Table 4.

Main results from the studies with non-selective CB₁R and CB₂R agonists.

Reference	Cannabinoid	Dosage	Major Results	Model Used
In vitro studies
Cao et al., 2014 [73]	Δ9-THC	0.25 nM–2.5 μΜ every 6 or 24 or 48h	↓ Aβ40 levels time- and dose-dependently, inhibition of Aβ40 aggregation ↓ Aβ protein production after administration every 24h ↓ GSK-3β, TAU phosphorylation, dose-dependently	In vitro experiments in N2a/AβPPswe cells
Gugliandolo et al., 2023 [74]	Δ8-THC	20 μΜ	↑ Cell viability ↓ ER stress Restoration of proteostasis ↑ Expression of PSMB5, ubiquitin, Bcl-2 ↓ UPR, expression of Bax	In vitro experiments in SH-SY5Y cells treated with Aβ1–42
Hughes and Herron, 2019 [75]	CBD	10 μΜ	Prevention of LTP reduction Therapy due to activation of PPAR-γ, no involvement of CB1R	In vitro experiments in sections from CA1 hippocampus region of Aβ-treated C57Bl/6 mice
Askari et al., 2018 [76]	β-Amyrin	4–16 μΜ	↑ Cell viability ↓ Levels and expression of TNF-a, IL-1β, IL-6, PGE-2, and COX-2 ↑ Arginase-1/iNOS, urea/NO ratios Promotion of M2 anti-inflammatory phenotype	In vitro experiments in LPS/IFN-γ-treated rat microglial cells
Aguirre-Rueda et al., 2015 [77]	WIN55,212-2	10 μΜ	↑ Cell viability, ↓ pro-inflammatory cytokines (IL-1β, TNF-a) ↓ Expression of p65, COX-2, iNOS ↑ Expression of PPAR-γ, Cu/Zn SOD	In vitro experiments in rat cortical astrocytes treated with Aβ
Gajardo-Gómez et al., 2017 [21]	WIN55,212-2	5 μΜ	Prevention of increase in Cx43 hemichannels ↓ Cx43 activity in hippocampal astroglial and pyramidal cells, compared to Aβ group ↓ Death rates of pyramidal neurons compared to the Aβ group Implication of CB1R in the observed results	In vitro experiments in cells from rat hippocampal slices treated with Aβ25–35
	2-AG
	Methanandamide
Soto-Mercado et al., 2021 [78]	CP55-940	1 μΜ	Inhibition of sAβPPβf aggregation and TAU phosphorylation Restoration of ΔΨm to normal levels ↓ ROS Inhibition of p52, c-Jun, PUMA, caspase-3 activation Restoration of Ca2+ influx function only after co-administration of anti-Aβ42 antibody	In vitro experiments in PSEN1 E280A cells (familial AD model)
	SR141716 (CB1R inverse agonist)
	Anti-Aβ42 antibody
	2-AG
	CP55-940
	WIN55,212-2
	URB597 (FAAH inhibitor)
Chiricosta et al., 2024 [79]	Cannabinerol	20 μΜ	↑ Cell viability Restoration of mitochondrial function by regulating genes involved in oxidative phosphorylation Endoplasmic reticulum function improvement by regulating genes related to protein folding and degradation Metabolic regulation by regulating genes related to glucose and lipid metabolism	In vitro experiments in SH-SY5Y cells treated with Aβ
In vivo studies
Coles et al., 2020 [80]	CBD	5 mg/kg i.p.	↑ Spatial learning speed, persistence, ability to recognize new objects Unsuccessful results in a variety of other behavioral experiments	In vivo experiments in female APP/PS1 mice
Amini and Abdolmaleki, 2022 [81]	CBD with nano-chitosan coating	120 mg/kg p.o.	↓ Escape latency, distance travelled, ↑ time spent in the target quadrant (MWM test) ↑ Expression of CB1R, CB2R in the hippocampus	In vivo experiments in Aβ1–42-treated rat AD model
Hao and Feng, 2021 [82]	CBD	5 mg/kg/day i.p.	Upregulation of immune response factors and cellular autophagy pathway	In vivo study in APP/PS1 mice through analysis of DEGs
Kim et al., 2023 [83]	CBDA	6 μΜ, 3 μL (intrahippocampal injection)	↓ Escape latency by CBDA and Δ9-THCA compared to Aβ group (MWM test) ↑ Discrimination index (NOR) ↓ Expression of Aβ in the hippocampus ↓ Expression of p-TAU in the hippocampus	In vivo experiments in ICR mice after injection of Aβ1–42
	Δ9-THCA	12 μΜ, 3 μL (intrahippocampal injection)
Long et al., 2021 [84]	NlTyr	60 mg/kg p.o.	Increased time spent on the rod (RRT test) Motor coordination enhancement ↓ Escape latency (MWM test) Improvement of cognitive and learning abilities ↓ Aβ42 in the CA1 hippocampal region	In vivo experiments in AD APP/PS1 mouse model
Mahdi et al., 2021 [85]	WIN55,212-2	0.5 mg/kg 1 mg/kg 2 mg/kg	Improved escape latency and time spent in target quadrant (MWM test) ↑ SOD, GSH, nestin, GFAP Mitigation of cellular abnormalities in the hippocampus ↓ MDA	In vivo experiments in a AlCl3 + D-Gal -treated Wistar rat model
Human studies
Defrancesco and Hofer, 2020 [86]	Dronabinol drops (Δ9-THC)	4.9–6.7 mg/day p.o.	Improvement in emotional state Mitigation of disruptive behaviour, aggression and suppression Absence of ADRs	Case report on a 69-year-old AD patient with severe NPS (depression, paranoid perception)
Alexandri et al., 2023 [87]	CBD oil drops	3% p.o. for 6 months	↓ NPI score Improvement in BPSD	Comparative study in 20 patients with dementia between 3% CBD and usual treatment
Herrmann et al., 2019 [88]	Nabilone	1–2 mg/day p.o.	↓ NPS (NPI-NH) ↓ Anxiety (CMAI) ↓ Malnutrition (MNA-SF) ↑ Cognitive function (sMMSE)	Randomized, double-blind, crossover clinical trial in 39 patients with moderate to severe AD
van den Elsen et al., 2015 [89]	Δ9-THC	1.5 mg/3 times/day	Non-statistically significant differences in NPI score, CMAI, Quality of Life-Alzheimer’s Disease, Barthel Index between Δ9-THC and placebo groups Well-tolerated treatment with no severe ADRs	Randomized controlled trial in 50 patients with dementia
van den Elsen et al., 2015 [90]	Δ9-THC	0.75 mg/2 times/day 1.5 mg/2 times/day	Non-statistically significant differences in NPI score Well-tolerated treatment with no severe ADRs	Randomized controlled trial in 22 patients with dementia and clinically relevant NPS
Palmieri and Vadalà, 2023 [91]	Cannabins extract in oil	1 mL/day (22% Δ9-THC, 0.5% CBD) p.o.	↓ Irritability, restlessness, sleep disturbances, apathy (NPI) ↓ Behaviors of physical and verbal aggression (CMAI) ↓ Cognitive impairment from mild to moderate (MMSE)	Limited-size cohort study in 30 patients with moderate-to-severe AD
Ruver-Martins et al., 2022 [32]	Cannabis extract	Microdoses (most often 500 µg p.o.) of 8:1 Δ9-THC:CBD extract for 22 months	↑ MMSE ↓ ADAS-COG Stabilization of results with continued treatment	Case report on a 75-year-old patient with mild AD (memory impairment, spatiotemporal disorientation)
van den Elsen et al., 2017 [92]	Δ9-THC	1.5 mg/2 times/day for 3 days	↑ Standing sway with eyes closed, trunk sway, stride length No changes in dual-task walking	Randomized controlled trial in 18 patients with dementia

