Therapeutic mechanisms of psychedelics and entactogens

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.

Automated summary

Recent evidence suggests that psychedelics and entactogens have rapid and sustained therapeutic effects. However, there is a disconnect between their clinical use and preclinical studies, leading to a lack of understanding of the mechanisms underlying their positive impacts on mental health. Human studies focus on non-pharmacological factors, while animal studies focus on neuronal changes. Several hypotheses are proposed to bridge this gap, suggesting that the modulation of circuits, rather than single molecular targets, might explain the therapeutic effects of these compounds. Targeting specific circuits might be more effective in identifying novel compounds with similar therapeutic effects.