Understanding ayahuasca effects in major depressive disorder treatment through in vitro metabolomics and bioinformatics.

Metabolomic studies of major depressive disorder have focused on energy, oxidative stress, and neurotransmission pathways. Hub metabolites—key nodes in biochemical networks—integrate metabolism and signaling. This work used an in vitro primary astrocyte model with untargeted metabolomics of secretome and intracellular content after ayahuasca treatments based on DMT concentration. Mass spectrometry data identified significant hub metabolites predicting pathway alterations. Ayahuasca treatment was associated with branched-chain amino acid, vitamin B6, and vitamin B3 metabolism as housekeeping pathways. At the lowest DMT concentration (1 µmol L-1), dopamine synthesis was overrepresented in network results. Building reaction networks with metabolites like nicotinamide, L-DOPA, and L-leucine can guide dose decisions and pathway selection in future studies.

Study at a glance

Abstract

Emerging insights from metabolomic-based studies of major depression disorder (MDD) are mainly related to biochemical processes such as energy or oxidative stress, in addition to neurotransmission linked to specific metabolite intermediates. Hub metabolites represent nodes in the biochemical network playing a critical role in integrating the information flow in cells between metabolism and signaling pathways. Limited technical-scientific studies have been conducted to understand the effects of ayahuasca (Aya) administration in the metabolism considering MDD molecular context. Therefore, this work aims to investigate an in vitro primary astrocyte model by untargeted metabolomics of two cellular subfractions: secretome and intracellular content after pre-defined Aya treatments, based on DMT concentration. Mass spectrometry (MS)-based metabolomics data revealed significant hub metabolites, which were used to predict biochemical pathway alterations. Branched-chain amino acid (BCAA) metabolism, and vitamin B6 and B3 metabolism were associated to Aya treatment, as "housekeeping" pathways. Dopamine synthesis was overrepresented in the network results when considering the lowest tested DMT concentration (1 µmol L-1). Building reaction networks containing significant and differential metabolites, such as nicotinamide, L-DOPA, and L-leucine, is a useful approach to guide on dose decision and pathway selection in further analytical and molecular studies.