PHARMACEUTICALS · Published 2026-08-04 · DOI 10.3390/ph19081226
<b>Background</b>: Minor phytocannabinoids engage CB<sub>1</sub> and CB<sub>2</sub> receptors, as well as broader receptors and ion-channel targets. However, fragmented evidence limits translation into central nervous system (CNS) therapeutics. This review introduces pharmacological switching, defined as a dose-, state-, or model-dependent shift in the dominant determinant of a compound’s net effect that reverses the direction, rather than merely the magnitude, of that effect on a defined functional endpoint, as a framework for compound–indication matching. Unlike biased agonism, which redistributes downstream coupling without reversing direction, switching requires directional reversal between or within receptor systems. <b>Methods</b>: This narrative review integrates receptor pharmacology, preclinical CNS disease-model data, early-phase clinical evidence, and pharmacokinetics identified through a structured literature search. <b>Results</b>: Three mechanistic axes recurred: PPARγ/CB<sub>2</sub>/Nrf2-linked neuroinflammatory modulation; TRP/GABA<sub>A</sub>/5-HT<sub>1</sub>A-linked control of neuronal excitability; and low-efficacy CB<sub>1</sub> antagonism with 5-HT<sub>1</sub>A potentiation. Their expression was context-dependent: tetrahydrocannabivarin is reported to shift from CB<sub>1</sub> antagonism toward partial agonism as receptor occupancy rises, cannabidiolic acid shows stress-conditional anxiolytic and antiemetic activity, and cannabigerolic acid displays seizure-model-dependent bidirectionality. No instance yet meets all five defining criteria; each is graded provisional or proposed pending systematic testing. Human evidence remains limited: inconclusive cannabidivarin efficacy in epilepsy and neuropathic pain, proof-of-mechanism neuroimaging in autism, and early tetrahydrocannabivarin safety data. <b>Conclusions</b>: Minor phytocannabinoids are pharmacologically diverse but clinically underdeveloped. A tiered, biomarker-guided framework is proposed to match compound–indication pairs to the doses, formulations, and subgroups most likely to express their therapeutic pharmacology.
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Bagher, A. (2026). Pharmacological Switching in Minor Phytocannabinoids: A Mechanistic Framework for Compound–Indication Matching and Precision Neurotherapeutic Development. PHARMACEUTICALS. https://doi.org/10.3390/ph19081226