Therapeutic mechanisms of psychedelics and entactogens.

Psychedelics and entactogens can produce rapid and lasting therapeutic effects, but there is a disconnect between how they are used in human clinics and how they are studied in animals. Human research emphasizes extra-pharmacological factors like set, setting, and integration, which are poorly modeled in animal experiments. Animal studies focus on neuronal activation and structural plasticity, which are hard to measure in humans. The paper proposes bridging this gap by focusing on the circuits these compounds modulate rather than single molecular targets, suggesting that selective circuit modulation of behavioral phenotypes may be more fruitful for identifying novel compounds with similar therapeutic effects.

Study at a glance

Abstract

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.