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Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis

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Background and Objective We previously discovered that serotonin 5-HT2A receptor activation with psychedelics has potent anti-inflammatory activity in both cell culture and whole animals, which indicated potent anti-inflammatory effects in vascular tissues among others. More recently we found that the psychedelic (R)-DOI potently prevents the development of allergic asthma in a mouse model. The effects of (R)-DOI were found to not result from a generalized anti-inflammatory process, but due to specific inflammatory pathways inhibition in both innate and Th2 cells. In this work, we have examined the therapeutic effects of the psychedelic (R)-DOI in the ApoE −/− high-fat model of atherosclerosis.

Methods Osmotic minipumps were used to deliver very low doses of (R)-DOI to male ApoE −/− mice that were divided into four treatment groups [Saline, normal chow; (R)-DOI, normal chow; Saline, hi-fat diet; (R)-DOI, hi-fat diet]. After 16 weeks, mice were euthanized and tissues collected for analysis

Results Calculated steady state levels of ~0.0013 mg/kg (R)-DOI resulted in a significant reduction of mRNA expression for inflammatory markers like Il6 in vascular tissue, reduced levels of glucose, and a reduction in circulating cholesterol in the high fat fed animals. Additional ongoing studies are examining arterial plaque size and heart pathology.

Summary Extremely low levels of the psychedelic (R)-DOI were sufficient to significantly block the development of vascular inflammation, normalize glucose homeostasis, and prevent the increase in cholesterol associated with a hi-fat ‘western’ high diet. Activation of serotonin 5-HT2A receptor therefore represents a powerful new strategy to treat inflammatory-related vascular disease.

Nichols, C. D., Sebastian, M., & Flanagan, T. (2017). Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis. The FASEB Journal31(1 Supplement), 825-3.
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