Individual differences in the pharmacokinetic profiling of Δ9-THC may be associated with differential motivational effects of Δ9-THC on cognitive performance

Abstract Rationale Cannabis is the most widely used illicit substance in the United States, and its use is increasing with the recent push for legalization and decriminalization, as well as the growing use for medicinal purposes. While cannabis can have positive effects in some individuals, there are potential negative consequences including dependence, psychosis, and cognitive impairments. The top reported reasoning for using cannabis is to alleviate stress, however, whether cannabis differentially induces positive or negative effects under stress has not been studied.

Objectives: The current study investigates whether stress affects working memory, and if THC can exacerbate or ameliorate its effect. An additional aim is to determine if plasma THC concentrations are associated with cognitive performance Methods Adult male and female Sprague Dawley rats performed a delay-match-to-sample working memory task. Rats assigned to the stress group were exposed to acute restraint stress prior to administration of either vehicle, 0.5,1, or 3 mg/kg THC. Blood samples were collected 5, 25, 60, and 120 minutes after administration.

Results: Acute restraint stress and THC did not impact working memory. However, acute administration of 3mg/kg THC disrupted motivation-related engagement in the task in a subset of rats. These non-responders exhibited greater plasma THC and metabolite concentrations compared to rats who maintained baseline response rates after 3mg/kg THC administration.

Conclusions: Individual differences in the pharmacokinetic/metabolic profile of THC may be associated with differential sensitivity to cognitive/motivational effects of THC and highlight one potential mechanism for the diversity of reported adverse versus positive outcomes after THC exposure.