PROJECT SUMMARY/ABSTRACT PROJECT 2: ADULT STUDY As cannabis legalization continues to spread across the United States, average Δ9-tetrahydrocannabinol (THC) concentrations in recreational products have significantly increased, with levels as high as 90-95% in concentrated preparations. Our preliminary data suggest that concentrate use elicits blood THC levels more than twice as high as cannabis flower use, and that concentrate use is associated with greater tolerance and loss of control over cannabis use, prompting concern about the risks of these products. Several previous studies have found that the non-intoxicating cannabinoid cannabidiol (CBD), which may antagonize the effects of THC on CB1 and CB2 receptors, reduces cannabis use, subjective response to THC, and craving. Pilot data from our lab also suggest that CBD reduces THC effects, drug reward, anxiety, and overall THC use, suggesting that CBD may mitigate the harms of high-THC products. However, the therapeutic dose of CBD necessary to achieve these effects is unknown. The overarching aim of this proposal is to combine our naturalistic cannabis administration paradigm with a placebo-controlled, dose-ranging RCT of plant-derived CBD to evaluate CBD effects on cannabis concentrate use, subjective effects, and cannabis cue reactivity. We will recruit 120 frequent concentrate users to complete a four-week protocol during which they will complete two sessions in our mobile pharmacology lab. In each session, participants will use their typical cannabis concentrate on an ad libitum basis. Amount of THC self-administration during these sessions will be quantified by THC blood levels, obtained in the mobile lab immediately before and after use. Subjective drug effects and exogenous and endogenous cannabinoid biomarkers will also be quantified before and after THC use. Immediately after the first mobile lab session, participants will be randomly assigned to take either 200 mg or 400 mg of plant-derived, broad spectrum CBD or matched placebo (40 participants per group) daily for four weeks. Participants will return after two weeks to provide a blood sample that will be analyzed for the THC metabolite 11-nor-9-carboxy-Δ9-THC (THC-COOH) to detect recent cannabis use and for CBD levels to detect medication adherence. At this session, participants will also complete a cannabis cue reactivity paradigm. Participants will complete a second mobile lab session after four weeks of study medication ingestion.