Clinical pharmacology.

To design therapeutic trials and select the most appropriate substance and dose for an indication, a detailed understanding of clinical pharmacology is crucial. In recent years, several studies have explored the human pharmacology of different psychedelics and 3,4-methylendioxymethylamphetamin (MDMA). This chapter summarizes pharmacological characteristics of the serotonergic psychedelics psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), and MDMA. We summarize their mechanisms of action, pharmacokinetics, pharmacodynamics, metabolism, and safety, with a focus on human data from modern clinical trials. Additionally, we provide recommendations for dosing, dose adjustment, and interactions with other medications. We show that the different serotonergic psychedelics produce overall comparable acute subjective and somatic effects primarily through interactions with 5-HT_2A receptors. However, the exact mechanisms of their potential therapeutic benefits in patients remain to be elucidated. Moreover, classic psychedelics differ substantially in their pharmacokinetics and metabolism, resulting mainly in different durations of action, which may influence their suitability for specific therapeutic uses and indications. In contrast, MDMA has a psychopharmacological profile that is distinct from serotonergic psychedelics, characterized by acute stimulant-like and empathogenic effects. In terms of pharmacokinetic-pharmacodynamic relationships, acute effects of the psychedelics mirror their plasma-concentration-time curves, whereas acute effects of MDMA are shorter-lasting than its presence in the body. Thus, MDMA, but not the psychedelics, exhibits marked acute pharmacological tolerance. A good understanding of the pharmacology of classic psychedelics and MDMA forms the basis for their clinical use and the design of clinical therapeutic trials.