A systematic review of minor phytocannabinoids with promising neuroprotective potential

Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ⁹ -tetrahydrocannabinol, including Δ⁹ -tetrahydrocannabinolic acid, Δ⁹ -tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg^-1 ) and cannabidivarin (range 0.2 to 400 mg·kg^-1 ) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10-75 mg·kg^-1 ), Δ⁹ -tetrahydrocannabinolic acid (20 mg·kg^-1 ), and tetrahydrocannabivarin (range 0.025-2.5 mg·kg^-1 ) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003 and VCE.003.2, and Δ⁹ -tetrahydrocannabinolic acid mediated some of their effects through PPAR-γ, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.