Tim Karl | The therapeutic potential of medicinal cannabis for

Tim Karl, Western Sydney University, Australia Title: The therapeutic potential of medicinal cannabis for neurodegenerative diseases – a preclinical perspective Abstract: Introduction: Cannabinoids exert neuroprotective, antioxidant, and anti-inflammatory effects and promote neurogenesis. This makes them an interesting therapeutic candidate for neurodegenerative diseases including Alzheimer’s disease (AD) and motor neuron disease (MND). Over the last decade, our laboratory has used transgenic mouse models that mimic key pathological features of AD (amyloid-β aggregation and tau hyperphosphorylation) and MND (e.g. overexpression of mutant SOD1) to preclinically evaluate the beneficial properties of medicinal cannabis. Methods: Therapeutic-like remedial effects of different chronic doses of cannabidiol (CBD), a combination of CBD and low-dose delta-9-tetrahydrocannabinol (THC), or a CBD-rich cannabis extract were characterized in APP/PS1 and TAU58/2 transgenic mouse models for AD. Mice were comprehensively assessed for cognition, anxiety, locomotion, and motor functions. Molecular analyses were conducted to follow up on beneficial treatment effects and focused on disease-relevant markers such as amyloid burden, oxidative stress, and neuroinflammation. CBD treatment was also evaluated in the SOD1G93A transgenic mouse model for familial MND. The research also explored sex-dependent effects, different disease stages, as well as preventative oral treatment strategies. Results: Chronic CBD treatment improved cognitive deficits in AD transgenic mice, including object recognition memory. CBD also demonstrated moderate beneficial effects on disease-relevant pathologies including inflammation and amyloid-β production. CBD treatment was less impactful on the disease progression of MND transgenic mice. Findings also highlighted sex and dose-dependent properties as well as undesired side effects when treatments included THC. Summary: Cannabinoids, and in particular CBD, appear to hold promise as multi-target therapeutic agents in neurodegenerative diseases. However, outcomes depend on dose, cannabinoid composition, disease stage, and mouse model system chosen. The research underscores the importance of rigorous preclinical evaluation in mouse models to inform translation into human clinical trials, while also highlighting that cannabinoid-based therapies are not universally beneficial and require careful optimisation.