Age-and sex-dependent pharmacodynamics and pharmacokinetics of oral and smoked delta-9-THC

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Project Summary: With rapid changes in cannabis regulation (i.e., legalization) and expanded availability across the United States (US), rates of cannabis use and Cannabis Use Disorder (CUD) have increased among populations vulnerable to the negative effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. These populations include emerging adults (18-25 years of age), older adults (≥ 55 years of age), and females. Prevalence of cannabis use is highest among emerging adults; this is of particular concern given the known risks of THC exposure during this period of late-adolescent neurodevelopment and brain maturation. While rates of use among females used to be half that of males, the gap between sexes is closing with 5.6% of female emerging adults reporting near daily use. Sensitivity to THC’s effects in females is also hypothesized to lead to negative outcomes including the accelerated progression to CUD. The most remarkable increase in cannabis use is among older adults. Prevalence of past month use among adults ages 55-64 years more than doubled between 2013 to 2019, with over 25% of older adults reporting use 1-4 times per week. Because of physiological and neurobiological changes that occur during aging, older adults may be particularly vulnerable to the negative effects of THC. Despite the increase in cannabis use among these groups, no studies to date have prospectively probed the adverse effects of acute THC exposure across adulthood. Another trend impacting the vulnerability of older adults and females to adverse effects of cannabis is the high rate of medical cannabis use in these populations with pain cited as the predominant symptom for use. This trend further establishes the urgent need to assess THC analgesia alongside adverse effects that increase risk including abuse liability, intoxication, and impairment. To understand cannabis’s acute effects that indicate increased risk of exposure among these vulnerable populations, the proposed study will compare the dose-dependent effects of smoked and oral THC, two popular routes of administration, on endpoints directly related to adverse consequences of use including abuse liability, intoxication, and impairment as a function of age and sex. Specifically, healthy male and female emerging adults (18-25 years; N=30, 15M, 15F), middle-aged adults (35-45 years; N=30, 15M, 15F) and late middle-aged adults (55-65 years; N=30, 15M, 15F) who occasionally use cannabis will be recruited for this double-blind, double-dummy, placebo-controlled study. Using a within-subjects design, all participants will be administered placebo (0mg THC), 2, 5mg unit-doses of THC (10mg), and 4, 5mg unit-doses of THC (20mg) via smoked cannabis and by oral administration. Adverse effects, analgesia, and THC pharmacokinetics will be assessed several times after smoked and oral THC administration. Findings from this study will be instrumental in establishing age and sex as biological variables in the prevention, intervention, and treatment of negative sequelae associated with cannabis use.