The Combined Effects of Nicotine and Cannabis on Cortical Thickness Estimates in Adolescents and Emerging Adults.

Early life substance use, including cannabis and nicotine, may result in deleterious effects on the maturation of brain tissue and gray matter cortical development. The current study employed linear regression models to investigate the main and interactive effects of past-year nicotine and cannabis use on gray matter cortical thickness estimates in 11 bilateral independent frontal cortical regions in 223 16-22-year-olds. As the frontal cortex develops throughout late adolescence and young adulthood, this period becomes crucial for studying the impact of substance use on brain structure. The distinct effects of nicotine and cannabis use status on cortical thickness were found bilaterally, as cannabis and nicotine users both had thinner cortices than non-users. Interactions between nicotine and cannabis were also observed, in which cannabis use was associated with thicker cortices for those with a history of nicotine and tobacco product (NTP) use in three left frontal regions. This study sheds light on the intricate relationship between substance use and brain structure, suggesting a potential modulation of cannabis' impact on cortical thickness by nicotine exposure, and emphasizing the need for further longitudinal research to characterize these interactions and their implications for brain health and development.

Neurite Orientation Dispersion and Density Imaging (NODDI) of Brain Microstructure in Adolescent Cannabis and Nicotine Use.

INTRODUCTION: Despite evidence suggesting deleterious effects of cannabis and nicotine tobacco product (NTP) use on white matter integrity, there have been limited studies examining white matter integrity among users of both cannabis and nicotine. Further, updated white matter methodology provides opportunities to investigate use patterns on neurite orientation dispersion and density (NODDI) indices and subtle tissue changes related to the intra- and extra-neurite compartment. We aimed to investigate how cannabis and NTP use among adolescents and young adults interacts to impact the white matter integrity microstructure. MATERIALS AND METHODS: A total of 221 participants between the ages of 16 and 22 completed the Customary Drinking and Drug Use Record (CDDR) to measure substance use, and underwent a magnetic resonance imaging (MRI) session. Participants were divided into NTP-control and NTP groupings and cannabis-control and cannabis groupings (≥26 NTP/cannabis uses in past 6 months). Tract-Based Spatial Statistics (TBSS) and two-way between-subjects ANOVA investigated the effects of NTP use group, cannabis use group, and their interaction on fractional anisotropy (FA) and NODDI indices while controlling for age and biological sex. RESULTS: NTP use was associated with decreased FA values and increased orientation dispersion in the left anterior capsule. There were no significant effects of cannabis use or the interaction of NTP and cannabis use on white matter outcomes. DISCUSSION: NTP use was associated with altered white matter integrity in an adolescent and young adult sample. Findings suggest that NTP-associated alterations may be linked to altered fiber tract geometry and dispersed neurite structures versus myelination, as well as differential effects of NTP and cannabis use on white matter structure. Future work is needed to investigate how altered white matter is related to downstream behavioral effects from NTP use.

First Used Nicotine/Cannabis Product and Associated Outcomes in Late Adolescents.

BACKGROUND: Nicotine and tobacco product (NTP) and cannabis use are common in adolescence/young adulthood and increase risk for negative psychosocial outcomes. This study investigated associations among adolescent/young adults' initial experiences with NTPs, lifetime frequency of substance use, substance-related problems, and mental health symptoms. METHOD: Adolescents and young adults enrolled in a study on NTP and cannabis use were asked at what age they initiated the use of NTPs and were assigned to groups based on which product or substance(s) they reported using at the earliest age. Participants who reported use of NTPs (in isolation, without cannabis) first (N = 78, "NTP-only"), simultaneous use of NTPs and cannabis first (e.g., blunt or bowl; N = 25, "Simult-only"), use of both NTPs in isolation and simultaneous use at the same age (N = 48, "NTP + Simult"), and no NTP use (N = 53, "NTP-naïve") were compared on substance use, substance-related problems, and mental health symptoms. RESULTS: Groups differed on lifetime frequency of NTP, simultaneous, and cannabis use, with NTP users reporting more substance use episodes and substance-related problems than the NTP-naïve group. The lifetime frequency of cannabis use did not differ across NTP use groups. NTP use was associated with increased anxiety and depression, with no significant differences between groups. CONCLUSIONS: Adolescents and young adults who use nicotine may be at increased risk for greater nicotine use and mental health consequences, but initiating NTP use simultaneously with cannabis may not increase the risk of negative outcomes above and beyond nicotine initiation. Prospective longitudinal research is needed to establish temporal associations between first-used NTP/cannabis products and relevant outcomes.

