Although the focus of recent interest in psychedelics has been on the treatment of neuropsychiatric disorders including depression and addiction, there is a great potential for the use of psychedelics to treat disorders of the periphery at sub-behavioral levels. We have discovered that certain psychedelics have potent and profound anti-inflammatory properties in cell-based in vitro systems as well as in animal models of human disease, such as asthma, ocular, and cardiovascular disease. The potency of some psychedelics to treat symptoms in rodent models of asthma is on the order of 0.005 mg/kg, which is 30-50 fold less than their threshold behavioral potency. Remarkably, the anti-inflammatory effects of psychedelics do not correlate with either canonical signaling or behavioral potencies, indicating that the relevant signaling pathways remain to be discovered. The precise mechanisms underlying anti-inflammatory effects are unknown. To elucidate these mechanisms, to better understand why certain psychedelics are better than others as an anti-inflammatory, and to develop new anti-inflammatory psychedelics, we have been examining the functional selectivity of a library of psychedelics from the three major structural classes at the 5-HT2A receptor. SAR analysis of data with respect to cellular signaling, anti-inflammatory, and behavioral effects will be presented. Together, these data are informing on mechanistic components of psychedelic drug action and discovery processes.

Functional selectivity of psychedelic drugs at the 5-HT2A receptor and their development as anti-inflamamory medications

ACS Spring 2022

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