Few group differences in cortical thickness were observed; the majority of areas were no longer significant after controlling for lifetime alcohol use. Thicker medial temporal lobe estimates were found in the user group at baseline and follow-up when ICV and lifetime alcohol use were controlled for. We observed subtle decreasing thickness estimates from baseline to follow-up in seven regions, but no interactions were identified. We found quite divergent relationships between cumulative lifetime alcohol and marijuana use and cortical thickness in the user group. More reported marijuana use was related to thinner cortices in temporal and frontal regions, and more lifetime alcohol use was related to thicker cortices in all four lobes of the cortex bilaterally. Improvement in cognitive functioning over time in both the users and controls was observed, given the short retest interval and anticipated gains in performance. We did not see greater improvement in cognition in the user group following abstinence or, surprisingly, consistent group differences in cognition across the five domains as suggested in the literature and previous studies in our laboratory . MJ + ALC did not improve in their performance on the Complex Figure Copy sub-test; however, this pattern of performance was not found across the other tests. In general, thinner cortices were related to better global cognitive performance in the larger sample with the exception of the right entorhinal cortex and cognitive functioning in the user group at baseline, in which thicker cortices were associated with better attentional processing. Lopez-Larson and colleagues cross-sectionally examined cortical thickness in teens, ages 16–19 years, with heavy cannabis vertical farming use histories. They found decreased thickness in frontal regions and the insula, along with increased thickness in lingual, temporal, and parietal regions .
Our findings are similar given that we found increased thickness in temporal and posterior regions, such as the entorhinal cortex , and relationships showing thinner cortices associated with increased severity of use in frontal regions. The authors discuss multiple pathways for tissue disruption, including altered neurodevelopmental trajectories and/or tissue loss or remodeling. Similarly, Mata and colleagues found flattening and thinning of the sulciin frontal regions in adolescent marijuana users, suggesting chronic cannabinoid exposure may link to atypical trajectories of the gyral folding process. Marijuana may interfere with the cannabinoid system by altering patterning, plasticity, and connectivity during neurodevelopment, and trigger neurochemical and protein activity in response to neural injury . Macrostructural findings typically focus on structures with a high density of cannabinoid type 1 receptors , and findings show larger structural volume in areas such as the anterior cerebellum and amygdala , whereas others show decreased gray matter volume and density . Cousijn and colleagues found that amygdala and hippo campal volume negatively correlated with weekly cannabis use, as more use was related to smaller limbic structures. In our study, cortical thickness differences persisted after controlling for alcohol in the entorhinal cortex. Given the high concentration of CB1 receptors in temporal lobe structures , marijuana use may be particularly influencing developmental events in this anatomical region. Positive associations between thickness in the entorhinal cortex and cognitive functioning is in contrast to the finding that thinner cortices are related to better global cognitive performance in the larger sample.
However, greater reported marijuana use and earlier age of initiation were also associated with thinner cortices in frontal and temporal brain regions. We suggest that endocannabinoid system alterations or marijuana-related toxicity may trigger developmental consequences such as premature cortical thinning and subsequent declines in cognitive functioning. It is unclear why associations between age of initiation and thickness estimates were observed at follow-up only. Subtle neural architectural changes may be occurring over the abstinence period, and the acute impact on neural development may not be fully captured at baseline for this predictor. Neural recovery is likely to extend past 28 days and well into the year following cessation of use, as residual effects of marijuana use have been reported in cognitive and neuroimaging markers from days to months following cessation of use . Pre-existing structural differences are also likely to contribute, as smaller orbitofrontal cortex volume predicted initiation of cannabis use by age 16 . The positive dose-dependent relationships with lifetime alcohol use are particularly notable given the sub-clinical heavy episodic drinking patterns reported by the sample. Thickness estimates in these regions were related to number of heavy drinking episodes reported, which is particularly concerning given the consistently high rates of heavy episodic drinking reported by adolescents in the United States . The cerebral cortex is highly vulnerable to the effects of alcohol . Squeglia and colleagues found that female heavy episodic drinkers had thicker cortices in frontal brain regions compared to female controls, and thicker cortices were associated with worse cognitive functioning for both males and females. However, thinner cortices were identified for male heavy episodic drinkers compared to controls , similar to recent prospective findings showing decreased thickness estimates in adolescents who transitioned into sub-clinical heavy episodic drinking .
