OPEN Foundation

M. Sebastian

Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis

Abstract

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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Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models

Abstract

Only recently has the full therapeutic value of serotonin [5-hydroxytryptophan (5-HT)] receptor activation begun to be explored. Currently there are two 5-HT2A receptor agonists in human clinical trials for the treatment of depression and obesity. An exciting new therapeutic avenue in which 5-HT2A agonists might be employed is the modulation of inflammation in allergic airways disease. Our lab has previously used an ovalbumin (OVA)-induced asthma model to demonstrate that administration of (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] prior to allergen challenge prevents many of the symptoms of allergic asthma. Here we have utilized a modified protocol to test the effectiveness of (R)-DOI in treating persistent allergic asthma. We demonstrate that administration of (R)-DOI in a chronic model attenuates the elevated airway hyperresponsiveness (AHR) typically observed in an asthmatic response. We also have probed for the expression of inflammatory markers in the lung and BALF. We concurrently are testing for the impact psilocybin and other tryptamines have on AHR in rodents using our OVA model. Overall our strategy is to develop 5-HT2A receptor agonism as a viable treatment modality against asthma and other inflammatory disorders.
Flanagan, T. W., Sebastian, M. N., & Nichols, C. D. (2017). Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models. The FASEB Journal31(1 Supplement), 820-4.
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