The effects of nicotine use during adolescence and young adulthood on gray matter cerebral blood flow estimates.

Nicotine and tobacco product (NTP) use remains prevalent in adolescence/young adulthood. The effects of NTPs on markers of brain health during this vulnerable neurodevelopmental period remain largely unknown. This report investigates associations between NTP use and gray matter cerebral blood flow (CBF) in adolescents/young adults. Adolescent/young adult (16-22 years-old) nicotine users (NTP; N = 99; 40 women) and non-users (non-NTP; N = 95; 56 women) underwent neuroimaging sessions including anatomical and optimized pseudo-continuous arterial spin labeling scans. Groups were compared on whole-brain gray matter CBF estimates and their relation to age and sex at birth. Follow-up analyses assessed correlations between identified CBF clusters and NTP recency and dependence measures. Controlling for age and sex, the NTP vs. non-NTP contrast revealed a single cluster that survived thresholding which included portions of bilateral precuneus (voxel-wise alpha < 0.001, cluster-wise alpha < 0.05; ≥7 contiguous voxels). An interaction between NTP group contrast and age was observed in two clusters including regions of the left posterior cingulate (PCC)/lingual gyrus and right anterior cingulate cortex (ACC): non-NTP exhibited positive correlations between CBF and age in these clusters, whereas NTP exhibited negative correlations between CBF and age. Lower CBF from these three clusters correlated with urine cotinine (rs=-0.21 - - 0.16; ps < 0.04) and nicotine dependence severity (rs=-0.16 - - 0.13; ps < 0.07). This is the first investigation of gray matter CBF in adolescent/young adult users of NTPs. The results are consistent with literature on adults showing age- and nicotine-related declines in CBF and identify the precuneus/PCC and ACC as potential key regions subserving the development of nicotine dependence.

Young Adult E-Cigarette and Combustible Tobacco Users Attitudes, Substance Use Behaviors, Mental Health, and Neurocognitive Performance.

Nicotine and tobacco product (NTP) use has escalated, largely due to the advent of e-cigarettes. The NTP administration method (i.e., combustible cigarette, e-cigarette) may be an important differentiator. We assessed young adult substance use history, nicotine attitudes, mental health, and neurocognition by the NTP use method. Emerging adults (16-22 year olds) were divided into combustible NTP users (Combustible+ = 79, had used any combustible NTP in the last 6 months), non-combustible users (E-Cig = 43, had used non-combustible NTP, in the past 6 months), and NTP Naïve (n = 79; had not used NTP in the past 6 months) based on past 6-month NTP use patterns. Participants completed self-report and objective neurocognition measures. Analysis of covariance assessed mental health and neurocognition by group, controlling for confounds and correcting for multiple comparisons. Nicotine groups reported more favorable attitudes toward combustible cigarette and e-cigarette use, with taste as the primary reason for e-cigarette use. Combustible+ reported more nicotine dependence and craving. Substance use differed by group, with Combustible+ using the most NTP, alcohol, and cannabis. Nicotine groups reported higher depression and stress symptoms; male Combustible+ reported higher depression symptoms than other same-gender groups. Groups did not differ on neurocognition, though cannabis use was associated with inaccurate emotional Stroop responses. Overall, research suggests that young adult combustible users are likely qualitatively different from non-combustible users. Understanding the unique characteristics related to NTP product use will help guide intervention and prevention development.

The Effects of Nicotine and Cannabis Co-Use During Late Adolescence on White Matter Fiber Tract Microstructure.

OBJECTIVE: Co-use of cannabis and nicotine and tobacco products (NTPs) in adolescence/young adulthood is common and associated with worse outcomes than the use of either substance in isolation. Despite this, little is known about the unique contributions of co-use to neurostructural microstructure during this neurodevelopmentally important period. This study sought to investigate the interactive effects of nicotine and cannabis co-use on white matter fiber tract microstructure in emerging adulthood. METHOD: A total of 111 late adolescent (16-22 years old) nicotine (NTP; n = 55, all past-year cannabis users) and non-nicotine users (non-NTP; n = 56, 61% reporting cannabis use in the past year) completed demographic and clinical interviews and a neuroimaging session comprising anatomical and diffusion-weighted imaging scans. Group connectometry analysis identified white matter tracts significantly associated with the interaction between nicotine group and past-year cannabis use according to generalized fractional anisotropy (GFA). RESULTS: Nicotine Group × Cannabis Use interactions were observed in the right and left cingulum and left fornix tracts (false discovery rate = 0.053), where greater cannabis use was associated with increased GFA in the cingulum and left fornix, but only when co-used with nicotine. CONCLUSIONS: This report represents the first group connectometry analysis in late adolescent/young adult cannabis and/or NTP users. Results suggest that co-use of cannabis and NTPs results in a structurally distinct white matter phenotype as compared with cannabis use only, although to what extent this may change over time with more chronic nicotine and cannabis use remains to be examined in future work.

