Δ9-tetrahydrocannabinol functions as a G protein-biased dopamine D2 receptor agonist that drives sustained ERK signaling via an EGFR-coupled feed-forward loop.

Δ9-Tetrahydrocannabinol (THC), the principal psychoactive constituent of Cannabis sativa, exerts its central effects predominantly through the cannabinoid CB1 receptor (CB1R). However, molecular mechanisms underlying THC actions beyond canonical CB1R signaling have been suggested but remain incompletely defined. Systematic screening of 14 structurally diverse cannabinoid compounds identified THC as a direct agonist at the dopamine D2 receptor (D2R). THC selectively activated ERK signaling through D2-like receptors, directly bound D2R with submicromolar affinity, and functioned as a G protein-biased agonist that engages Gi/o-dependent signaling without recruiting arrestin pathways. Mechanistically, this biased signaling enabled D2R to transactivate EGFR via a cascade involving Src, PI3K, and PKC. Activated EGFR, in turn, sustained phosphorylation of Src and PKCβII, establishing a positive feed-forward loop that prolongs ERK activation. These findings demonstrate that THC directly engages D2R in parallel with the canonical CB1R-mediated disinhibition of dopaminergic neurons, providing a comprehensive molecular framework that links cannabis exposure to aberrant dopaminergic signaling. By acting as a Gi/o-biased partial agonist at D2R, THC is poised to both modulate canonical dopaminergic transmission and initiate a distinct EGFR-dependent signaling program. This dual mechanism offers a revised view of THC pharmacology and its potential contribution to neuropsychiatric effects associated with cannabis exposure.