TABLE 1.
Summary of included in vitro studies
| Phytocannabinoid | Compound | Concentration/Incubation period | Neuro model | Cells used | n number | Results | Study |
|---|---|---|---|---|---|---|---|
| Cannabigerol (CBG) | Cannabigerol derivative VCE‐003.2 | 500 nM for 21 days | Huntington's disease | Mouse embryonic stem cells (R1 line)/P19 neurospheres | n = 3 | VCE‐003.2 increased CTIP‐2 positive cells, promoted neuronal like‐differentiation and significantly larger P19 neurospheres versus vehicle treated cells (P < 0.01) | Aguareles et al. (2019) |
| Cannabigerol derivative VCE‐003 | 1, 5, 10 μM (human T‐cells). 1 and 2.5 μM (RAW 264.7 cells) for 3 days post stimulation | Autoimmune Encephalomyelitis to model multiple sclerosis (MS) | Jurkat, BV2 RAW 264.7 cells. Human peripheral T‐cells | n = 3 a | 1 μM reduced expression of iNOS in BV2 microglial cells. Antagonists AM630 (CB2) and GW9662 (PPARγ) blocked these effects. Prevented T cell division at 1 and 5 μM and inhibition of the release of all soluble mediators (T‐cells) | Carrillo‐Salinas et al. (2014) | |
| Cannabigerol derivatives: VCE‐003 and VCE‐003.2 |
1–50 μM (N2a) for 24 h 50 nM–50 μM (HiB5) 30, 10, and 3 μM for 6 h |
Huntington's disease | (N2a cells/HiB5 cells) Immortalized striatal neuroblasts expressing huntingtin/mutant repeats | n = 3 a | VCE‐003.2 improved cell viability (10 and 25 μM) and prevented excitotoxicity in N2a cells. VCE‐003.2. Reduced the number of cells with aggregates (neuroblasts) and improved neuronal viability post serum deprivation | Diaz‐Alonso et al. (2016) | |
| VCE‐003 cannabigerol quinone derivative |
0.1‐, 1‐, 10‐, and 25‐μM CBG/VCE‐003 (HTT cells, 24 h) (microglia, 18 h; hippocampal cells; mice treated 15 days 5 mg·kg−1 i.p. VCE‐003 b ) |
Multiple sclerosis |
HEK293 cells and primary microglial cells. HT22 mouse hippocampal cells |
n = 3 a |
VCE‐003 protected neuronal cells from excitotoxity. Reduction in IL‐1β, IL‐6, TNF‐α, PGE2, and MIP‐1‐α in microglia (1, 10, and 25 μM) VCE‐003 ameliorated MS symptoms induced by TMEV |
Granja et al. (2012) | |
| VCE‐003.2 cannabigerol derivative |
BV2 cells 5 μM VCE‐003.2 for 21 h. VCE‐003.2 (M‐213 cells) Vehicle (0.1% DMSO) versus 0.1, 0.5, and 1 μM for 40 h |
Parkinson's disease model induced by LPS (conditioned medium from BV2 cells added to M‐213 cells) | Mouse microglial BV2 cells. M‐213 (striatal cell line) neuronal cells | BV2 cells: n = 14, 7 repeats | In BV2 cells, VCE‐003.2 significantly decreased TNF‐α COX‐2 and iNOS mRNA. Attenuated TNF‐α and IL‐1β secreted in medium of BV2 cells (5 μM) | Garcia et al. (2018) | |
| Cannabigerol |
MTT assay: 1, 2.5, 5, 7.5, 10, 12.5, 15, and 20 μM pretreated 24 h. NSC‐34: pretreated with 7.5 μM |
Neuroinflammation—medium from LPS stimulated macrophages | NSC‐34 motor neurons | n = 3 repeats |
CBG at 2.5 and 7.5 μM increased cell viability approximately 20% compared to control. CBG pretreatment inhibited apoptosis and reduced; IL‐1β, TNF‐α, INF‐Y (NSC‐34 motor neurons). CBG restored decreased Nrf2 levels |