Preliminary Evidence for Cannabis and Nicotine Urinary Metabolites as Predictors of Verbal Memory Performance and Learning Among Young Adults.

OBJECTIVE: Verbal memory deficits are linked to cannabis use. However, self-reported episodic use does not allow for assessment of variance from other factors (e.g., cannabis potency, route of consumption) that are important for assessing brain-behavior relationships. Further, co-occurring nicotine use may moderate the influence of cannabis on cognition. Here we utilized objective urinary measurements to assess the relationship between metabolites of cannabis, 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH), and nicotine (cotinine) on verbal memory in young adults. METHOD: Adolescents and young adults (n = 103) aged 16-22 completed urinary drug testing and verbal memory assessment (RAVLT). Linear regressions examined the influence of THCCOOH and cotinine quantitative concentrations, and their interaction, on RAVLT scores, controlling for demographics and alcohol. Cannabis intake frequency was also investigated. Secondary analyses examined whether past month or recency of use related to performance, while controlling for THCCOOH and cotinine concentrations. RESULTS: THCCOOH concentration related to both poorer total learning and long delay recall. Cotinine concentration related to poorer short delay recall. Higher frequency cannabis use status was associated with poorer initial learning and poorer short delay. When comparing to self-report, THCCOOH and cotinine concentrations were negatively related to learning and memory performance, while self-report was not. CONCLUSIONS: Results confirm the negative relationship between verbal memory and cannabis use, extending findings with objective urinary THCCOOH, and cotinine concentration measurements. No moderating relationship with nicotine was found, though cotinine concentration independently associated with negative short delay performance. Findings support the use of both urinary and self-report metrics as complementary methods in substance use research.

The Influence of Cannabis and Nicotine Co-use on Neuromaturation: A Systematic Review of Adolescent and Young Adult Studies.

Accumulating evidence suggests that the use of cannabis and nicotine and tobacco-related products (NTPs) during the adolescent years has harmful effects on the developing brain. Yet, few studies have focused on the developing brain as it relates to the co-administration of cannabis and NTPs, despite the high prevalence rates of co-use in adolescence. This review aims to synthesize the existing literature on neurocognitive, structural neuroimaging, and functional neuroimaging outcomes associated with cannabis and NTP co-use. A systematic search of peer-reviewed articles resulted in a pool of 1107 articles. Inclusion criteria were 1) data-based study; 2) age range of 13 to 35 years or, for preclinical studies, nonadult subjects; 3) cannabis and NTP group jointly considered; and 4) neurocognitive, structural neuroimaging, or functional neuroimaging as an outcome measure. Twelve studies met inclusion criteria. Consistent with the literature, cannabis and nicotine were found to have independent effects on cognition. The available research on the co-use of cannabis and NTPs demonstrates a potential nicotine-related masking effect on cognitive deficits associated with cannabis use, yet there is little research on co-use and associations with neuroimaging indices. In neuroimaging studies, there is preliminary evidence for hippocampal volume differences in co-users and a lack of evidence for co-use differences related to nucleus accumbens activity during reward processing. Notably, no structural neuroimaging studies were found to examine the combined effects of nicotine and cannabis in adolescent-only populations. Further research, including longitudinal studies, is warranted to investigate the influence of cannabis and NTP co-use on maturation.

The effects of nicotine and cannabis co-use during adolescence and young adulthood on white matter cerebral blood flow estimates.

