Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome.
Antonio Inserra, Giada Giorgini, Sebastien Lacroix, Antonella Bertazzo, Jocelyn Choo, Athanasios Markopolous, Emily Grant, Armita Abolghasemi, Danilo De Gregorio, Nicolas Flamand, Geraint Rogers, Stefano Comai, Cristoforo Silvestri, Gabriella Gobbi, Vincenzo Di Marzo
British journal of pharmacology March 1, 2023 DOI: 10.1111/bph.15977
Summary
Regular doses of LSD not only enhance social behavior in mice but also trigger fascinating changes in brain chemistry and gut bacteria. The psychedelic reduced specific brain compounds in the hippocampus while altering the gut microbiome's composition. These changes may explain how LSD promotes sociability and positive mood through the endocannabinoid system and kynurenine pathways.
Abstract
Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing. LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D2 (PGD2 ) and F2α (PGF2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9. The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome.