ABSTRACT G protein‐coupled receptors (GPCRs) are core transducers of psychoactive drug action, shaping second messenger signaling, ion channel function, and neurotransmitter release in reward‐ and stress‐related circuits. Despite decades of therapeutic targeting, GPCR‐based strategies for substance use disorders have delivered uneven clinical benefit, in part because in vivo receptor signaling is strongly shaped by receptor context, circuit state, and exposure history. This narrative review focuses on three mechanistic routes to therapeutic selectivity: (i) GPCR heteromerization, (ii) biased agonism, and (iii) allosteric modulation. We synthesize evidence across dopaminergic, opioid, cannabinoid, and group II metabotropic glutamate receptor systems, selected because they are central to mesocorticolimbic function and because they provide the strongest current case studies for these selectivity mechanisms. For receptor heteromers, we apply an evidence‐graded interpretation that distinguishes proximity‐based findings from native‐tissue signatures and from in vivo functional validation. For μ‐opioid receptor biased agonism, we critically reassess the preclinical rationale and the clinical experience with proposed “G protein‐biased” ligands, emphasizing how assay amplification, intrinsic efficacy, and endpoint choice can confound bias claims and limit safety translation. For allosteric modulation, we highlight the relapse‐relevant preclinical evidence for mGlu2/3 positive allosteric modulators and discuss predictable hurdles including probe dependence, species differences, and durability of benefit. Across these themes, the central translational message is that single‐receptor, single‐pathway models are often insufficient; progress is most likely when mechanistic claims are matched to evidence strength and when target engagement is linked to circuit‐level outcomes and clinically meaningful endpoints. Future advances will depend on integrating structure‐informed pharmacology with in vivo biomarkers, standardized relapse outcomes, and longer‐term trials, alongside careful safety evaluation and equitable access to effective treatments.
Alhosaini et al. (Sun,) studied this question.