Association of Cannabis Use During Adolescence With Neurodevelopment, Matthew D. Albaugh et al., 2021

Association of Cannabis Use During Adolescence With Neurodevelopment

Matthew D. Albaugh, PhD; Jonatan Ottino-Gonzalez, PhD; Amanda Sidwell, BS; Claude Lepage, PhD; Anthony Juliano, PsyD; Max M. Owens, PhD; Bader Chaarani, PhD; Philip Spechler, PhD; Nicholas Fontaine, BS; Pierre Rioux, MSc; Lindsay Lewis, PhD; Seun Jeon, PhD; Alan Evans, PhD; Deepak D’Souza, MD; Rajiv Radhakrishnan, MD; Tobias Banaschewski, MD, PhD; Arun L.W. Bokde, PhD; Erin Burke Quinlan, PhD; Patricia Conrod, PhD; Sylvane Desrivières, PhD; Herta Flor, PhD; Antoine Grigis, PhD; Penny Gowland, PhD; Andreas Heinz, MD, PhD; Bernd Ittermann, PhD; Jean-Luc Martinot,MD, PhD; Marie-Laure Paillère Martinot,MD, PhD; Frauke Nees, PhD; Dimitri Papadopoulos Orfanos, PhD; Tomáš Paus, MD, PhD; Luise Poustka, MD; Sabina Millenet, PhD; Juliane H. Fröhner, MSc; Michael N. Smolka, MD; HenrikWalter,MD, PhD; Robert Whelan, PhD; Gunter Schumann, MD; Alexandra Potter, PhD; Hugh Garavan, PhD; for the IMAGEN Consortium

JAMA Psychiatruy / Original Investigation, 2021, June 16, E1-E10.

doi : 10.1001/jamapsychiatry.2021.1258



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 : Datawere 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 usewas 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 nativeMR 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.

Key Points

Question To what extent is cannabis use associated with magnetic resonance imaging–measured cerebral cortical thickness development during adolescence?

Findings In this cohort study, linear mixed-effects model analysis using 1598magnetic resonance images from 799 participants revealed that cannabis use was associated with accelerated age-related cortical thinning from 14 to 19 years of age in predominantly prefrontal regions. The spatial pattern of cannabis-related cortical thinning was significantly associated with a positron emission tomography–assessed map of cannabinoid 1 receptor availability.

Meaning Results suggest that cannabis use during middle to late adolescence may be associated with altered cerebral cortical development, particularly in regions rich in cannabinoid 1 receptors.


Cannabis is a commonly used psychoactive drug, particularly among adolescents and young adults. Relative to the general population, past-year prevalence rates of cannabis use are greatest among teenagers, and more than one-third of 12th graders in the United States report using cannabis in the past year.1,2 Seventy-eight percent of firsttime cannabis users are between the ages of 12 and 20 years.3

These prevalence rates raise concern as cannabis use during adolescence has been linked to enduring impairments of executive functioning and impulse control.4 Such longitudinal associations appear specific to cannabis use and independent of concomitant alcohol use; however, the neurobiological mechanisms that might mediate a long-term behavioral associationwith cannabis use remain unclear.4 The potential association of cannabis usewith adolescent development represents an increasingly relevant public health issue, particularly given evidence of increased problematic cannabis use among adolescents in areas where recreational cannabis use has been legalized.5

The transition from late adolescence to early adulthood is characterized by significant structural change in the brain, most notably in areas of the cerebral cortex that are known to exhibit protracted developmental trajectories and undergo relatively late myelination.6-9

Extant research studies suggest that changes in endocannabinoid signaling can have a significant associationwith aspects of mammalian brain development.10,11 Evidence further indicates that the adolescent brain may be particularly sensitive to disruptions in normative fluctuations in endocannabinoid signaling, associated with altered neurodevelopment and behavior.12-15

Despite such findings in the animal literature, few longitudinal neuroimaging studies have examined putative ties between cannabis use and adolescent brain development, to our knowledge.

Here, we examined the association between cannabis use and cerebral cortical development in a longitudinal, community-based sample of adolescents. From the larger IMAGEN sample, we identified participants who reported being cannabis naive at study baseline and had neuroimaging data available at study baseline and 5-year follow-up. First, in a series of cross-sectional analyses, we examined the extent to which lifetime cannabis use was associated with cortical thickness at 5-year follow-up (approximately 19 years of age).To test the temporality of this association,we then examined the extent to which cortical thickness at age 14 years was associated with lifetime cannabis use at 5-year follow-up. In our primary longitudinal analysis, a linear mixed-effects model (LMM) was implemented to test the degree to which initiation of cannabis use was associated with age-related cortical thickness change (from ages 14 to 19 years). Follow-up analyses were conducted to test the extent to which cannabis-related cortical thinning was associated with aspects of impulsive behavior.

We also tested the association between the longitudinally derived map of cannabis-related cortical thinning and positron emission tomography (PET)–derived cannabinoid 1 (CB1) receptor availability (collected from an independent sample of young adults) with the hypothesis that areas demonstrating cannabis-related thinning would exhibit, on average, relatively greater CB1 receptor availability. We further hypothesized that cannabis-related thinning would be most evident in cortical regions undergoing the greatest structural change during the developmental window studied.