Marijuana, or Cannabis sativa, is the most commonly used illicit drug worldwide, and rates of its abuse have increased during the past twenty-five years. In fact, in the United States, individuals with disorders related to cannabis exposure are two times higher than for any other illicit drug. Increased levels of use primarily occur during adolescence and young adulthood, which is of concern from a public health perspective since these are also critical periods of neural development. This fear is further underscored by the fact that cannabis may act as a gateway drug, since its use may predispose individuals to abuse other illicit drugs. In addition, the potency of cannabis (concentration of delta-9-tetrahydrocannabinol (? 9-THC)), is now exceeding 10% in the U.S. (compared to 4% in 1983), which could have unforeseen consequences for normal brain function. Given the vast number of individuals who consume cannabis on a regular basis, a thorough understanding of its long-term effects on neural function is vitally important. Cannabis and associated phytocannabinoids exert their effects through the activation of central cannabinoid receptors (CB1R). It is now well-established that repeated exposure to cannabis results in the development of tolerance, dependence, and a withdrawal syndrome upon cessation of use. Long-term cannabinoid exposure also induces a decrease in the number of CB1Rs. However, the functional implications of these changes remain unclear. The resting-state default mode network and "task-positive" control network may be dependent on an intact endocannabinoid system, which could be compromised by heavy cannabis use. Therefore, the purpose the proposed study is to examine the effects of chronic cannabis use, acute withdrawal, and sustained abstinence on default mode and control brain networks. Functional magnetic resonance imaging (fMRI) will be used to evaluate the default mode network and control network in cannabis-dependent individuals at baseline (smoking as usual), following brief (48 hour) confirmed abstinence (when cannabis withdrawal is most likely to occur), and after prolonged (4 weeks) confirmed abstinence. A sample of healthy control individuals will also be assessed. It is anticipated that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on brain function, and will shed new light on the status and function of neural networks during active cannabis use, withdrawal, and prolonged abstinence.
The public health relevance of this proposal can be summarized as follows: Cannabis exposure produces neural changes in the endogenous cannabinoid system, and the effect of such changes on information processing within the brain is unclear. This grant application proposes to use neuroimaging to study the changes in brain networks as a result of heavy cannabis use, 2 days after stopping cannabis use and again after 4 weeks of abstinence from cannabis.