TABLE 2.
Summary of included in vivo studies
| Phytocannabinoid | Compound | Dose/route/time | Neuro model | Animalsa | n number | Results | Study |
|---|---|---|---|---|---|---|---|
| Cannabigerol (CBG) | Cannabigerol derivatives VCE‐003 and VCE‐003.2 | 10 mg·kg−1 of body weight intraperitoneally per day until kill | Two models of Huntington's disease | M CD1 mice (12 weeks) | n = 7 each group | QA model: VCE‐003.2 RotaRod performance, prevented neuronal loss, microglial activation and reduced astrogliosis. 3NP model: VCE‐003.2 improved motor deficits, reduced all pro‐inflammatory mediator release, and prevented neuronal loss. | Díaz‐Alonso et al. (2016) |
| Cannabigerol derivative VCE‐003.2 | 10 mg·kg−1 oral once daily for 3 days before kill | Huntington's disease | M C57/6 N mice (10 weeks) | n = 3–6 mice/condition | VCE‐003.2 promoted neurogenesis, increased GFAP‐positive cells, and reduced microglial activation. Mice performed better on the RotorRod test drug treated versus vehicle. | Aguareles et al. (2019) | |
| Cannabigerol derivative VCE‐003.2 | Oral 10 mg·kg−1, 20 mg·kg−1, 16 h after LPS for 28 days daily | LPS‐induced Parkinson's disease | C57BL/6 F mice, 7–11 months old | n = 6 mice per group | 20 mg·kg−1 partly corrected altered cylinder rearing test but poor activity in rotarod and CAA tests. VCE—003.2 attenuated TNF‐α, IL‐1β (greatest effect at 20 mg·kg−1) and recovered TH nigrostriatal neurons. | Burgaz, García, Gómez‐Cañas, Muñoz, and Fernández‐Ruiz (2019) | |
| Cannabigerol derivative VCE‐003 | Daily 5 mg·kg−1 i.p. for 21 days | Autoimmune encephalomyelitis (EAE) to model MS | F C57BL/6 mice | n = 6 animals per group | 5 mg·kg−1 of VCE‐003 decreased EAE symptoms. VCE‐003 decreased microglial/macrophage activation, reduced demyelination, maintained myelin structure, and reduced axonal damage lesions. Significant decrease in all measured inflammatory mediators. | Carrillo‐Salinas et al. (2014) | |
| VCE‐003 cannabigerol quinone derivative | 15 days 5 mg·kg−1 i.p. VCE‐003 treated 60 days after infection | Multiple sclerosis (MS) induced by TMEV | SJL/J mice | n = 12 | Clinical score (0–5) was significantly improved with VCE‐003 treatment. VCE‐003 completely recovered motor activities to normal levels. | Granja et al. (2012) | |
| VCE‐003.2 cannabigerol derivative | 10 mg·kg−1 i.p. 16 h post LPS and then daily for 21 days | Parkinson's disease model—LPS induced | M C57BL/6 mice | n = 4–6 subjects per group | VC‐003.2 prevented nigrostriatal neuronal loss and reduced microgliosis. Elevation in iNOS was decreased by VC‐003.2 versus control. | García et al. (2018) | |
| Cannabigerol | 50–200 mg·kg−1 i.p. 1 h before PTZ seizures | PTZ seizure model (85 mg·kg−1 i.p.) | M Wistar Kyoto rats | n = 72 | CBG had no effect on seizure severity, incidence, or timing and did not alter animal mortality. CBG displayed no anti‐convulsant effects. | Hill et al. (2014) | |
| Cannabigerol derivative VCE‐003 | 10 mg·kg−1 i.p. animals 60 days old up to age 18 weeks | Amyotrophic lateral sclerosis | M B6SJL‐Tg (SOD1*G93A) 1Gur/J versus WT | n = 5–6 animals per group | In SOD1 mice, VCE‐003.2 delayed disease progression and reduced a number of neuropathological signs. Weight loss was reduced, as were anomalies in clinical score. | Rodríguez‐Cueto et al. (2018) | |
| Cannabigerol (CBG) | 4 intraperitoneal injections every 24 h at a dose of 10 mg·kg−1 for 6 weeks (4 weeks after birth to 10 weeks) | Huntington's disease induced by 3NP/R6/2 variant mice | 16‐week‐old M C57BL/6 mice/4‐ to 10‐week‐old R6/2 mice | n = 6–8 animals/experiment |
CBG improved motor activities, prevented neuronal loss, increased GFAP staining, and decreased Iba‐1 staining. CBG down‐regulated Huntington associated genes and decreased inflammatory mediators. |
Valdeolivas et al. (2015) | |
| Cannabidivarin (CBDV) | Cannabidivarin (CBDV) | Pretreatment vehicle versus 400 mg·kg−1 CBDV oral for 3.5 h | Seizures induced by PTZ 95 mg·kg−1 | Wistar‐Kyoto rats (3/4 weeks old). | n = 51 | 400 mg·kg−1 CBDV significantly decreased seizure severity and increased latency to first signs of seizure. CBDV did not significantly affect gene expression changes induced by PTZ. | Amada et al. (2013) |
