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. 2021 Jun 16;78(9):1-11.
doi: 10.1001/jamapsychiatry.2021.1258. Online ahead of print.

Association of Cannabis Use During Adolescence With Neurodevelopment

Matthew D Albaugh  1 , Jonatan Ottino-Gonzalez  1 , Amanda Sidwell  1 , Claude Lepage  2 , Anthony Juliano  1 , Max M Owens  1 , Bader Chaarani  1 , Philip Spechler  1 , Nicholas Fontaine  1 , Pierre Rioux  2 , Lindsay Lewis  2 , Seun Jeon  2 , Alan Evans  2 , Deepak D'Souza  3 , Rajiv Radhakrishnan  3 , Tobias Banaschewski  4 , Arun L W Bokde  5 , Erin Burke Quinlan  6 , Patricia Conrod  7 , Sylvane Desrivières  6 , Herta Flor  8   9 , Antoine Grigis  10 , Penny Gowland  11 , Andreas Heinz  12   13   14 , Bernd Ittermann  15 , Jean-Luc Martinot  16 , Marie-Laure Paillère Martinot  17   18   19 , Frauke Nees  4   8   20 , Dimitri Papadopoulos Orfanos  10 , Tomáš Paus  21   22   23 , Luise Poustka  24 , Sabina Millenet  4 , Juliane H Fröhner  25 , Michael N Smolka  25 , Henrik Walter  12   13   14 , Robert Whelan  26 , Gunter Schumann  6   6   27   28   29 , Alexandra Potter  1 , Hugh Garavan  1 ; IMAGEN Consortium
Affiliations

Association of Cannabis Use During Adolescence With Neurodevelopment

Matthew D Albaugh et al. JAMA Psychiatry. .

Abstract

Importance: Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans.

Objective: To examine the degree to which magnetic resonance (MR) imaging-assessed cerebral cortical thickness development is associated with cannabis use in a longitudinal sample of adolescents.

Design, setting, and participants: Data were obtained from the community-based IMAGEN cohort study, conducted across 8 European sites. Baseline data used in the present study were acquired from March 1, 2008, to December 31, 2011, and follow-up data were acquired from January 1, 2013, to December 31, 2016. A total of 799 IMAGEN participants were identified who reported being cannabis naive at study baseline and had behavioral and neuroimaging data available at baseline and 5-year follow-up. Statistical analysis was performed from October 1, 2019, to August 31, 2020.

Main outcomes and measures: Cannabis use was assessed at baseline and 5-year follow-up with the European School Survey Project on Alcohol and Other Drugs. Anatomical MR images were acquired with a 3-dimensional T1-weighted magnetization prepared gradient echo sequence. Quality-controlled native MR images were processed through the CIVET pipeline, version 2.1.0.

Results: The study evaluated 1598 MR images from 799 participants (450 female participants [56.3%]; mean [SD] age, 14.4 [0.4] years at baseline and 19.0 [0.7] years at follow-up). At 5-year follow-up, cannabis use (from 0 to >40 uses) was negatively associated with thickness in left prefrontal (peak: t785 = -4.87, cluster size = 1558 vertices; P = 1.10 × 10-6, random field theory cluster corrected) and right prefrontal (peak: t785 = -4.27, cluster size = 1551 vertices; P = 2.81 × 10-5, random field theory cluster corrected) cortices. There were no significant associations between lifetime cannabis use at 5-year follow-up and baseline cortical thickness, suggesting that the observed neuroanatomical differences did not precede initiation of cannabis use. Longitudinal analysis revealed that age-related cortical thinning was qualified by cannabis use in a dose-dependent fashion such that greater use, from baseline to follow-up, was associated with increased thinning in left prefrontal (peak: t815.27 = -4.24, cluster size = 3643 vertices; P = 2.28 × 10-8, random field theory cluster corrected) and right prefrontal (peak: t813.30 = -4.71, cluster size = 2675 vertices; P = 3.72 × 10-8, random field theory cluster corrected) cortices. The spatial pattern of cannabis-related thinning was associated with age-related thinning in this sample (r = 0.540; P < .001), and a positron emission tomography-assessed cannabinoid 1 receptor-binding map derived from a separate sample of participants (r = -0.189; P < .001). Analysis revealed that thinning in right prefrontal cortices, from baseline to follow-up, was associated with attentional impulsiveness at follow-up.

