Cannabis Use in Adolescence : A Review of Neuroimaging Findings
Yann Chye, Erynn Christensen & Murat Yücel
Journal of Dual Diagnosis, 2019
Doi : 10.1080/15504263.2019.1636171
Objective : Shifting policies and widespread acceptance of cannabis for medical and/or recreational purposes have fueled worries of increased cannabis initiation and use in adolescents. In particular, the adolescent period is thought to be associated with an increased susceptibility to the potential harms of repeated cannabis use, due to being a critical period for neuromaturational events in the brain. This review investigates the neuroimaging evidence of brain harms attributable to adolescent cannabis use.
Methods : PubMed and Scopus searches were conducted for empirical articles that examined neuroimaging effects in both adolescent cannabis users and adult user studies that explored the effect of age at cannabis use onset on the brain.
Results : We found 43 studies that examined brain effect (structural and functional magnetic resonance imaging) in adolescent cannabis users and 20 that examined the link between onset age of cannabis use and brain effects in adult users. Studies on adolescent cannabis users relative to nonusers mainly implicate frontal and parietal regions and associated brain activation in relation to inhibitory control, reward, and memory. However, studies in adults are more mixed, many of which did not observe an effect of onset age of cannabis use on brain imaging metrics.
Conclusions : While there is some evidence of compromised frontoparietal structure and function in adolescent cannabis use, it remains unclear whether the observed effects are specifically attributable to adolescent onset of use or general cannabis use–related factors such as depressive symptoms. The relative contribution of adolescent onset of cannabis use and use chronicity will have to be more comprehensively examined in prospective, longitudinal studies with more rigorous measures of cannabis use (dosage, exposure, dependence, constituent compounds such as the relative cannabinoid levels).
KEYWORDS : Cannabis; adolescence; neuroimaging; MRI; substance use disorder; addiction
Cannabis is not only a widely used substance of abuse worldwide, it remains the second most preferred substance of initiation in adolescents behind alcohol, with over a third of final year high school students in America having reported using cannabis (Johnston et al., 2019). Past-year prevalence of cannabis use has also been found to be significantly higher in 15- to 16-year-olds relative to the general population worldwide (United Nations Office on Drugs and Crime, 2018). Further, recently shifting attitude toward cannabis alongside a global move toward legalization of cannabis for medical and/or recreational purposes prompts worries of increasing adolescent cannabis use (Hopfer, 2014). Despite the increasingly recognized therapeutic benefit of cannabinoid compounds for a range of neurological conditions and mental health needs (Chye, Christensen, Solowij, & Y€ucel, 2019; Hurd, 2017; Lattanzi, Brigo, Trinka, Zaccara, & Cagnetti, 2018), the potential psychosocial and brain harms that accompany adolescent cannabis use remain a public health concern.
The adolescent period is defined as the transitional period from childhood to adulthood roughly associated with the age of 10 to 19 years, although the precise age range of adolescence is ill defined (Brenhouse & Andersen, 2011). It is accompanied by a number of behavioral and social changes, such as increased peerdirected social interactions and greater risk taking, that assist in adolescents attaining independence from the family unit (Crews, He, & Hodge, 2007; Spear, 2000). Initiation of cannabis use during this period may be symptomatic of such increased exploration and novelty-seeking (Chen & Kandel, 1995; Crews et al., 2007). Indeed, over half of cannabis use begins in adolescence (Degenhardt et al., 2008). Worryingly, the adolescent period is also thought to be the period of greatest vulnerability to substance use–related problems (Chambers, Taylor, & Potenza, 2003). Adolescent cannabis users (i.e., those who begun before age 15) are also more likely to persist use and experience greater use-related problems later in life, compared to late-onset users (Anthony & Petronis, 1995; DeWit, Offord, & Wong, 1997). A majority of admissions to treatment facilities for cannabis use–related problems (almost 30%) also occur between the age of 12 to 17, highlighting the potential danger of early cannabis use (Substance Abuse and Mental Health Services Administration, 2018).
The adolescent period is also accompanied by important neurodevelopmental events that drive
behavioral changes and cognitive maturation (Brenhouse & Andersen, 2011). Neuromaturational changes during adolescence largely relate to increased functional specialization, whereby synapses that are overproduced in the brain during prenatal and early postnatal periods are eliminated during the transition to adulthood (Selemon, 2013). This massive synapse loss (termed “synaptic pruning”) and reduction in synaptic connectivity and density occur across widespread cortical and subcortical regions that guide complex brain function including goal planning, reasoning, and impulse control (Crews et al., 2007; Gogtay et al., 2004; Luna, Garver, Urban, Lazar, & Sweeney, 2004). It is proposed that the maturation across corticolimbic networks, in particular an increase in inhibitory connections across frontal and limbic regions, drives a shift from more impulsedriven behavior typified by the adolescence period to more regulated behavior (Spear, 2000; Viveros, Marco, & File, 2005). Worryingly, external insults such as exposure to substances of abuse (e.g., cannabis) during this critical neurodevelopmental period may interfere with normal maturational events, presenting an elevated risk of cognitive problems later in life (Jacobus & Tapert, 2013, 2014; Lubman, Cheetham, & Y€ucel, 2014; Solowij, Lorenzetti, & Lubman, 2012).
The endocannabinoid system in adolescence
The particular vulnerability of the adolescent brain to cannabis exposure may be partly related to the developmental trend of the endogenous cannabinoid system (ECS) in the brain. The ECS consists of cannabinoid receptors that not only direct the effect of cannabis in the brain but are crucially involved in neural development throughout postnatal and adolescent periods (Dow-Edwards & Silva, 2017). In particular, the cannabinoid 1 receptor (CB1R) is widely distributed across the brain, but also heavily concentrated in striatal, limbic, and cortical regions that direct the cognitive and emotive function that
continue to develop into adulthood (Pertwee & Ross, 2002; Westlake, Hewlett, Bonner, Matsuda, &
Herkenham, 1994). Rodent studies have shown that CB1R levels as well as endogenous cannabinoid levels increase across development, peaking in early adolescence before decreasing to adult levels, particularly across corticolimbic regions involved in reward and cognition (i.e., prefrontal cortex and nucleus accumbens; Belue, Howlett, Westlake, & Hutchings, 1995; Ellgren et al., 2008). These dynamic changes in the ECS during adolescence are understood to modulate critical maturational processes involving synaptic pruning and plasticity (Meyer, Lee, & Gee, 2018). Perturbation of ECS signaling by cannabis administration during this period may be particularly deleterious, as it may impede the normal maturational process of corticolimbic circuits and their ascribed function (Meyer et al., 2018). Indeed, rat studies demonstrate that the desensitization and downregulation of cannabinoid receptors in response to chronic cannabinoid exposure differ in magnitude in adolescents compared to adults (Burston, Wiley, Craig, Selley, & Sim-Selley, 2010; Dalton & Zavitsanou, 2010). While adolescent rats found cannabis to be less aversive than adult rats, they exhibited greater alteration to protein expression in the hippocampus and greater cognitive impairment (learning and memory) in response to chronic cannabis administration, as compared to adult rats, reflecting increased susceptibility to the potential harms of repeated cannabis use (Cha, White, Kuhn, Wilson, & Swartzwelder, 2006; Quinn et al., 2008; Schneider & Koch, 2003).