Cortical surface morphology in long-term cannabis users: A multi-site MRI study

Abstract

Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface – including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Introduction

Cannabis is a widely used recreational substance, valued for both its pharmacological and psychoactive properties (Atakan, 2012). While cannabis remains illegal in most countries, a number of countries have begun to decriminalise or permit its use for personal or medical purposes. This general shift in attitude has raised concerns about the potential harm of long-term cannabis use, particularly for users who begun using at an early age (Hall and Lynskey, 2016, Levine et al., 2016). The majority of cannabis initiates are adolescents under the age of 18 (Center for Behavioral Health Statistics and Quality, 2011). Early adolescent initiates may be at a greater risk of worse functional outcomes including, poorer academic performance and delinquency (Brook et al., 1999, Fergusson and Horwood, 1997, Lynskey et al., 2015, Meier et al., 2015). Additionally, initiation of use during adolescence is associated with a greater likelihood of persistent use and dependence later in life (Center for Behavioral Health Statistics and Quality 2011, DeWit et al., 1997, Perkonigg et al., 2008). Not only do dependent cannabis users experience a range of physiological and psychological problems (e.g., social, interpersonal, and mental health issues including mood, anxiety and behavioural disorders) related to use (American Psychiatric Association 2013, Hasin et al., 2013, van der Pol et al., 2013), cannabis dependence may also be associated with distinct brain alterations relative to non-dependent use (Chye et al., 2017b, Chye et al., 2017c, Filbey and Dunlop, 2014). With the increasingly liberal cannabis policies globally likely to increase the number of new users (Hall and Weier, 2015), it is even more pertinent to verify how different aspects of cannabis use, including regular use, early initiation of use, and dependence may be associated with structural brain alterations.

The psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), exerts its effect through cannabinoid receptors (CB1R) that are widely distributed in the human brain, particularly across the cortical surface (Gaoni and Mechoulam, 1964, Westlake et al., 1994). The cortical surface undergoes extensive developmental changes (e.g., in thickness, volume, and gyrification) across adolescence (Cao et al., 2017, Coupé et al., 2017, Jacobus and Tapert, 2014, Toga et al., 2006). Importantly, such neurodevelopmental changes are in part driven by CB1Rs, as part of an endogenous cannabinoid system (ECS) involved in fundamental processes such as neuronal cell proliferation, differentiation, morphogenesis and synaptogenesis (Harkany et al., 2008, Svíženská et al., 2008). Notably, THC exposure, especially during adolescence relative to adulthood, has been shown to demonstrably alter CB1R expression and neuronal growth in rats, potentially contributing to neurostructural alterations across the cortical surface (Burston et al., 2010, Dalton and Zavitsanou, 2010, Dean et al., 2001, Grigorenko et al., 2002, Molina-Holgado et al., 2002, Rubino et al., 2015, Villares, 2007). Furthermore, rodent research shows that CB1R density increases during normal development, peaking in adolescence, before decreasing to adult values (de Fonseca et al., 1993). Thus, the evidence not only points toward a dynamic ECS heavily involved in modulating neuromaturational events during adolescence, but also implies a potential for the ECS to be more sensitive to cannabinoid insult during adolescence, that may contribute to observable neurostructural alterations along the cortical surface.

Previous human neuroimaging studies have demonstrated differences in cortical thickness in cannabis users relative to non-using controls. However, these studies have not been consistent in the direction of reported results, nor the affected brain regions. For example, one study found that cannabis users had a thinner cortex in the right fusiform gyrus relative to non-using controls (Mashhoon et al., 2015a), while another reported thicker cortices in cannabis users in a number of regions across the frontal, parietal, temporal, and occipital lobes (Jacobus et al., 2015). Yet another found no significant difference in cortical thickness between cannabis users and controls (Mata et al., 2010). Adolescent onset of cannabis use may also moderate cortical thickness differences between cannabis users and controls, with one study finding that cannabis dosage was positively associated with cortical thickness across the frontal and temporal lobes in early onset (<16 years of age) users, but negatively associated with cortical thickness in late onset users (Filbey et al., 2015). However, other studies have instead demonstrated thinner cortices in the frontal and inferior and middle temporal brain regions; and thicker cortices in lingual, parietal, and paracentral regions, of early adolescent cannabis users relative to non-users (Jacobus et al., 2014, Lopez-Larson et al., 2011), making it difficult to infer a consistent effect of adolescent onset of cannabis use on cortical morphology. Finally, emerging evidence suggests that cannabis-associated effects on subcortical neuroanatomy and cortico-subcortical connectivity may be more reflective of problematic cannabis use (i.e., cannabis dependence) rather than recreational use (Chye et al., 2017b, Chye et al., 2017c, Filbey and Dunlop, 2014). These studies particularly implicated frontal and limbic areas, thought to be involved in aberrant reward and decision-making processes in dependence (Volkow et al., 2003). The effect of cannabis dependence vs. non-dependent use, however, has yet to be explored in relation to cortical thickness. In sum, the lack of consistency of study findings to date makes it difficult to infer specific cortical morphological changes that may be associated with cannabis use, onset age, or dependence.

In addition to cortical thickness, the surface morphology of the brain can also be examined via surface area and gyrification, both of which have been found to change with age, particularly during childhood and adolescence (Raznahan et al., 2011). The gyrification index is a quantitative approach to measuring the degree of cortical folding (Zilles et al., 1988). Only three studies, to our knowledge, have examined surface area and gyrification in relation to cannabis use, finding reduced gyrification and trend level reduction in surface area in frontal brain regions (Filbey et al., 2015, Mata et al., 2010, Shollenbarger et al., 2015). In this study we explored the cortical surface morphology – i.e., cortical thickness, surface area and gyrification index, in a multisite sample of regular cannabis users and controls aggregated from pre-collected data across four independent research sites (Batalla et al., 2013, Cousijn et al., 2014, Solowij et al., 2013, Yücel et al., 2016). We attempted to delineate the relation between cortical morphology, and (i) cannabis use, (ii) cannabis dependence, and (iii) cannabis onset age. While we are not able to formulate a directional hypothesis given the inconsistencies in the literature to date, we expect indices of surface morphology to be altered in cannabis users relative to controls, and that these differences will be more pronounced in dependent, as well as early-onset cannabis users.