This review (2023) highlights the promising rapid and sustained therapeutic effects of psychedelics and entactogens based on recent clinical and preclinical evidence. To better comprehend their impact on mental health, the review emphasizes the importance of bridging the gap between human and rodent studies and shifting the focus to circuit modulation rather than individual molecular targets.
Abstract of 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.”
Authors: Boris D. Heifets & David E. Olson
Summary of Therapeutic mechanisms of psychedelics and entactogens
Psychedelics are re-emerging as regulated medical therapies, delivered in controlled settings with close therapeutic monitoring, to treat disorders like post-traumatic stress disorder, depression, and substance disorder. However, their therapeutic mechanisms remain opaque, and they have not been optimized to maximize efficacy and scalability while minimizing adverse side effects.
Early, highly promising clinical results have already inspired major industrial efforts to identify psychedelic derivatives optimized for pharmacokinetics, toxicity, and more manageable subjective effects. However, many aspects of human therapeutic trials are not well captured in animal models. While there is controversy surrounding the use of rodent models to predict human disease, we can use a framework for animal experimentation to help us arrive at an answer.
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Therapeutic mechanisms of psychedelics and entactogens
https://doi.org/10.1038/s41386-023-01666-5
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Cite this paper (APA)
Heifets, B. D., & Olson, D. E. (2023). Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology. https://doi.org/10.1038/s41386-023-01666-5