The majority of the >1.2 million registered medical cannabis patients in the U.S. cite pain relief as their primary reason for using cannabis products. Although cannabis and its constituents (cannabinoids) have potential for the treatment of chronic pain, there are critical gaps in our knowledge regarding the effects of repeated cannabis administration on pain, abuse liability and circulating endogenous cannabinoid (eCBs) levels. The endocannabinoid system plays a critical role in CNS function, yet the impact of cannabis use on circulating eCBs is poorly understood. There is also little known about the effects of cannabis with varying concentrations of oral D9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most commonly used cannabinoids by medical cannabis patients. This project is designed to answer three questions that will fill important voids in our understanding of sustained cannabis use: 1) does tolerance develop to the analgesic and abuse-related effects of repeatedly administered cannabis with varying ratios of THC and CBD, and is this tolerance reversible following a period of abstinence; 2) is abrupt cessation of cannabis with varying ratios of THC and CBD associated with withdrawal-induced hyperalgesia; 3) how does repeatedly administered cannabis with varying ratios of THC and CBD modulate levels of circulating eCBs, and are these changes associated with altered pain sensitivity and abuse liability? Prior to inpatient testing of cannabis administration, we will use contingency management procedures to engender sustained abstinence in healthy cannabis users in order to minimize existing tolerance. We will then enroll participants (N=100) inpatient for 15 days. They will be randomized to one of four cannabis conditions (n=25/group): 1) high THC:low CBD, 2) low THC:low CBD, 3) high THC:high CBD, 4) low THC:high CBD). Cannabis will be administered repeatedly for the first 7 inpatient days, followed by a 7-day abstinence period. The last study day (day 15) will re-introduce the assigned active cannabis dose to assess reversal of tolerance. At set time points within each condition, we will measure abuse-related effects (“Good Drug Effect”), plasma eCB levels and two distinct types of experimental pain: The Cold Pressor Test and Quantitative Sensory Testing Thermal Temporal Summation. Given the widespread use of cannabis for pain, understanding the consequences of daily repeated administration of cannabis with THC:CBD ratios that are representative of most medical cannabis products on pain, abuse liability, and eCBs is imperative. Tolerance to the abuse-related but not analgesic effects would be salutary, but the converse could contribute to the higher incidence of cannabis use disorder observed in medical cannabis patients. Similarly, if abrupt cannabis cessation exacerbates pain, medical cannabis patients will have difficulty ceasing cannabis use. Demonstrating a relationship between circulating eCBs and pain sensitivity can be...