Psychedelic compounds from natural sources have been consumed for centuries. Modern scientists now use computational tools, cellular assays, and behavioral metrics to study how these compounds cause changes across molecular, cellular, circuit, and system levels. This paper reviews the history of psychedelics in science, medicine, and culture, outlines current pharmacological research techniques, and identifies gaps in knowledge about the physiological changes induced by psychedelics, the limits of their therapeutic potential, and how to improve treatments becoming accessible worldwide.
Activation of mGluR2, the primary presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological effects of psychedelics. The mechanisms behind this are debated, with two competing hypotheses: direct actions via mGluR2/5-HT2A heterodimers, or presynaptic inhibition of glutamate release. In mice expressing tagged receptors, mGluR2 agonist pretreatment reduced the head twitch response induced by the psychedelic DOI. Multiple orthogonal in vivo and in vitro approaches found no evidence for receptor colocalization or oligomerization under basal or agonist-exposed conditions, nor for mGluR2-mediated modulation of 5-HT2A ligand binding. The findings support models where mGluR2 signaling modulates 5-HT2A receptor activity in layer V pyramidal neurons rather than requiring mGluR2/5-HT2A multimers.