Adolescent Cannabis Use : What is the Evidence for Functional Brain Alteration ?, V. Lorenzetti et al., 2016

Adolescent Cannabis Use : What is the Evidence for Functional Brain Alteration ?

V. Lorenzetti, S. Alonso-Lanaa, G. J. Youssef, A. Verdejo-Garcia, C. Suo, J. Cousijn, M. Takagi,
M. Yücel and N. Solowij

Current Pharmaceutical Design, 2016, 22, 1-14.

DOI: 10.2174/1381612822666160805155922



Background : Cannabis use typically commences during adolescence, a period during which the brain undergoes profound remodeling in areas that are high in cannabinoid receptors and that mediate cognitive control and emotion regulation. It is therefore important to determine the impact of adolescent cannabis use on brain function.

Objective : We investigate the impact of adolescent cannabis use on brain function by reviewing the functional magnetic resonance imaging studies in adolescent samples.

Method : We systematically reviewed the literature and identified 13 functional neuroimaging studies in adolescent cannabis users (aged 13 to 18 years) performing working memory, inhibition and reward processing tasks.

Results : The majority of the studies found altered brain function, but intact Behav task performance in adolescent cannabis users versus controls. The most consistently reported differences were in the frontal-parietal network, which mediates cognitive control. Heavier use was associated with abnormal brain function in most samples. A minority of studies controlled for the influence of confounders that can also undermine brain function, such as tobacco and alcohol use, psychopathology symptoms and family history of psychiatric disorders and substance use.

Conclusion : Emerging evidence shows abnormal frontal-parietal network activity in adolescent cannabis users, particularly in heavier users. Brain functional alterations may reflect a compensatory neural mechanism that enables normal Behav performance. It remains unclear if cannabis exposure drives these alterations, as substance use and mental health confounders have not been systematically examined.

Keywords : Cannabis, brain, adolescence, functional neuroimaging, parietal cortex, frontal cortex, hyperactivity



Adolescence is a critical period for experimenting with psychoactive substances including cannabis. Cannabis is the most highly consumed illicit drug worldwide, with typical ages of onset ranging between 16 and 19 years [1]. Annual prevalence rates of adolescent cannabis use (i.e., 12, 14 and 16 years of age) fluctuated over the past 15 years, with decreases from year 2002 to 2006, and increases from year 2007 onwards [2]. Adolescent cannabis use may interfere with brain development [3-5]. Exposure to exogenous cannabinoids alters the endocannabinoid system [6], which is critical for shaping key neurodevelopmental processes (e.g., regulates synaptic connectivity [7, 8] and plasticity [9], in the adolescent brain and contributes to determine connectivity patterns [10]). Further, the main psychoactive compound of cannabis, delta- 9-tetrahydrocannabinol (THC [11]), can have neurotoxic effects in rodents and primates [12-14] and psychotogenic properties in humans [15, 16]. THC levels in the commonly smoked cannabis are high and have been increasing over time [17, 18], suggesting that the potential adverse effects of cannabis on the developing brain may also be increasing.

Prefrontal, parietal and temporal brain regions [19-22] may be particularly vulnerable to the adverse effects of cannabis use during adolescence, as they have a high density of cannabinoid receptors [23, 24], undergo marked neuroanatomical changes during neurodevelopment, and regulate emotion, reward [25, 26] and cognitive processes – the refinement of which occurs during adolescence [27]. Mental health problems and cognitive impairment are commonly observed in adolescent cannabis users, including psychotic, depressive and conduct disorders [28, 29], and poorer learning, memory,attention and impulsivity [30-32]; these outcomes may be linked to alteration of the above-mentioned brain regions. Studying the neural substrates of adolescent cannabis use is important given that neural deficits may mediate cognitive and emotion impairments in adolescent users, which can persist throughout adulthood [33-37] and have a broader functional impact on future outcomes (e.g., school and work performance, low socioeconomic status, poorer educational achievement [38-40]). Furthermore, investigating the neurobiology of adolescent cannabis use is a timely issue in light of the recent global trends towards decriminalisation of cannabis products [41].

Several reviews have summarized evidence on the influence of cannabis on brain function [42-46]. The two most recent reviews of functional Magnetic Resonance Imaging (fMRI) studies of adolescent cannabis users highlight abnormalities in the function of prefrontal and parietal cortices [45, 46]. These reviews, based on only 5 [45] or 11 studies [46], could not draw strong conclusions on the nature of brain functional abnormalities in adolescent cannabis users (i.e., direction of alteration, which cognitive domains are most consistently linked to brain alterations, whether cannabis versus other variables drive the alterations). The studies reviewed at that time were largely focused on the same cognitive domain – spatial working memory – leaving the neural substrates of multiple other domains relatively unexplored (e.g., inhibition, reward processing, decision making, verbal learning and memory). Further, no review to date has exclusively focused on the fMRI evidence in adolescent cannabis users, preventing a comprehensive examination of the literature to date. Careful consideration must be given to the characterisation and measurement of cannabis and other substance use, the mental health of the samples examined to date, approaches undertaken to disentangle the impact of cannabis versus these and other potential confounders entrenched with cannabis use, as well as in depth examination of the tasks employed, MRI analysis approach and ultimate functional brain findings and their interpretation. Thus, we are currently unable to delineate in detail, the gaps in knowledge in the evidence to date, and to inform future directions.

This review integrates the most recent evidence on fMRI studies of adolescent cannabis users to characterise more accurately the neural substrates of adolescent cannabis use. First, we overview sample characteristics of the included studies with a focus on demographics (age, gender), cannabis use, mental health and cognitive performance, and the confounders controlled for in analyses. Second, we overview results pertaining to group comparisons (cannabis users versus nonusers) in brain activity across the cognitive domains of interest. Third, we summarise the emerging associations between brain activity and chronicity of cannabis use, and other relevant variables (psychopathology symptoms, use of substances
other than cannabis, task performance). Finally, we discuss the themes emerging in the fMRI literature in adolescent cannabis users, identify limitations and suggest future directions to advance research in this field.