RATIONALE: Co-use of cannabis and nicotine is common among adolescents/young adults and is associated with poorer psychological and physical outcomes, compared with single substance use. Little is known about the impact of co-use on the developing brain. OBJECTIVES: Preliminary investigation of the effects of nicotine on white matter (WM) cerebral blood flow (CBF) in adolescents/young adults and its potential moderation by cannabis use. METHODS: Adolescent/young adult (16-22 years old) nicotine and tobacco product users (NTP; N = 37) and non-nicotine users (non-NTP; N = 26) underwent a neuroimaging session comprised of anatomical, optimized pseudo-continuous arterial spin labeling, and diffusion tensor imaging scans. Groups were compared on whole-brain WM CBF estimates and their relation to past-year cannabis use. Follow-up analyses assessed correlations between identified CBF clusters and corresponding fractional anisotropy (FA) values. RESULTS: Group by cannabis effects were observed in five clusters (voxel-wise alpha < 0.001, cluster-wise alpha < 0.05; ≥ 11 contiguous voxels): non-NTP exhibited positive correlations between CBF and cannabis use in all clusters, whereas no significant relationships were observed for NTP. Greater CBF extracted from one cluster (including portions of right superior longitudinal fasciculus) was associated with reduced FA for non-NTP group only. CONCLUSIONS: This is the first investigation of WM health as indexed by CBF, and its association with FA, in adolescents/young adults with nicotine and/or cannabis use. Results suggest that cannabis use by itself may be related to increased CBF in WM fiber tracts demonstrating poorer structural intergrity, yet the occurrence of even infrequent NTP use (greater than once per month) appears to diminish this relationship.

Cannabis and the developing brain: What does the evidence say?

Cannabis use during adolescence has been linked to deleterious effects on brain integrity. This article summarizes findings from two prospective investigations (3 and 6 years, on average) on adolescent cannabis use from our laboratory that utilize structural neuroimaging and neurocognitive assessment approaches. Across most studies, findings suggest recency, frequency, and age of onset of cannabis use are likely key variables in predicting poorer neural health outcomes. There is some evidence that preexisting differences in brain architecture may also contribute to vulnerability and outcome differences. Ongoing large-scale prospective studies of youth will be able to disentangle how both cannabis use as well as pre and postexposure differences play a role in divergent outcomes among youth who use cannabis.

Orbitofrontal cortex volume prospectively predicts cannabis and other substance use onset in adolescents.

BACKGROUND: Identifying neural characteristics that predict cannabis initiation is important for prevention efforts. The orbitofrontal cortex is critical for reward response and may be vulnerable to substance-induced alterations. AIMS: We measured orbitofrontal cortex thickness, surface area, and volume prior to the onset of use to predict cannabis involvement during an average nine-year follow-up. METHODS: Adolescents (n=118) aged 12-15 years completed baseline behavioral assessment and magnetic resonance imaging scans, then were followed up to 13 years with annual substance use interviews. Logistic regression examined baseline (pre-substance use) bilateral medial and lateral orbitofrontal cortex characteristics (volume, surface area, or cortex thickness) as predictors of regular cannabis use by follow-up. Post-hoc multinomial logistic regression assessed whether orbitofrontal cortex characteristics significantly predicted either alcohol use alone or cannabis+alcohol co-use. Brain-behavior relationships were assessed through follow-up correlations of baseline relationships between orbitofrontal cortex and executive functioning, reward responsiveness, and behavioral approach traits. RESULTS: Larger left lateral orbitofrontal cortex volume predicted classification as cannabis user by follow-up (p=0.025, odds ratio=1.808). Lateral orbitofrontal cortex volume also predicted cannabis+alcohol co-user status (p=0.008, odds ratio=2.588), but not alcohol only status. Larger lateral orbitofrontal cortex volume positively correlated with greater baseline reward responsiveness (p=0.030, r=0.348). There were no significant results by surface area or cortex thickness (ps>0.05). CONCLUSIONS: Larger left lateral orbitofrontal cortex measured from ages 12-15 years and prior to initiation of substance use was related to greater reward responsiveness at baseline and predicted classification as a cannabis user and cannabis+alcohol co-user by final follow-up. Larger lateral orbitofrontal cortex volume may represent aberrant orbitofrontal cortex maturation and increasing vulnerability for later substance use.

Preliminary evidence that computerized approach avoidance training is not associated with changes in fMRI cannabis cue reactivity in non-treatment-seeking adolescent cannabis users.

