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

Huang L.; Peng L.; Tian X.; Wang M.; Kim K. · Biochemical pharmacology · 2026

**Background & Methods** This is a review article examining the molecular mechanisms of THC pharmacology beyond canonical cannabinoid receptor signaling. The study involved systematic screening of 14 structurally diverse cannabinoid compounds to identify off-target receptor interactions and characterize their downstream signaling pathways. **Key Findings** • THC functions as a direct agonist at the dopamine D2 receptor (D2R) with submicromolar binding affinity, acting as a G protein-biased agonist that selectively activates Gi/o-dependent signaling while avoiding arrestin recruitment, demonstrating a distinct pharmacological profile from traditional D2R antagonists. • THC-mediated D2R activation initiates a transactivation cascade involving Src, PI3K, and PKC that culminates in EGFR activation, establishing a positive feed-forward loop wherein activated EGFR sustains phosphorylation of Src and PKCβII, thereby prolonging ERK signaling and creating sustained downstream effects. • These findings reveal that THC engages dopaminergic circuitry through dual parallel mechanisms: direct D2R agonism in addition to canonical CB1R-mediated disinhibition of dopaminergic neurons, providing a more comprehensive molecular framework for understanding cannabis-associated neuropsychiatric effects. **Dosage & Administration** Not reported. This review does not present experimental dose-response data or specify THC concentrations used in screening studies. **Safety & Adverse Effects** Not reported. The abstract does not discuss adverse effects or safety outcomes. The mechanistic findings suggest potential relevance to neuropsychiatric effects associated with cannabis exposure, but specific safety data are not presented. **Evidence Quality** This is a review article summarizing mechanistic research findings rather than a primary experimental study or clinical trial. The evidence represents preclinical/biochemical findings in controlled laboratory conditions. Key limitations include: lack of in vivo validation data presented in the abstract, absence of human subject data, uncertainty regarding physiological relevance of submicromolar binding affinities to actual cannabis exposure levels, and reliance on systematic screening rather than comprehensive pharmacological characterization. The biased signaling mechanisms described represent novel findings but require independent replication. As a 2026 review, it represents contemporary knowledge synthesis but does not constitute the highest level of clinical evidence for therapeutic or adverse outcome predictions in humans.

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