Characterization of Novel Tryptamines’ Anxiolytic and Anti-Inflammatory Effects in Relation to their Psychoactive Effects

Abstract

<b>Abstract ID 19236</b> <b>Poster Board 142</b> Psychedelics are a class of drugs characterized by their psychoactive properties through primary action of the serotonin system, specifically the serotonin 2A receptor (5-HT2aR). Recent clinical research has shown efficacy for treatment-resistant depression, end-of-life anxiety, and substance use disorders. There are two main classes of psychedelics, phenethylamines and tryptamines, that have slightly different affinities for the various 5-HT receptors, and therefore display slightly different effects. The purpose of the current research is to distinguish the anti-inflammatory, anxiolytic, and psychoactive effects of an established phenethylamine, DOI, and three novel tryptamines, compound 1, 2, and 3, that are structural analogs of psilocybin. To evaluate the anti-inflammatory effects of these compounds, RAW macrophages were exposed to lipopolysaccharide (LPS) and treated with a range of concentrations of each psychedelic. After 24 hours the supernatant was evaluated for NOx levels (Griess assay) and TNF-a (Elisa). To investigate the potential role of the 5-HT2aR in the anti-inflammatory response, the same assays were run using the 5-HT2aR antagonist, M100907. Differences in psychoactive effects were established by the Head Twitch Response (HTR). Differences in anxiolytic properties were established using the elevated zero maze (EZM) with acute and chronic administration of psychedelics, evaluating the role of downregulation of the 5-HT2aR on anxiety. The results suggest that DOI produces the most robust anti-inflammatory response in both NOx and TNF-a assays of all four compounds, while compound 2 showed the most robust anti-inflammatory response out of the three novel tryptamines. In vivo DOI displayed the most robust HTR while also demonstrating robust anxiolytic effects. Of the three tryptamines, compound 1 &amp; 3 had the most robust HTR and anxiolytic response while compound 2 had the inverse. These results suggest that the magnitude of the anxiolytic response relies on the magnitude of the psychoactive effects, but further studies are needed to determine this.