Therapeutic options for the treatment of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) are limited, but recent research suggests that phytochemicals from Cannabis sativa, including cannabidiol (CBD) and low-dose delta-9-tetrahydrocannabinol (THC), have antioxidant and anti-inflammatory properties, can ameliorate amyloid-ß (Aß) and tau neuropathologies, and improve cognition in aged and transgenic mouse models of AD, such as the APPSwe/PS1ΔE9 (APP/PS1) mouse model. Treatments involving a combination of THC and CBD can produce greater therapeutic effects than cannabinoid isolates alone and given the ‘entourage effect’, cannabis extracts containing additional phytochemicals might be even more therapeutically beneficial than a CBD+THC regimen. The optimal dosage, cannabinoid ratio, and form of cannabis combinations (isolate combination versus plant extract) for AD therapy have not yet been established. This thesis aimed to conduct two preclinical investigations to examine a CBD+THC isolate regimen and a cannabis extract regimen (both CBD-rich and with a low dose of THC) for their ability to rescue AD-relevant cognitive deficits in 14-month-old male and female APP/PS1 mice and MCI-relevant cognitive deficits and neuropathologies in 6-month-old male APP/PS1 mice, respectively. Wild type-like (WT) and transgenic female and/or male mice were treated with 50 mg/kg CBD + 3 mg/kg THC or 125 mg/kg Eve (79.75 mg/kg CBD; 3.00 mg/kg THC) or vehicle via daily intraperitoneal (i.p.) injection for 3 weeks before a battery of behavioural paradigms was conducted (with continued treatment). The brains of Eve-treated animals were then collected for analysis of amyloid pathology via enzyme-linked immunosorbent assay (ELISA) and analysis of the endocannabinoid system and a marker of microglial activation using western blot. Both cannabinoid regimens successfully reversed cognitive flexibility spatial memory impairments in APP/PS1 mice. For the Eve- treated animals, this was associated with a reduced Aβ42 to Aβ40 ratio, although there were no changes to increased neuroinflammation. Eve treatment also appeared to improve object recognition across genotypes. However, both CBD+THC and Eve treatments also resulted in side effects, including hypolocomotion, increased anxiety, impaired social recognition, and changes to sensorimotor gating. These side effects could potentially be mitigated in future studies by reducing the dosage or adjusting the cannabinoid ratios. Further research is required to evaluate the suitability of multi-cannabinoid and THC-containing strategies for AD, with continued exploration of pure CBD-focused regimens for AD also recommended, given the previously demonstrated low side effect profile.
Preclinical evaluation of the therapeutic potential of cannabinoid combination treatment regimens for dementia
Coles, M. (Author). 2024
Western Sydney University thesis: Doctoral thesis