Weeding Through Marijuana’s Effects on the Brain

The changes in legislation surrounding cannabis use in the UnitedStates andworldwidehaveplaced researchers in a race against time to get ahead of potential pitfalls and quagmires that come with venturing into the unknown of whether cannabis affects thebrain. Statistics illustrating that 4.2 million (60.9%) of 6.9 million illicit drugusers in theUnited States with a substance use disorder have cannabis use disorder1 brings this problem to bear. In vivo human neuroimaging research has delivered indicators of divergent brain patterns associated with cannabis use.2 Along with the increasingnumberof findingsdemonstratingalteredbrainstructure and function associated with cannabis use is also the mounting need to determine whether these brain anomalies are the cause or the consequence of cannabis use. The implications of the answer to this important question are boundless. If we knew that these alterations precede the onset of cannabisuse,wecan identify individualswhowouldbeat risk for cannabisusedisorders and interveneearlyon.On theother hand, if observed alterations are a consequence of cannabis use, individuals (and clinicians) could make informed decisions surrounding cannabis use and its applicability.Of timely relevance, this knowledge could guide reasonable, justified, and relevant policies. A vital question surrounding the issue of cannabis use is whether cannabis “hijacks the brain.”According to the incentive sensitizationmodel proposedbyRobinsonandBerridge,3 drugs sensitize the dopaminergic reward circuitry that consequently disrupts natural reward processes. The outcomeof this disruption is a shift of the rewardpathway signaling from inherent natural rewards (eg, food and sex) to stimuli related to the drug.4,5 This mechanism may drive continued drug seeking,while givingupother stimuli previously enjoyed.On the other hand, it is also possible that heightened sensitivity to rewarding stimuli may be attributed to a generalized hyperarousal to all rewards—such is the basis of the rewarddeficiency syndrome.6 This idea suggests that alterations within the reward circuitry are such that only highly potent stimuli, such as drugs of abuse, are capable of normalizing dopamine in this circuitry.7 The study byMartz and colleagues8 in this issue of JAMA Psychiatry addressed this question by evaluating cannabis users’ brain response to a nondrug reward (ie, money) to determinegeneral reward function,2 takingadvantageofaunique longitudinal data set (ie, theMichigan Longitudinal Study) to prospectivelydeterminehowthebrain changes subsequent to cannabis use and focusing on the nucleus accumbens, a key region within the reward circuitry.8 The authors used functionalmagnetic resonance imagingwhilepresenting individuals with a widely used task to determine reward processing called the monetary incentive delay task. They collected this information on 108 young adults (39 female [36.1%]; 84 with a family history of substance use disorder [77.8%]) who underwent 3 functional magnetic resonance imaging scans at approximately 20 (time 1), 22 (time 2), and 24 (time 3) years of age. Focusing on the brain’s response during anticipation for potential monetary gains, cross-lagged analyses revealed that past-year cannabis use was associated with activation in the nucleus accumbens during anticipation for monetary reward. Of importance, the authors also ruled out potential influences of prior cannabis use on nucleus accumbens activation at time 1, thereby replicating existing cross-sectional studies. Because blunted response in the nucleus accumbens was only present with escalating cannabis use, one interpretation is that cannabis use triggered these changes. If so, these findings show support for the incentive sensitization model of addiction, which is concordant with studies that directly compare cannabis and nondrug rewards such as food9 and sex.10 That is, cannabis use disrupts natural reward processes resulting in hypersensitivity of the brain’s reward circuitry to cannabis over that of natural rewards. However, it remainsunclearwhether thesechangesare the cause or the consequence of cannabis use. While Martz and colleagues8 did not find that past use correlatedwith nucleus accumbens activation at time 1, age at onset of use showed a trend-level association, which propagates the widely accepted idea that early-onset cannabis use is associated with brain alterations. Thus, because someof the individuals from the studywere already using cannabis at time 1, there was no baseline (ie, precannabis use) comparison where one’s cannabis-naive brain response couldbe comparedwith their own cannabis-exposed brain response to determine the true effect. Nevertheless, the first prospective studyof the effects of cannabis—the Dunedin Study in New Zealand—reported an 8-point decrease in IQ in those who had persistent cannabis use from time 1 (13 years of age; IQ collected prior to initiation of cannabis use) through time 2 (38 years of age).11 Together, these 2 prospective studies suggest that changes in the brain areaconsequenceofcannabisuse.However, it shouldbenoted that there could have been variables not tested thatmayhave confounded these observed effects. Observational studies (vs manipulation studies) are limited in this regard. Wellcontrolled large-scale studies, such as the National Institutes of Health’s recently initiated Adolescent Brain Cognitive Development Study holds promise for being able to determine these questions with greater resolution. Related article page 838 Opinion