Microdosing uses very low, radionuclide-labeled drug doses for early human imaging or pharmacokinetic studies, requiring only a reduced preclinical toxicology package to lower cost and speed development. The approach limits exposure and risk by testing small populations for short periods. However, extrapolating results to therapeutic doses demands special attention to low-dose behavior, especially for small organic molecules versus protein therapeutics. The article reviews these aspects and discusses microdosing's role in drug development according to three pillars: tissue distribution and target access, target engagement, and induction of relevant tissue responses.
MDMA triggers neuronal activation in limbic projection areas involved in emotional processing, shown by localized increases in glucose metabolism measured with 18F-FDG fPET. Simultaneously, it causes global cerebral and extracerebral hemodynamic decreases detected by BOLD fMRI. The hemodynamic reductions strongly correlate with serotonin transporter occupancy and are of a nonneuronal, peripheral origin. Increased serotonin from SERT blockage leads to neurovascular uncoupling via direct vascular effects. These findings challenge interpretations of previous fMRI studies that suggested MDMA mainly inhibits brain activity, and recommend 18F-FDG fPET as a more robust measure for pharmacological research on psychedelics.