Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer’s disease

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“Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies.

Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential.

CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies.

Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.”

“This mini review highlights that multi-cannabinoid combination treatment strategies are valid candidates for novel AD therapies. However, further investigations, and in particular, clinical studies, are required to determine optimal dose and ratio of cannabinoids for treatment of behavioral, cognitive, and pathological symptoms of AD thereby also considering other cannabinoids in addition to the current focus on THC and CBD (most cannabis extract studies did not profile cannabinoid content beyond those two phytocannabinoids). Importantly, all relevant studies reviewed were carried out in one sex/gender only. Given that sex-specificity is evident in AD transgenic mouse models (van Eersel et al., 2015Jiao et al., 2016) and gender differences are seen in dementia (Oveisgharan et al., 2018) as well as in the ECS and the response to cannabis (Craft et al., 2013), it is pertinent that these future investigations consider both sexes.”

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