Abbreviations: Aβ: amyloid beta; AD: Alzheimer’s disease; ADAS-COG: Alzheimer’s Disease Assessment Scale—Cognitive Subscale; ADR: adverse drug reaction; 2-AG: 2-arachidonylglycerol; AlCl₃: aluminum chloride; Bax: Bcl-2-associated X protein; Bcl-2: B cell leukemia/lymphoma 2 protein; BPSD: behavioral and psychological symptoms of dementia; CBD: cannabidiol; CBDA: cannabidiol acid; CB₁R: cannabinoid receptor 1; CB₂R: cannabinoid receptor 2; CMAI: Cohen-Mansfield agitation inventory; COX-2: cyclooxygenase-2; DEGs: differentially expressed genes; D-Gal: D-galactosidase; ΔΨm: mitochondrial membrane potential; ER: endoplasmic reticulum; FAAH: fatty acid amide hydrolase; GFAP: glial fibrillary acidic protein; GSH: glutathione; GSK-3β: glycogen synthase kinase-3 beta; ICR: Institute of Cancer Research; IFN-γ: interferon γ; IL-1β: interleukin-1β; IL-6: interleukin-6; iNOS: inducible nitric oxide synthase; i.p.: intraperitoneally; LPS: lipopolysaccharide; LTP: long-term potentiation; MDA: malondialdehyde; MMSE: mini mental state examination; MNA-SF: mini-nutritional assessment short-form; MWM: Morris water maze; NlTyr: N-linoleyltyrosine; NO: nitric oxide; NOR: novel object recognition; NPI: neuropsychiatric inventory; NPI-NH: neuropsychiatric inventory—nursing home; NPS: neuropsychiatric symptoms; PGE-2: prostaglandin E2; p.o.: per os; PPAR-γ: peroxisome proliferator-activated receptor-γ; PSMB5: proteasome subunit beta type-5; p-TAU: phosphorylated TAU; PSEN1: presenilin 1; PUMA: p53 upregulated modulator of apoptosis; ROS: reactive oxygen species; RRT: rotarod test; sMMSE: standardized mini mental state examination; SOD: superoxide dismutase; Δ⁹-THC: tetrahydrocannabinol; Δ⁹-THCA: tetrahydrocannabinolic acid; TNF-a: tumor necrosis factor-a; UPR: unfolded protein response.