A systematic review of minor phytocannabinoids with promising neuroprotective potential

Abstract

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.

In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

“…In vivo, THCV produced cataleptic (10 mg/kg), hypothermic (10 mg/kg), anti-nociceptive (3 and 10 mg/kg), hypolocomotive (3 and 10 mg/kg), and anxiolytic (3 and 10 mg/kg) effects. These effects are consistent with others' observations of anti-epileptic, hypolocomotive, neuroprotective effects in the range of 0.25-2.5 mg/kg 32,33 ; reviewed in 19 . Bolognini et al 34 demonstrated that THCV is able to reduce hyperalgesia in mice via both CB1R and CB2R, because anti-hyperalgesic effects were limited by both the CB1R antagonist SR141716A and the CB2R antagonist SR144528.…”

“…It is possible that the phytocannabinoids tested bound only a subset of amino acids in the CB1R ligand binding site(s) compared to CP55,940, as has been shown for CBD, Org27569, rimonabant, and anandamide 10,18,27,28 . ∆ 9 -THC that is commonly consumed in cannabis products is a decarboxylated derivative of the naturally present ∆ 9 -THCa 19 . In this study, ∆ 9 -THCa partially displaced [ 3 H]CP55,940 from CB1R and CB2R, with greater affinity for CB2R; and was a weak partial agonist of CB1R-dependent inhibition of cAMP accumulation and a weakly potent agonist of CB2R-dependent cAMP accumulation.…”

“…THCV has been posited to act at both CB1R and CB2R, and is considered by some to behave as a CB1R antagonist and CB2R agonist [31][32][33] ; reviewed in 19 . Here, we found that THCV was able to displace [ 3 H]CP55,940 from both CB1R and CB2R.…”

“…Comparatively, little research has been done to isolate and characterize the wide variety of naturally-occurring cannabinoids of Cannabis (i.e. phytocannabinoids) 2,19 . The work that has been done indicates that many of these ligands are active at CB1R, CB2R, and other receptors 2,19 .…”

“…The work that has been done indicates that many of these ligands are active at CB1R, CB2R, and other receptors 2,19 . Within the last three years, an influx of high-quality studies has examined the pharmacology of subsets of these phytocannabinoids for their specific activity, receptor affinity, ligand bias, and neuroprotective properties in rodent models [19][20][21][22] . Previously, our group has characterized the pharmacology of endogenous, synthetic, and plant-derived cannabinoids in vitro and in vivo 10,11,15,23,24 .…”