Parkinson's disease (PD) involves neuroinflammation, excitotoxicity, mitochondrial dysfunction, and diminished trophic support. The endo-cannabinoid system (comprising small bioactive compounds, their synthetic and catabolic enzymes, their metabotropic and ionotropic receptors, and their transporters) has been implicated in neurophysiology and neurodegeneration, leading to the proposal of medicines derived from Cannabis sativa as new PD therapies. Here, the potential for cannabinoid-based PD therapies is reviewed. The clinical significance of cannabinoids in PD presents both promise and paradox, with varied data emerging from disparate model systems, clinical trials, and delivery modalities, including medical applications of native (plant-derived) and synthetic cannabis products. This picture is complicated further by the multivariate involvement of metabotropic and ionotropic receptors, an emerging understanding of new cannabinoid targets (e.g., PPARγ and GPRs18, 55, and 119), and the potential role of entourage compounds (e.g., geraniol, apigenin) in any protective or therapeutic effects observed.

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