| Cannabidivarin (CBDV) | 50, 100, and 200 mg·kg−1 i.p. injection 1 h/30 min before induced seizures. 400 mg·kg−1 oral gavage 13.5/3.5 h before intraperitoneal PTZ | Epilepsy (mES seizures; 30 mA, 100 Hz for 200 ms, or generalized seizures 85 mg·kg−1 PTZ injected intraperitoneally | F/M adult Wistar Kyoto rats. Non‐Agouti (DBA/) mice 3–4 weeks, ICR (CD‐1) mice 5 weeks old | n = 80 (10/group). 640 Wistar rats 3–4 weeks old (n = 15/group) | 200 mg·kg−1 CBDV—90% of mice remained seizure free. In rats, CBDV significantly decreased PTZ seizure severity and rodent mortality (200 mg·kg−1) and delayed seizure onset. On co‐administration experiments, 2.9% of rats (n = 7) exhibited a fatal reaction to CBDV administration. | Hill et al. (2012) | |
| Cannabidivarin (only data from purified CBDV is reported here) |
1 h pretreatment 50, 100, and 200 mg·kg−1 i.p. (rats) 10–200 mg·kg−1 i.p. (mice) |
PTZ seizures (85 mg·kg−1) or pilocarpine (380 mg·kg−1). | M Wistar Kyoto rats, M MF1 mice, DBA/2 mice 3–4 weeks |
n = 10 mice n = 15 rats |
CBDV significantly affected observed seizure severity >50 mg·kg−1. Mortality was reduced by CBDV administration and suppressed seizure activity (100 mg·kg−1) | Hill et al. (2013) | |
| Cannabidivarin (CBDV) | 2, 20, and 100 mg·kg−1 versus vehicle control, daily intraperitoneally for 14 consecutive days | Rett syndrome | 5‐month‐old MeCP2–308 (B6.129S‐MeCP2tm1Heto/J | n = 70 |
20 mg·kg−1 CBDV improved motor learning ability. Brain weight was increased with CBDV treatment. CBDV had no effect on GPR55 levels and neurotrophin levels. |
Vigli et al. (2018) | |
| Cannabidivarin (96.4% CBDV, 3.6% CBD; started on postnatal day 28, lasting until day 67) | 0.2, 2, 20, and 200 mg·kg−1 i per day i.p. initiated postnatal day (PND) 28 until PND 67. | Rett syndrome model; (WT vs. Mecp2 KO) | Mecp2–mouse (WT vs. KO). | n ≥ 5 per treatment group total n = 112 | 2–200 mg·kg−1 per day CBDV reduced tremors, and 0.2 mg·kg−1 per day was ineffective. CBDV reduced hind limb clasping but again not at the lowest dose tested. CBDV improved breathing and gait abnormalities, reduced total symptom score, and improved neurological motor deficits. | Zamberletti et al. (2019) | |
| Cannabichromene (CBC) | CBC | 0.01 ml·g−1 and 25, 50, and 75 mg·kg−1 CBC (mice), 1.0 ml·kg−1, 10–75 mg·kg−1 CBC (rats) i.p. for 1 h prior to electroshock | Electroshock seizure test: 50 mA intensity for 0.2 s | M ICR albino mice or male Sprague–Dawley rats | n = 90 (mice), 193 mice, 106 rats | CBC/THC had no effect on tonic hindlimb extension. CBC did not alter latency. CBC (lowest dose) shortened the duration of extension. All doses of CBC depressed motor activity (first 10‐min interval). | Davis and Hatoum (1983) |
| Cannabinol (CBN) | CBN | 5 mg·kg−1·day−1 subcutaneous pouch (25‐g mouse). 28 days up to 12 weeks | Amyotrophic lateral sclerosis (ALS) SOD1 model | M Tg (SOD1‐G93A) 2Gur (11) mice. Assigned 6 weeks of age | n = 18 |
Motor abnormalities were delayed by CBN versus vehicle. No significant difference for PaGE test assessment or the age at which animals reached end stage. |
Weydt et al. (2005) |
| Tetrahydrocannabidivarin (∆9‐THCV) | ∆9‐THCV | 2 mg·kg−1 i.p. for 14 days | Parkinson's disease (by 6‐hydroxytryptamine‐6‐HT) or LPS | M Sprague–Dawley rats/CB2 knockout mice | n = 5–6 rats per group | THCV improved motor activities, reduced neuronal loss and reduced microglial activation. THCV was able to preserve TH positive neurons (LPS model). | García et al. (2011) |
| ∆9‐THCV | 0.025, 0.25, and 2.5 mg·kg−1 i.p. + vehicle prior to initiating seizures | Seizures induced by 80 mg·kg−1 PTZ | M Wistar rats | 64 rats in total; n = 16 per group | Median seizure severity, duration, progression, or latency was unaffected by any dose of THCV. 33% of animals exhibited a complete absence of seizures at a dose of 0.25 mg·kg−1 THCV. | Hill et al. (2010) | |
| Tetrahydrocanvnabidiolc acid (∆9‐THCA) | ∆9‐THCA | 20 mg·kg−1 i.p. 30 min before 3NPA, every 24 h for 4 days | Huntington's disease (3 NPA model) | M C57BL/6 mice | n = 70; 9 animals per group | THCA improved hindlimb dystonia and locomotor activity. THCA down‐regulated all pro‐inflammatory mediators. | Nadal et al. (2017) |
a
Animal sex denoted by F (female) and M (male).