Phase 0 clinical trials, including microdosing, limit drug exposure in first-in-human studies to reduce risks, costs, and time in drug development. These exploratory trials, governed by ICH M3 guidelines, involve subtherapeutic doses—for small molecules, no greater than 100 μg or 1/100th of the NOAEL—and require sensitive analytical tools like LC-MS/MS. Evidence supports extrapolating pharmacokinetic and pharmacodynamic data from microdose to therapeutic doses, though validity depends on drug properties and modeling. Applications include studying metabolism, receptor binding, and local drug effects. Ethical advantages include reduced human and animal exposure. The term 'in humano' is proposed for such limited human testing. An increasing number of applications demonstrate the versatility of these approaches.
The psychedelic compound DMT is cleared from the body at a very high rate—26 L/min—indicating its elimination is independent of blood flow. Plasma concentrations follow a two-compartment model, with DMT metabolized to indole 3-acetic acid. The intensity of the psychedelic experience is linked to DMT concentration at an effect site, with half-maximal effect at 95 nM. Simulated median intensity ratings after doses of 1, 4, 7, 14, and 20 mg were zero, 2, 4, 8, and 9 on a 0–10 scale. The model can help predict suitable doses for clinical studies based on desired subjective experience intensity.