ABSTRACT - Substance Use Disorders (SUDs) and the psychiatric comorbidities that accompany them are underserved, vicious disorders that leave individuals, their loved ones and society negatively impacted. Psychoactive substances, such as those containing a tryptamine moiety (i.e. psilocin), show promise in relieving SUD tendencies yet the underlying mechanism responsible is yet to be fully elucidated. Classical approaches aimed at deducing the receptor and mechanism of action involve probing specific receptors, hypothesized to be responsible for downstream processes resulting in symptom relief, with chemical probes possessing affinity for said receptor and observing if symptoms improve. A widely acknowledged weakness with this approach is the lack of specificity a compound can exhibit for a receptor or interest, leading to off-target receptor binding thereby confounding the independent variable. The same specificity issue found in stimulatory experiments holds true in suppressive like experiments, where a blocker is used to block a receptor binding sight leading to suppression of a specific pathway. Therefore, elucidating the exact mechanism is inherently difficult and would require molecular probes which are more specific than what are found currently. In lieu of synthesizing new compounds, we propose the development of rapid analytical methodologies, leveraging tandem mass spectrometry, capable of screening biomass to discover preexisting natural products containing a tryptamine moiety. Ion-activation methods such as Higher-energy Collisional Dissociation (HCD) and Ultra-Violet Photon Dissociation (UVPD) will serve as complimentary methods for both identifying and characterizing compounds containing a tryptamine moiety. HCD gradually imparts internal energy thereby cleaving the lowest energy bonds whereas UVPD imparts internal energy rapidly resulting in more stochastic cleavages. HCD and UVPD are therefore complimentary as HCD in tandem with computational models can identify compounds with a tryptamine or indole moiety, due to the stable heterocyclic ring remaining intact under activation, and UVPD can characterize the candidate structure more extensively. The outcome of this project will result in methodologies capable of screening biomass to rapidly identify and characterize new psychoactive compounds. The new compounds discovered from this method will enable researchers to better study the mechanistic explanation responsible for psychoactive compounds efficacy leading to more effective therapies with reduced off target consequences.

PROJECT NARRATIVE – Psychoactive substances demonstrate promise in alleviating Substance Use Disorders yet the mechanism(s) remains partially uncertain. Mass spectrometry tools in conjunction with computational tools offers a promising means to discover new, accurate molecular probes. More specific molecular probes derived from nature can help decipher with receptors are responsible for therapeutic benefit in hopes of devising safer, more effective therapy.