BACKGROUND: Cognitive Bias Modification (CBM) has garnered interest as a potential addiction treatment. CBM interventions such as Approach Avoidance Training (AAT) are designed to alter automatic tendencies to approach drugs or drug-related cues. In our previous work, the cannabis AAT (CAAT) reduced cannabis approach bias, which was related to reduced cannabis use, among 80 non-treatment-seeking cannabis-using youth (Jacobus et al., 2018). In this preliminary examination, a subsample of these youth underwent neuroimaging to explore CAAT's effect on cannabis cue-related neural activation. METHODS: Sub-study participants were 41 cannabis-using youth ages 17-21 (mean age = 18.83; 47.5% female). Participants completed a cannabis cue-reactivity task during a functional MRI scan pre- and post CAAT-training or CAAT-sham to examine CAAT-related neural changes. RESULTS: Thirty-seven youth completed all six CAAT (n = 19) or CAAT-sham (n = 18) training sessions and had usable neuroimaging data. The group*time interaction on cannabis approach bias reached trend-level significance (p = .055). Change in approach bias slopes from pre-to post-treatment was positive for CAAT-sham (increased approach bias) and negative for CAAT-training (change to avoidance bias), consistent with the larger study. No significant changes emerged for cannabis cue-induced activation following CAAT-training or CAAT-sham in whole brain or region of interest analyses. However, active CAAT-training was associated with small-to-medium decreases in amygdala (Cohen's dz = 0.36) and medial prefrontal cortex (Cohen's dz = 0.48) activation to cannabis cues. CONCLUSIONS: Despite reducing cannabis use in the larger sample, CAAT-training did not alter neural cannabis cue-reactivity in the sub-study compared to CAAT-sham. More research is needed to understand neural mechanisms underlying AAT-related changes in substance use.

Investigating a novel fMRI cannabis cue reactivity task in youth.

OBJECTIVE: Adult and adolescent studies suggest increased motivational responses to cannabis cues among regular cannabis users. However, functional magnetic resonance imaging (fMRI) studies have not explored neural activation in response to visual cannabis cues among adolescents in the United States. Gaining a better understanding of the neural circuits related to cue-elicited craving during adolescence may shed light on the neural basis for the development of problematic cannabis use that could ultimately be targeted for interventions. METHODS: 41 non-treatment-seeking youth (ages 17-21; mean age = 18.83; 46.3% female) who reported regular cannabis use underwent fMRI scanning involving a visual cannabis cue task and completed self-report and biological measures. Whole-brain activation was examined for cannabis cues compared to non-cannabis cues, and for active versus passive cannabis cues. Associations between self-reported substance use and task activation were examined. RESULTS: Cannabis images were identifiable to adolescents and were rated as more rewarding than matched non-cannabis images (p < .05). Greater activation was found for the cannabis cues compared to non-cannabis cues in bilateral posterior cingulate, cuneus, fusiform, precuneus, inferior temporal and parahippocampal gyri, as well as left thalamus, medial frontal and superior frontal gyri. Cue-elicited activation was not significantly associated with self-reported cannabis use (ps > 0.05). No differences were observed for the active versus passive cue contrast. CONCLUSIONS: Cannabis-using youth show more activation to cannabis cues than non-cannabis cues in brain regions underlying incentive salience, reward, and visual attention. This task could be useful for future studies examining neural underpinnings of reward processes in adolescent cannabis users.

Adolescent Brain Surface Area Pre- and Post-Cannabis and Alcohol Initiation.

OBJECTIVE: Changes in gray matter volume and thickness are associated with adolescent alcohol and cannabis use, but the impact of these substances on surface area remains unclear. The present study expands on previous findings to examine the impact of alcohol and cannabis on surface area before and after use initiation. METHOD: Scans for 69 demographically similar youth were obtained at baseline (ages 12-14 years; before substance use) and at 6-year follow-up (ages 17-21 years). Participants were classified into three groups based on substance use: alcohol use initiators (ALC, n = 23), alcohol and cannabis use initiators (ALC+CU, n = 23), and individuals with minimal substance use (<3 lifetime alcohol and 0 marijuana use episodes; CON, n = 23). For each hemisphere, group differences in surface area across time (pre- and post-substance use initiation) and significant group-by-time interactions were examined individually for 34 cortical regions using repeated measures analysis of covariance. A vertex-wise analysis assessed group differences in surface area percent change. RESULTS: A significant group-by-time interaction was found in three regions, bilateral medial orbitofrontal cortices and right insula. Although all regions showed decreases in surface area over time (ps < .05), a more substantial decrease was identified in the ALC group. Of note, the right medial orbitofrontal cortex survived the conservative vertex-wise analyses (p < .001), as a more substantial decrease was found in the ALC compared to the ALC+CU group in this region. CONCLUSIONS: Surface area in the medial orbitofrontal cortex may be a useful intermediate phenotype for exploring the mechanisms underlying the effects of substance use on brain development.

