The overarching aim of this proposal is to combine a naturalistic cannabis administration paradigm with a placebo-controlled, dose-ranging randomized controlled trial of plant-derived cannabidiol (CBD) to evaluate CBD effects on cannabis concentrate use, subjective effects, and cannabis cue reactivity. To achieve this aim, 120 adult frequent concentrate users will be recruited to complete a four-week protocol during which they will complete three sessions in a mobile pharmacology laboratory. Up to 200 participants may be consented/enrolled to account for screen failures and attrition. In two of the sessions, participants will use their typical cannabis concentrate on an ad libitum basis. Amount of delta-9-tetrahydrocannabinol (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 complete a second mobile lab session after two weeks to provide a blood sample that will be analyzed for cannabinoid levels. 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, during which blood draws and THC self-administration will be repeated.
There are three aims:
Aim 1. Test the effect of CBD, relative to placebo and to baseline, on cannabis use over four weeks and THC self-administration in the mobile laboratory.
Hypothesis 1a. Both doses of CBD, relative to placebo, will reduce THC metabolite levels at weeks 2 and 4.
Hypothesis 1b. Both doses of CBD, relative to placebo and to baseline, will reduce the amount of THC that participants choose to consume in the mobile laboratory, as assessed by pre- vs. post-use THC blood levels.
Aim 2. Test the effect of CBD, relative to placebo and to baseline, on subjective drug effects (intoxication, psychotomimetic symptoms, anxiety, and negative affect) following acute cannabis concentrate use.
Hypothesis 2. Both doses of CBD, relative to placebo and to baseline, will reduce intoxication, paranoia, anxiety, and negative affect following acute use, even after controlling for between-group differences in amount of concentrate used.
Aim 3. Test the effect of CBD, relative to placebo, on cannabis cue-elicited craving and evaluate whether this effect mediates CBD effects on cannabis use.
Hypothesis 3a. Both doses of CBD, relative to placebo, will reduce cannabis craving.
Hypothesis 3b. CBD's effect on craving at week 2 will mediate its effect on THC metabolite levels at week 4.
For all aims, a linear effect of CBD dose is hypothesized, with the greatest effects in the 400 mg CBD group. Successful achievement of these aims will allow determination of an efficacious dose of CBD that reduces high-THC cannabis use, subjective drug effects, and craving, setting the stage for a subsequent RCT of plant-derived CBD to treat these outcomes in treatment-seeking high-THC cannabis concentrate users.
