TABLE 1.
Summary of the effects of CBD:THC cannabinoid combination treatments in AD-relevant cell and animal models as well as in people with AD from clinical studies.
| Model System | Treatment | Effect | References |
| In vitro studies | |||
| Oxytosis induced HT22 | THC+CBD | Additive neuroprotective effect against ROS | Schubert et al., 2019 |
| cells (via glutamate) | THC+CBN | Synergistic neuroprotective effect against ROS, non-ECS mechanism | |
| Oxytosis induced SH-SY5Y cells (via H2O2) | THC, CBD | THC (IC50 = 0.4 μg/mL) had a higher potency in combating ROS cf. CBD (IC50 = 42.7 μg/mL) | Raja et al., 2020 |
| THC-rich cannabis extracts | ↓ ROS by 70–80%, IC50 = 0.4–1.2 μg/mL | ||
| CBD-rich cannabis extracts | ↓ ROS by 60+%, IC50 = 0.5–0.6 μg/mL | ||
| Combinations of CBD:THC | 10:90 CBD:THC; IC50 = 2.5 μg/mL 25:75 CBD:THC; IC50 = 0.4 μg/mL, most effective antioxidant 50:50 CBD:THC, IC50 = 0.5 μg/mL 75:25 CBD:THC, IC50 = 1 μg/mL 90:10 CBD:THC, IC50 = 5 μg/mL, least effective antioxidant |
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| In vivo studies | |||
| Young AD model APP/PS1 transgenic male mice 6 months old |
CBD-rich cannabis extract (0.75 mg/kg CBD), daily i.p., 5 weeks | Reversed the object recognition memory deficit ↓ astrogliosis |
Aso et al., 2015 |
| THC-rich cannabis extract (0.75 mg/kg THC), daily i.p., 5 weeks | Reversed the object recognition memory deficit ↓ astrogliosis ↓ the object recognition memory of WT mice*** |
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| 1:1 CBD:THC cannabis extract (0.75 mg/kg each CBD and THC), daily i.p., 5 weeks | Reversed the object recognition memory deficit and improved learning impairments ↓ cortical soluble Aβ42 peptides (and ↑ Aβ42/ Aβ42 ratio in amyloid plaques) ↓ astrogliosis, microgliosis, and modified inflammatory markers No effect on the object recognition memory of WT mice |
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| Aged AD model APP/PS1 transgenic male mice 12 months old |
1:1 CBD:THC cannabis extract (0.75 mg/kg each CBD and THC), daily i.p., 5 weeks | Reversed the object recognition memory deficit No effect on amyloid pathology or gliosis No effect on the age-related object recognition memory deficit of aged WT mice cf. non-aged controls |
Aso et al., 2016b |
| Tauopathy model PK–/–/TauVLW transgenic male mice 6 months old |
1:1 CBD:THC cannabis extract (1.5 mg/kg each CBD and THC), daily i.p., 1 month | ↓ hippocampal and cerebral Aβ and tau deposition and ↑ autophagy ↓ neuroinflammation and gliosis ↑ reduced/oxidized glutathione ratio, ↓ levels of free radicals and iNOS ↓ stress, aggressive behavior, and stereotypy |
Casarejos et al., 2013 |
| Aged mice C57BL/6J male mice 18 months old |
THC (1 mg/kg), daily s.c. via osmotic mini pump, 4 weeks | ↑ spatial learning No effect on spatial memory |
Nidadavolu et al., 2021 |
| 1:1 CBD:THC (1 mg/kg each CBD and THC), daily s.c. via osmotic mini pump, 4 weeks | No effect on spatial learning or memory | ||
| Lafora disease model Mice homozygous for the EPM2B deletion (malin knock-out; sex not specified) 4 and 10 months old |
CBD-rich cannabis extract (35 mg/kg CBD, 4.8 mg/kg THC), 5 days per week p.o., 2 months | Reversed the object recognition memory deficit of 12-month-old malin knock-out mice ↓ the object recognition memory of 6-month-old WT mice*** |
Aso et al., 2020 |
| Clinical studies | |||
| 10 people with AD and BPSD, open label prospective trial gender not specified |
THC-rich cannabis extract (2.5 mg THC, titrated to 5 or 7.5 mg in 3 patients), two times daily p.o., 4 weeks, adjunctive therapy to usual care | ↓ Clinical Global Impression severity scale from 6.5 to 5.7 ↓ Neuropsychiatric Inventory scale from 44.4 to 12.8; improvements to delusions, agitation/aggression, irritability, apathy, sleep, and caregiver distress Side effects: confusion in one patient at 5 mg*** |
Shelef et al., 2016^ |
| 10 women with severe dementia and BPSD, prospective observational pilot study | CBD:THC tincture or oil (average 13.2–18 mg/day CBD and 7.6–9 mg/day THC, titrated), three times daily p.o., 2 months | ↓ Neuropsychiatric Inventory scale from 71.1 to 38.3 ↓ agitation (Cohen-Mansfield Agitation Inventory) from 74.5 to 47.5 ↓ rigidity (Unified Parkinson’s Disease Rating scale) from 3.4 to 1.7 ↓ Visual analog scale from 9 to 5; improvements to invalidating behavior problems including screaming and aggression Side effects: mouth ulcers when tincture was used*** |
Broers et al., 2019^ |
Detrimental effects of the treatment are indicated by “***”. “^” denotes where clinical trial registration numbers were not reported in the study and could not be located retrospectively on clinical trial registries.
Aβ, Amyloid-β; AD, Alzheimer’s disease; APP/PS1, APPSwe/PS1ΔE9 mouse model; BPSD, behavioral and psychological symptoms of dementia; CB1R, cannabinoid 1 receptor; CBD, cannabidiol; CBN, cannabinol; ECS, endocannabinoid system; H2O2, hydrogen peroxide; IC50, half-maximal inhibitory concentration; i.p., intraperitoneal; p.o., per os; ROS, reactive oxygen species; s.c., subcutaneous; THC, delta-9-tetrahydrocannabinol; WT, wild type-like.