A multi-site proof-of-concept investigation of computerized approach-avoidance training in adolescent cannabis users.

BACKGROUND: Few effective treatment options exist for cannabis-using youth. This pilot study aimed to test Approach-Avoidance Training to reduce cannabis use with non-treatment-seeking adolescents. METHODS: Eighty cannabis-using non-treatment-seeking adolescents (average age 19) were recruited from San Diego, California and Charleston, South Carolina, and randomized to complete either six sessions of Cannabis Approach-Avoidance Task Training (CAAT-training) designed to reduce automatic approach biases for cannabis cues or CAAT-sham training. Change in two primary outcome variables was examined: 1) cannabis approach bias and 2) percent cannabis use days over study enrollment. Change in percent alcohol use days over study enrollment was explored as a secondary outcome. RESULTS: A mixed models repeated measures analysis confirmed the group by time interaction effect for approach bias failed to reach statistical significance (p = .06). Significant group by time interaction effects (ps < 0.05) predicted percent days of cannabis and alcohol use over study enrollment. Participants randomized to the avoid cannabis condition (CAAT-training) reported 7% fewer days of cannabis use compared to 0% change for sham; unexpectedly, those in the avoid cannabis condition reported 10% percent more alcohol use days compared to 3% more for sham. CONCLUSIONS: Computerized cognitive bias modification paradigms may have utility in reducing adolescent cannabis use. Future work should consider developing a paradigm that addresses both cannabis and alcohol, as well as alternative computerized approaches for coping with addictive behavior in conjunction with bias modification.

Longitudinal Studies on the Etiology of Cannabis Use Disorder: A Review.

PURPOSE OF REVIEW: This review summarizes the literature to date that has capitalized on the longitudinal research study framework in order to elucidate the etiology of cannabis use disorders (CUDs). RECENT FINDINGS: The studies are mixed with respect to reliable predictors of CUD development. Of the studies outlined, the most consistently indicated risk factors for CUD development include: male sex, past cannabis and other substance use (especially tobacco), and the presence of pre/comorbid psychopathology (especially mood disorders). Social motives and peer involvement may also play a role in this transition. Many of these CUD risk factors appear to be distinct from other factors linked with overall cannabis use. SUMMARY: CUD development is likely the product of interactions between biological, psychological, social, and environmental factors. However, many more well-planned and developmentally sensitive prospective studies are needed to identify specific and reliable risk factors for CUD development.

Changes in marijuana use symptoms and emotional functioning over 28-days of monitored abstinence in adolescent marijuana users.

RATIONALE: Advancing marijuana prevention and intervention efforts are important given the decreasing perception of harm among adolescents and increasing marijuana legalization. OBJECTIVES: This study evaluates how a monitored abstinence protocol may contribute to emotional functioning and changes in marijuana problems that can enhance successful outcomes for non-treatment-seeking adolescent marijuana users. METHODS: Adolescent marijuana users (n = 26) and demographically matched controls (n = 30) completed 28 days of monitored abstinence confirmed by biweekly urine toxicology. Participants were given measures of emotional functioning, marijuana use symptoms, and reward sensitivity during monitored abstinence. RESULTS: All participants (n = 56) completed the protocol, and 69% of marijuana users (n = 18 of 26) were confirmed abstinent for 28 days, with all users showing decreasing marijuana use. Reductions in subsyndromal depression, positive marijuana use expectancies, and poor sleep quality were observed by the end of the monitored abstinence period (n = 26, p values < .05). Marijuana users also reported more attentional impulsivity and less responsiveness to reward stimuli during the second week of abstinence compared to controls. Later age of onset of regular marijuana use and more cumulative lifetime use were associated with a greater degree of emotional change and increased recognition of the negative effects of marijuana use. CONCLUSIONS: Monitored abstinence programs may be beneficial in reducing marijuana use, subsyndromal emotional distress symptoms, and changing beliefs about marijuana use. Future prevention and intervention efforts may consider targeting reward sensitivity and impulsivity, in addition to marijuana use, expectancies, and emotional functioning.