Gugliandolo et al. (2018) | |
| Cannabidiol* and cannabigerol |
Electrophysiology: 1/10 μM 20 min. hNAv cells: 1 nM–200 μM for 100 s |
PTZ seizures | Transverse hippocampal slices, SH‐SY5Y, hNAv cell lines |
SH‐SY5Y—n = 6 mouse cortical neurons n = 8 hNAv n = 3 |
10‐μM CBG significantly reduced peak Nav current in SH‐SY5Y cells and mouse cortical neurons. CBG was also effective as a low affinity Nav channel blocker. | Hill et al. (2014) | |
| Cannabigerol derivative VCE‐003.2 | 0.1, 0.5, 1, and 5 μM added 1 h prior to LPS, for 24 h | Amyotrophic lateral sclerosis | Astroglial cells (mutant SOD1 mice) | n = 4, 6 samples per group | VCE.003.2 at 1 and 5 μM attenuated levels of TNF‐α and IL‐1β, elevated due to LPS stimulation | Rodrígueuz‐Cueto et al. (2018) | |
| Cannabigerol | 6 h—supplementary information cannot be accessed | Huntington's disease | Immortalized striatal progenitor cells: STHdhQ7/Q7 and STHdh Q111/Q111 cells | n = 3 repeats | CBG dose‐dependently activated PPARγ | Valdeolivas et al. (2015) | |
| Cannabigerol | 1‐μM 24‐h ATP assay/viability and differentiation for 2 days | Neuroprotection | Adult neural stem cells/progenitor cells (NSPC) | n = 6 | CBG had no significant effect on any of the endpoints measured. | Shinjyo & Di Marzo (2013) | |
| Cannabidivarin (CBDV) | Cannabidivarin |
1, 10, and 100 μM 30 min after epileptiform activity for 30 min |
Epilepsy‐spontaneous local field potentials (LFPs) | Transverse hippocampal slices male/female Kyoto rats | n > 5 slices from n > 5 animals | CBDV decreased amplitude and duration of LFPs and increased Mg2 + free induced LFPs frequency (>10 μM). | Hill et al. (2012) |
| Cannabidivarin (+CBD) |
3, 10, 30 μM 30–40 min after control readings for 1 min |
Epilepsy | HEK cells (HEK293) transfected with TRPV1, TRPV2, and TRPA1. | n = 4 |
CBDV was anticonvulsant, and TRPV1 antagonist capsazepine blocked this effect. 10 μM CBDV tended to increase phosphorylation at the S800 site of TRPV1. |
Iannotti et al. (2014) | |
| Cannabichromene (CBC) | Cannabichromene | 1‐μM 24‐h ATP assay/viability and differentiation for 2 days | Neuroprotection | Adult neural stem cells/progenitor cells (NSPC) | n = 6 | CBC raised viability in B27 medium. CBC had no significant effect on proliferation. In B27 medium, CBC up‐regulated nestin, but reduced GFAP. | Shinjyo & Di Marzo (2013) |
| Cannabinol (CBN) | Cannabinol/Δ8 THC | 100, 20, 4, 0.8, 0.16, or 0 μM for 48 h | Huntington's disease | PC12 cells expressing polynucleotide repeats (103 glutamines) | n = 2 repeats, average 3– 4 wells | Cannabinol reduced LDH activity in medium at 20 and 100 μM. At 100 μM, CBN decreased LDH release by 84%. Protective EC50 of CBN was determined to be 30 μM in this model. | Aiken, Tobin, & Schweitzer, 2004 |
| Cannabinol (+THC and CBD) | 0.1, 1, 2.5, 5, and 10 μM for 24 h | Oxidative stress and neuroprotection | Primary cerebral granule cells (rats/mice), CB1 expressing cell lines. PC12 and HT22 cell lines | n = 3 | Cannabinol was shown to be a potent antioxidant. | Marsicano, Moosmann, Hermann, Lutz, and Behl (2002) | |
