Marijuana is the most commonly used illicit drug in the United States, and prevalence rates have increased over the past several years after a period of relative stability. Currently there is no approved medication to treat cannabis use disorder, and relapse rates following behavioral interventions remain unacceptably high. There is an urgent need for pharmacological and psychosocial interventions, but optimal treatment approaches cannot be developed or implemented without understanding mechanisms that underlie and maintain marijuana use. Exposures to drug-related stimuli and stress have been found to increase craving (humans) and drug-maintained responding (mostly in laboratory animals). Given that continued use and relapse likely result from multiple factors, exposure to drug-related cues during periods of stress may increase the likelihood and intensity of drug seeking behavior. Few clinical studies have focused on the interaction of stress and cues on craving and drug-seeking; thus our understanding of the separate and combined effects of stress and cue exposure on drug seeking is currently limited. In a double-blind, placebo controlled cross-over study, 14 males and females with mild-to-moderate cannabis use disorder will receive the pharmacologic stressor, yohimbine (0, 20, and 40 mg), prior to marijuana and neutral cue exposure. Our primary outcome measure is marijuana-seeking behavior assessed using a progressive ratio marijuana choice task. Participants will be given 11 choice opportunities on the choice task to work for either puffs from a marijuana cigarette (6.0% THC; max 11 puffs) or money alternative (max $22).
Specific aims are to determine whether: (1) presentation of polysensory marijuana cues increases marijuana craving and choice to self-administer marijuana; (2) placebo-controlled administration of a pharmacological stressor (yohimbine: 0-mg, 20-mg, and 40-mg, PO) alters marijuana craving and choice to self-administer marijuana; (3) marijuana-related cues and yohimbine have additive effects on marijuana craving and choice to self-administer marijuana; and, (4) craving elicited by marijuana-related cues, yohimbine, or both in combination mediates (within subject) marijuana puff-maintained responding. Our overarching hypothesis is that a sustained pharmacological stressor will potentiate cue-induced marijuana craving and seeking. The objective is to understand cue- and stress-induced cannabis abuse to effectively target these risk factors for intervention. To the best of our knowledge, this is the first study to investigate subjective, physiologic, and endocrine responses to a pharmacologic stressor combined with drug-related cues in chronic cannabis users, and to investigate their additive effects on marijuana craving and seeking. Results from this project will advance our understanding of mechanisms that underlie drug seeking behavior and relapse, as well as provide a test for compounds that reduce stress or craving and thus may prove beneficial for treatment of cannabis and other drug use disorders.
Exposure to marijuana-related cues and stress is associated with marijuana use, craving, and relapse to use. The proposed innovative project study would be the first to directly link exposure to marijuana cues to marijuana-seeking, and to demonstrate, in human subjects, that a well-defined stressor increases marijuana-seeking behavior. Results will significantly improve scientific understanding of the mechanisms that underlie the development of cannabis use disorder and will provide a method for testing compounds that can reduce stress or craving and thus may prove beneficial for treatment of cannabis and other drug use disorders.
