Toward a Translationally Relevant Preclinical Model of Cannabis Use

As the political and public landscape surrounding cannabis continues to shift, there is an urgent need to better understand how cannabis use impacts the brain and behavior. Preclinical studies are advantageous in this respect; however, there are drawbacks with current approaches that limit their translational value. Perhaps due to DEA-imposed restrictions, synthetic CB1R agonists have become the drug of choice in rodent models of cannabis exposure. However, the pharmacological properties of these compounds differ tremendously from that of cannabis, with synthetic CB1R agonists and THC recruiting different intracellular signaling pathways (Laprairie et al, 2014). Thus, the cellular effects of synthetic CB1R agonists often used in preclinical studies may not be indicative of the effects of THC, let alone cannabis. When THC is used, dosing is often excessively high and exposure regimens are not representative of human use patterns since a bolus THC injection differs dramatically from that of titrated cannabis inhalation. Moreover, cannabis is comprised of more than THC. There are over 120 phytocannabinoids in the cannabis plant, each with its own unique pharmacodynamic profile and the interaction between these phytocannabinoids may influence its effects. For instance, cannabidiol can inhibit THC-dependent intracellular signaling (Laprairie et al, 2016) and attenuate THC-induced paranoia and memory deficits in humans (Englund et al, 2013). Therefore, THC alone may produce effects that are not indicative of human cannabis consumption. This is supported by human studies indicating that intravenous THC delivery produces a myriad of adverse events that are most often associated with higher doses and faster infusion rates (Carbuto et al, 2012). In this regard, it is not surprising that intravenous THC self-administration has been notoriously difficult to demonstrate in rodents. Finally, inhalation is the most common route of cannabis administration and the pharmacokinetics vary markedly depending on whether the drug is injected, inhaled, or injested. Additionally, whereas intraperitoneal THC elicits conditioned avoidance, intrapulmonary THC actually produces a place preference in rats (Manwell et al, 2014). Thus, in order to effectively model cannabis use and understand its effects on the brain and behavior, there must be a fundamental shift in the experimental approach. To this end, we are currently developing a novel vapor inhalation model that uses ‘e-cigarette’ technology to deliver discrete ‘puffs’ of vaporized cannabis extracts in a response-contingent