| Tetrahydrocannabidivarin (∆9‐THCV) | ∆9‐THCV | 0, 5, 10, 20, 40, and 50 μM applied directly after epileptiform activity. 20‐min pretreatment at 10 μM | In vitro electrophysiology (epileptiform bursting) | Brain slices obtained from male and female outbred rats | n = 5 | ∆9‐THCV (20–50 μM) decreased burst incidence, PDS amplitude and frequency. The most significant effect was at 50 μM. ∆9‐THCV also decreased epileptiform burst speed (40 μM). ∆9‐THCV was found to act as a CB1 ligand in receptor binding assays. | Hill et al. (2010) |
| Tetrahydrocannabinolic acid (∆9‐THCA) | ∆9‐THCA | 0.01, 0.1, 1, and 10 μM for 48 h | Parkinson's disease | Dopaminergic neuronal cell culture | n = 3–4 wells/treatment | ∆9‐THCA had no effect on the survival of dopaminergic neurons, but at 10 μM led to an increased cell count (123%) and morphology was ameliorated versus control cultures. | Moldzio et al. (2012) |
| Mixed | ∆9‐Tetrahydrocannabinolic acid (∆9‐THCA) and cannabidiolic acid (CBDA), cannabigerol (CBG) | 0, 0.5, and 1 μM (∆9‐THCA) N2a cells—48 h. 0 and 0.1–15 μM (∆9‐THCA, CBDA, and CBGA in HEK‐293 T cells)—6 h. 1–10 μM ∆9‐THCA STHdhQ7/Q7 cells—1 h/CB | Huntington's disease/neurodegeneration |
HEK‐293 T Neuro‐2a STHdhQ7/Q7 And STHdh Q111/Q111 cells |
n = 5 repeats | ∆9‐THCA increased neuronal cell viability post serum deprivation and increased mitochondrial mass. This effect was blocked by a PPARγ antagonist GW9662. All cannabinoid acids induced PPARγ transcriptional activity in HEK293 cells. | Nadal et al. (2017) |
| Cannabichromene, cannabidiol, cannabidivarin, cannabigerol, cannabinol, ∆9‐tetrahydrocannabinol, ∆9‐tetrahydrocannabinolic acid | 0, 0.1, 1, and 10 μM for 48 h | Neuroprotection | N18TG2 cells (neuroblastoma cell line) | In triplicate with 2–5 repeats | Emerging phytocannabinoids did not affect the number of dopaminergic neurons. CBG and CBC decreased GSH levels (0.1 and 1 μM and 1 and 10 μM). 0.1 μM CBDV reduced GSH levels by 9.6%; THC, THCA, and CBN have no effect. CBDV and CBN decreased resazurin reduction at 10 μM (32.9 and 38.9%) and affected PI uptake at all concentrations. CBG also affected PI uptake at 0.1 and 10 μM. | Rosenthaler et al. (2014) | |
| Cannabigerol, cannabichromene, cannabidivarin, and cannabinol (as well as THC, CBD, and CBD derivative DMCBD*) |
250 nM–10 μM Oxytosis assay, 30 min. Energy loss assay: 22 h. Trophic factor withdrawal, 48 h |
Alzheimer's disease | MC65 cells (human nerve cell line), Ht22 cells (mouse hippocampal cell line), and BV2 microglial cell line | n = 6 (twice in triplicate) |
CBG, CBDV, CBC, CBN, and THCA prevented oxytosis. CBG, CBDV, CBC, and CBN preserved trophic factors. THCA was toxic to MC65 cells at 1 μM; however, CBDV, CBC, CBN, and CBDA prevented amyloid toxicity at ≤100 nM. CBDV, CBG, CBC, and CBN (100 nM) prevented MC65 neurons from accumulating amyloid β (Aβ). |
Schubert et al. (2019) |
Results from 3 independent experiments.
For in vivo data see Table 2.