Adolescent cortical thickness pre- and post marijuana and alcohol initiation.

Cortical thickness abnormalities have been identified in youth using both alcohol and marijuana. However, limited studies have followed individuals pre- and post initiation of alcohol and marijuana use to help identify to what extent discrepancies in structural brain integrity are pre-existing or substance-related. Adolescents (N=69) were followed from ages 13 (pre-initiation of substance use, baseline) to ages 19 (post-initiation, follow-up). Three subgroups were identified, participants that initiated alcohol use (ALC, n=23, >20 alcohol use episodes), those that initiated both alcohol and marijuana use (ALC+MJ, n=23, >50 marijuana use episodes) and individuals that did not initiate either substance regularly by follow-up (CON, n=23, <3 alcohol use episodes, no marijuana use episodes). All adolescents underwent neurocognitive testing, neuroimaging, and substance use and mental health interviews. Significant group by time interactions and main effects on cortical thickness estimates were identified for 18 cortical regions spanning the left and right hemisphere (ps<0.05). The vast majority of findings suggest a more substantial decrease, or within-subjects effect, in cortical thickness by follow-up for individuals who have not initiated regular substance use or alcohol use only by age 19; modest between-group differences were identified at baseline in several cortical regions (ALC and CON>ALC+MJ). Minimal neurocognitive differences were observed in this sample. Findings suggest pre-existing neural differences prior to marijuana use may contribute to initiation of use and observed neural outcomes. Marijuana use may also interfere with thinning trajectories that contribute to morphological differences in young adulthood that are often observed in cross-sectional studies of heavy marijuana users.

Cortical thickness in adolescent marijuana and alcohol users: A three-year prospective study from adolescence to young adulthood.

Studies suggest marijuana impacts gray and white matter neural tissue development, however few prospective studies have determined the relationship between cortical thickness and cannabis use spanning adolescence to young adulthood. This study aimed to understand how heavy marijuana use influences cortical thickness trajectories across adolescence. Subjects were adolescents with heavy marijuana use and concomitant alcohol use (MJ+ALC, n=30) and controls (CON, n=38) with limited substance use histories. Participants underwent magnetic resonance imaging and comprehensive substance use assessment at three independent time points. Repeated measures analysis of covariance was used to look at main effects of group, time, and Group × Time interactions on cortical thickness. MJ+ALC showed thicker cortical estimates across the brain (23 regions), particularly in frontal and parietal lobes (ps<.05). More cumulative marijuana use was associated with increased thickness estimates by 3-year follow-up (ps<.05). Heavy marijuana use during adolescence and into young adulthood may be associated with altered neural tissue development and interference with neuromaturation that can have neurobehavioral consequences. Continued follow-up of adolescent marijuana users will help understand ongoing neural changes that are associated with development of problematic use into adulthood, as well as potential for neural recovery with cessation of use.

Neuropsychological performance in adolescent marijuana users with co-occurring alcohol use: A three-year longitudinal study.

OBJECTIVE: The effect of adolescent marijuana use on brain development remains unclear despite relaxing legal restrictions, decreased perceived harm, and increasing use rates among youth. The aim of this 3-year prospective study was to evaluate the long-term neurocognitive effects of adolescent marijuana use. METHOD: Adolescent marijuana users with concomitant alcohol use (MJ + ALC, n = 49) and control teens with limited substance use histories (CON, n = 59) were given neuropsychological and substance use assessments at project baseline, when they were ages 16-19. They were then reassessed 18 and 36 months later. Changes in neuropsychological measures were evaluated with repeated measures analysis of covariance (ANCOVA), controlling for lifetime alcohol use, and examined the effects of group, time, and group by time interactions on cognitive functioning. RESULTS: MJ + ALC users performed significantly worse than controls, across time points, in the domains of complex attention, memory, processing speed, and visuospatial functioning (ps <.05). Earlier age of marijuana use onset was associated with poorer processing speed and executive functioning by the 3-year follow-up (ps ≤.02). CONCLUSIONS: Frequent marijuana use throughout adolescence and into young adulthood appeared linked to worsened cognitive performance. Earlier age of onset appears to be associated with poorer neurocognitive outcomes that emerge by young adulthood, providing further support for the notion that the brain may be uniquely sensitive to frequent marijuana exposure during the adolescent phase of neurodevelopment. Continued follow-up of adolescent marijuana users will determine the extent of neural recovery that may occur if use abates.