Our findings suggest widespread increases in cortical thickness with increased lifetime alcohol use and heaving drinking episodes. The present study, combined with Squeglia et al. , suggests that more often thicker cortices are associated with worse neurobehavioral performance. Despite the quantity of reported alcohol use in our users being more modest compared to that of treatment seeking individuals, differences in these studies of adolescents reporting similar alcohol use patterns may be attributed to methodological design or an interaction between co-occurring alcohol and marijuana use. Neuroprotective properties of marijuana may modulate neurotransmission and mitigate ethanol-induced neural injury; however, marijuana may trigger neurotoxic chemical cascades leading to changes in endocannabinoid signaling, altered developmental trajectories, increased alcohol administration, and worse psychosocial outcomes in the developing brain . Although initial cross-sectional studies in our laboratory suggested evidence for white matter neuroprotection in those using cannabis drying rack and alcohol , poorer outcomes for co-occurring use from adolescence to young adulthood were found after a 3-year follow-up . The mechanism of alcohol-related toxicity on the cerebral cortex remains unclear. Alcohol may interfere with temporal sequences of neurodevelopment , myelination, and/or generation and survival of cortical cells ; overall, the unanticipated associations with alcohol found in this study underscore the deleterious impact adolescent alcohol use likely has on neurodevelopment when used independently or concomitantly with marijuana. Our sample was predominantly male . Therefore, it is unlikely that excluding our female participants would have changed the observed relationships. However, gender may moderate these findings . Studies have found gender to play a significant role in gray and white matter neural architecture and neurocognition in both healthy adolescents/ young adults and those engaging in substance use . We suspect that findings represent a “longer-term” impact of marijuana and alcohol use, given the monitored abstinence period. The majority of findings present at baseline were present at follow-up, but this was not the case for all regions . The prospect of neural recovery after cessation of use is understudied in the adolescent literature, although there is some suggestion that brain structural changes can occur within the initial 24 months of abstinence from alcohol in an adult sample of former heavy alcohol users reporting 1 month to 26 years of abstinence . Our preliminary findings need to be replicated and expanded upon. Longer follow-up periods are necessary to understand changes in marijuana use trajectories over time and differences in residual versus acute effects. Given the preliminary and exploratory nature of this work, large number of analyses conducted, and modest effect sizes, replication of findings is crucial. Subtle alterations in neurodevelopmental trajectories may have long-term consequences for cognition and daily functioning. To identify how alcohol and marijuana use leads to brain changes, disentangling pre-existing, substance-related, and acute versus residual effects is important. The present findings raise concern for adolescent alcohol and marijuana users and provide more evidence for a longer-term effect on neural tissue development. Our future work will integrate longer follow-up periods with pre- and post-initiation data to understand how such commonly used substances affect the developing brain.Young adulthood is a critical developmental period that commonly includes multiple important life changes . This period is also marked by increased access and susceptibility to risky behaviors, including tobacco and other drug use.
Recent national data on 18-24 year old young adults indicate past-month prevalence of 22-25% for marijuana and 29.1% for cigarettes . In both cases rates were higher than those of older adults. While increasing use of marijuana and tobacco each raise public health concerns, recent escalation of concurrent use of both is evident in the literature. This trend has ignited interest in exploring whether marijuana use may potentiate exposure to tobacco-related harms. Recent analyses of national data suggest rates of co-use of tobacco and marijuana increased by 18.2% from 2003 to 2012, and 40.6 % of adults aged 18-25 reported past-month use of both products in 2012 . Our own analyses of Population Assessment of Tobacco and Health data suggest users of combustible tobacco products, e-cigarettes, and multiple tobacco products were 4-8 times more likely to report current marijuana use, and concurrent users of tobacco and marijuana were less likely to attempt tobacco cessation . National data indicate that co-use is particularly common among daily marijuana users and non-daily tobacco smokers . Experimentation with marijuana among tobacco smokers and experimentation with tobacco among marijuana users may in part be facilitated by product modifications that allow for consumption of both products simultaneously . Relatedly, advertisements for tobacco products may be designed to indicate that the products can be used to consume marijuana . Some initial findings suggest using tobacco products to deliver marijuana may both increase and normalize young adults’ use of tobacco products . Use of both products may potentiate smoking-related disease by not only increasing exposures to two sources of harmful constituents but by potentiating persistent use. Frequency of marijuana use has been linked consistently to greater nicotine dependence and more persistent tobacco use . Users of both products perceive marijuana as safer , report low interest in quitting both marijuana and tobacco , and are less likely to successfully quit using tobacco . Thus, young adults who use both products may be disproportionately vulnerable to doing so chronically. Evidence for overlapping negative health consequences of tobacco and marijuana smoking suggest high priority for understanding and preventing use in young adulthood. The context of both tobacco and marijuana use have changed dramatically in the past decade as a result of increasing availability, perceived safety and acceptability of non-cigarette tobacco products, and growing legalized access to marijuana . While a number of studies have demonstrated cross-sectional links between use of both products, less is known about the interplay between use of both over time among young adults. This potential bidirectional relationship may be especially important in the context of non-daily tobacco smoking. Pooled data from multiple national surveys show that adults aged 18-24 are more likely to be non-daily smokers than older adults . Further, preliminary evidence suggests a link between non-daily cigarette smoking and recent increases in daily cannabis use from 2.8% to 8.0% between 2002-2014 . However, the extent to which trajectories of marijuana and tobacco use may interact is unknown, and examination of young adult non-daily cigarette smokers provides an opportunity to identify risk factors for tobacco progression. Thus, the first goal of this study was to test the hypothesis that, among 18-24 year old non-daily cigarette smokers, greater frequency of marijuana use over two years would be positively associated with cigarette quantity and frequency, frequency of non-cigarette tobacco product use, and likelihood of poly tobacco use over time. Second, we tested for the existence of a bidirectional relationship, hypothesizing that more frequent use of tobacco would predict heavier marijuana use. Participants were recruited primarily via paid Facebook posts that were targeted by age and location. Clicking on these posts led to the study website, where eligibility was determined. Interested and eligible individuals provided informed consent and completed the baseline assessment on the website. They completed additional quarterly electronic assessments 3, 6, 9, 12, 15, 18, 21 and 24 months later via SurveyMonkey . At the baseline, 12, and 24 month time points, assessments consisted of a single survey that was typically completed in 15-20 minutes and for which participants received $25 compensation. At the 3, 6, 9, 15, 18, and 21 month time points, participants completed brief daily assessments for 9 consecutive days, and were compensated with $4 per day completed plus an additional $4 if all 9 days were completed . Because evidence suggests young adults smoke more cigarettes on weekend days , each 9-day period began on a Friday to standardize the number of weekend days included.