Therapeutic mechanisms of psychedelics and entactogens

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.

Fig. 1. Potential circuits mediating the effects of psychedelics and entactogens.

a Several circuits involved in the pathophysiology of various neuropsychiatric disorders have been identified via opto- and/or chemogenetic studies. Given that psychedelics increase structural plasticity in the PFC, these circuits might underlie their therapeutic properties. However, specific experiments testing those hypotheses are lacking. While the PFC and AMY have been implicated in the prosocial effects of LSD and MDMA, respectively, those specific circuits have yet to be elucidated. b Potential circuits mediating both the therapeutic and addictive effects of entactogens are shown. Serotonin efflux from DRN projections play a key role in many of MDMA’s beneficial effects. PFC  prefrontal cortex, dPAG  dorsal periaqueductal gray, DRN  dorsal raphe nucleus, NAc  nucleus accumbens, AMY  amygdala, VTA  ventral tegmental area, DS  dorsal striatum.

Fig. 2. Candidate processes mediating therapeutic outcomes.

Most clinical trials testing psychedelics and entactogens employ a common structure of preparation, drug administration and integration. These phases of care may all contribute to clinical outcomes, but there are few clinical studies where these factors are clearly dissociated. Preclinical (non-human animal) studies model various aspects of this overarching therapeutic structure. Preparation includes psychological states prior to dosing that are influenced by expectancy, intent, and underlying psychiatric disease. Drug Administration includes the acute behavioral and subjective effects induced by the drug, which may be influenced by the setting in which they are administered. Integration includes behavioral changes that may be leveraged for further therapeutic benefit. These cognitive, emotional, and behavioral processes have been evaluated for entactogens (blue), classical psychedelics (green), or both (purple).