trial, 24 healthy adults received single escalating intravenous infusions of DMT (9–21.5 mg freebase) over 10 minutes. All doses were safe and well tolerated, and peak plasma concentrations did not relate to body weight or BMI. These results support developing novel DMT infusion regimens for treating major depressive disorder.
Cytochrome P450 (CYP) enzymes are responsible for breaking down about 80% of medications, and differences in their activity between people can affect drug exposure and treatment outcomes. Measuring CYP activity in the body (phenotyping) typically uses therapeutic or subtherapeutic drug doses that can cause side effects. This review examined whether using microdoses (100 µg) of drug substrates could safely assess CYP activity. Based on current evidence, microdosing is not recommended for phenotyping CYP1A2, CYP2C9, CYP2D6, or CYP2E1. However, it can be used for CYP2C19 and CYP3A. For CYP2C19, a single 100 µg dose of omeprazole with a 24-hour blood level measurement is suggested. For CYP3A, a 0.1–75 µg dose of midazolam, measuring its clearance or area under the curve, is recommended.