TABLE 2.

Influence of CBD/THC or non-selective agonists on neuropathology in AD transgenic rodent models.

Neuropathology	CBD	Cannabinoid system modulators (CB1 and CB2 Activators; ECB Reuptake Inhibitors, THC + CBD Combined Treatment)
Aβ 42 and Tau-p	AbPP/PS1 Chronic treatment (i.p. 50 mg/kg; daily for 3 weeks): ↓ soluble Ab40 in hippocampus (Watt et al., 2020). Rat AD model PPARg-dependent: -Reduction in reactive gliosis and neuronal damage -Stimulated hippocampal neurogenesis (Esposito et al., 2011).	AbPP/PS1 Chronic THC + CBD Combined Treatment at early symptomatic stages: ↓Ab42 levels and altered plaque composition (Aso et al., 2015). Chronic THC + CBD Combined Treatment at later symptomatic stages: ↓GluR2/3 ↑ GABA A Ra1 (Aso et al., 2016). Hyperglycemic 3xFAD Mice Chronic low dose AM404 (0.5uM); GSK-3b inhibitor; AEA Reuptake Inhibitor) ↓Ab42 levels ↓tau phosphorylation (Huang et al., 2019).
Inflammation neuronal injury	AbPP/PS1 Chronic treatment (i.p. 50 mg/kg; daily for 3 weeks): NO EFFECT on markers of inflammation, degeneration, or PPARg, in the cortex (Watt et al., 2020). 5xFAD ↓ IL-5 (Khodadadi et al., 2021).	AbPP/PS1 Chronic THC + CBD Combined Treatment at early symptomatic stages: ↓astrogliosis, microgliosis and inflammatory markers (Aso et al., 2015). ↓ Oxidative phosphorylation ↓ TNF pathways ↑Tautophagy (Hao and Feng, 2021). 5x FAD Mice FAAH Inhibitors URB597 or SR1 No beneficial effect on cytokine expression (Vazquez et al., 2015). Hyperglycemic 3xFAD Mice Chronic low dose AM404 (0.5 μM; GSK-3b inhibitor; AEA Reuptake Inhibitor) ↓astrogliosis (GFAP), microgliosis (Iba1) (Huang et al., 2019).
Cognition/BPSD	AbPP/PS1 Chronic treatment (i.p. 20 mg/kg; daily for 3 weeks OR i.p. 50 mg/kg; daily for 3 weeks) Reversed social recognition and novel object recognition deficits without causing anxiety-related behaviors (Cheng et al., 2014; Watt et al., 2020). 5xFAD Improved cognitive function (Morris Water Maze) Reduced anxiety (Open Field Test) (Khodadadi et al., 2021). 14 month-old Tau 58/2 mice Chronic treatment (100 mg/kg i.p. daily for 3 weeks) ↓ anxiety-like behavior ↓ contextual-fear associated freezing (Kreilaus et al., 2022).	AbPP/PS1 Chronic THC + CBD Combined Treatment at early OR late symptomatic stages: -Preserved memory -Reduced memory impairment (Aso et al., 2015). 5x FAD mice FAAH Inhibitors URB597 or SR1 No effect on Morris Water Maze (Vazquez et al., 2015). Hyperglycemic 3xFAD Mice Chronic low dose AM404 (0.5 μM; GSK-3b inhibitor; AEA Reuptake Inhibitor) Improved learning and memory deficits in Morris Water Maze (Huang et al., 2019).