Conclusions and relevance: Results suggest that cannabis use during adolescence is associated with altered neurodevelopment, particularly in cortices rich in cannabinoid 1 receptors and undergoing the greatest age-related thickness change in middle to late adolescence.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Albaugh reported receiving grants from the National Institute of Mental Health (NIMH) during the conduct of the study. Dr Juliano reported receiving grants from the National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) during the conduct of the study. Dr D’Souza reported receiving grants from the NIDA, NIMH, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Brain and Behavior Foundation during the conduct of the study; grants from the NIDA, Wallace Foundation, Cluster Headache-Trigeminal Autonomic Cephalalgia, Heffter Institute, NIMH, Brain and Behavior Foundation, Dana Foundation, NIAAA, and Takeda; and personal fees from Abide Therapeutics and Jazz Pharmaceuticals outside the submitted work. Dr Banaschewski reported receiving personal fees from Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Takeda, Infectopharm, and Eli Lilly outside the submitted work; serving as an advisor or consultant to Bristol Myers Squibb, Desitin Arzneimittel, Eli Lilly, Medice, Novartis, Pfizer, Shire, UCB, and Vifor Pharma; receiving conference attendance support, conference support, or speaking fees from Eli Lilly, Janssen McNeil, Medice, Novartis, Shire, and UCB; being involved in clinical trials conducted by Eli Lilly, Novartis, and Shire; and receiving royalties from Hogrefe, Kohlhammer, CIP-Medien, and Oxford University Press. Dr Bokde reported receiving grants from the European Research Council during the conduct of the study; and grants from National Children’s Foundation–Tallaght and Health Research Board outside the submitted work. Dr Desrivières reported receiving grants from Medical Research Council, Medical Research Foundation, and NIH during the conduct of the study. Dr Ittermann reported receiving grants from the EU, King’s College London, and Charité Berlin during the conduct of the study. Dr Poustka reported receiving honoraria for public speaking by Shire, Takeda, and Infectopharm; and research funding from the EU, Deutsche Forschungsgemeinschaft, and Bundesministerium für Bildung und Forschung. Dr Föhner reported receiving personal fees from Bundesministerium für Bildung und Forschung during the conduct of the study. Dr Smolka reported receiving grants from Deutsche Forschungsgemeinschaft, the European Commission, and Bundesministerium für Bildung und Forschung during the conduct of the study. Dr Walter reported receiving grants from the EU Horizon 2020 ERC Advanced Grant “Stratify” (Brain network-based stratification of reinforcement-related disorders (694313) during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cross-Sectional Results
Brain areas where local cortical thickness is negatively associated with the dimensional measure of lifetime cannabis use at 5-year follow-up (N = 799). Random field theory was used to correct for multiple comparisons over the entire cortical mantle. The figure is shown at P ≤ .05, random field theory corrected. Blue areas are significant at the cluster level, and red corresponds to areas significant at the vertex level. Measures were controlled for age, total brain volume, sex, handedness, Alcohol Use Disorders Identification Test Alcohol Consumption score, and site.
Figure 2.
Figure 2.. Longitudinal Linear Mixed-Effects Model Results
Brain areas where local cortical thickness is associated with the time × cannabis interaction in a linear mixed-effects model analysis, controlling for the main effects of time point, lifetime cannabis use, total brain volume, sex, handedness, Alcohol Use Disorders Identification Test Alcohol Consumption score, and site (N = 799; 1598 magnetic resonance imaging scans). The figure is shown at P ≤ .05 with a whole-brain random field theory correction. Blue shades correspond to areas significant at the cluster level and red shades to areas significant at the vertex level.
Figure 3.
Figure 3.. Magnetic Resonance Imaging–Assessed Cortical Thinning at Varying Levels of Lifetime Cannabis Use
A, Right dorsomedial prefrontal cluster from linear mixed-effects analysis. B, Left dorsomedial prefrontal cluster from linear mixed-effects analysis. The bar graphs depict within-individual symmetrized percentage change (ie, change in cortical thickness, in millimeters per year, with respect to the mean cortical thickness across both time points) for each cluster at varying levels of lifetime cannabis use (at 5-year follow-up). Error bars represent 95% confidence intervals. Brain figures shown at P ≤ .05 with a whole-brain random field theory correction. Blue shades correspond to areas significant at the cluster level, and orange shades to areas significant at the vertex level.
Figure 4.
Figure 4.. Topographical Overlap Between Age-Related Thinning, Cannabis Effect, and Cannabinoid 1 (CB1) Receptor Availability
Topographical overlap between age-related cortical thinning in the sample (n = 799), areas in which age-related thinning was qualified by cannabis use, and positron emission tomography–assessed CB1 receptor availability (collected from a separate sample of 21 healthy adults). The r values correspond to Pearson correlation coefficients between unthresholded vertex-level surface maps. Please note that thresholds have been lowered for visualization purposes. Regional [11C]OMAR volume distribution is shown at >1.4, age-related thinning map is shown at t < −15, and cannabis-related thinning map is shown at t < −2.
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