Investigating cannabidiol rescue of stress-induced cognitive impairment and metabolism-driven safety in Human-on-a-Chip® models

This manuscript combined two studies that assessed the effects of cannabidiol (CBD) exposure in distinct organ-on-a-chip models. Hesperos, Inc.’s Human-on-a-Chip® (HoaC) technology utilizes custom-designed human-based, serum-free, and pumpless microphysiological systems (MPS). The first study, study 1, assessed the level of off-target toxicity for CBD and its associated metabolites, 7-carboxy cannabidiol and 7-hydroxy cannabidiol, using a multi-organ heart-liver system. In study 1, CBD was delivered to systems with and without the inclusion of a liver organ module to evaluate metabolic contributions to corresponding cardiac toxicity. The results suggested that metabolism of the parent compound into its metabolites resulted in significant effects when compared to exposure to the parent compound only. Interestingly, significant distinctions in cardiac function, such as beat frequency and contractile force, were detected even though no significant cytotoxic effects were noted. The second study, study 2, utilized the same HoaC technology and employed a central nervous system (CNS) model using human induced-pluripotent stem cell derived cortical neurons. This model assessed CBD efficacy in alleviating stress-induced neural dysfunction in a single-organ model of the CNS, mimicking neuromodulation through a CBD administration route that does not involve first-pass metabolism. The results indicated a concentration-dependent rescue of CBD on cortisol-induced deficits in long-term potentiation (LTP) in this model, which was mirrored by associated changes in anandamide levels. Overall, these studies highlight the potential of human-based in vitro systems to evaluate drug toxicity and efficacy profiles specific to target mechanisms for toxicity and efficacy.