PROJECT SUMMARY/ABSTRACT In this proposal, we seek to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the main analgesic and psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), among older adults – the fastest growing population of cannabis consumers, and the most likely age cohort to use cannabinoids to relieve pain. Although THC has been widely studied for its antinociceptive potential, most studies were conducted among younger individuals; as a result, how THC affects pain in older adults remains to be investigated. First, due to a combination of age-related physiological changes, older adults may experience more frequent THC-induced adverse events. Still, there is a dearth of data on the PK effects of THC among older adults. Second, the PD effects of THC for outcomes that are especially important for older adults – such as analgesia and abuse liability – remain unknown. Data generated among younger individuals cannot be generalized to older adults, as accumulating studies indicate that aging produces functional neuroadaptations in pain and reward systems – likely influencing the analgesic efficacy and abuse liability of THC. Further, older adults may be more sensitive to the cardiovascular and cognitive/psychomotor effects of THC. These adverse events may be detrimental to their health, increasing the risk of falls and accidents. To close this critical knowledge gap, we have designed a human laboratory study to characterize the acute PK and PD effects of THC, administered through the oral and inhaled route, among older adults. We propose a double-blind, placebo-controlled, crossover study, randomizing 20 men and women aged 65 years or older, to two doses of oral THC (5 mg and 10 mg) and vaporized THC (2 mg and 4 mg). Consistent with NOT-DA-21-049, these doses translate to one or two standard units (SU) of oral THC, and 0.4 and 0.8 SU of vaporized THC. Across 6 test sessions, participants will receive a random sequence of 6 conditions: 5 mg oral THC; 10 mg oral THC; oral placebo; 2 mg vaporized THC; 4 mg vaporized THC; and vaporized placebo. Blood sampling will be collected from an intravenous line, at regular intervals, up to 8 hours post-dose, to assess the PK of THC and its phase I and II metabolites (Aim 1). The PD effects of THC on pain responses will be measured with Quantitative Sensory Testing (QST), a reliable computerized technique used to measure analgesic efficacy (Aim 2a). The abuse liability of THC will be measured using an established drug reinforcement paradigm (Aim 2b). General adverse, cardiovascular, and cognitive/psychomotor effects of THC will be assessed with behavioral, physiological, and neuropsychological methods. We will also assess sex differences in PK/PD outcomes (Exploratory Aims). Finally, a one-week washout will separate test sessions. This timely study will serve as a benchmark to assess cannabinoids as therapeutics to relieve pain in older adults. Results will ...