Cortical thinness and volume differences associated with marijuana abuse in emerging adults
Introduction
In 2013, 180.6 million or 3.9% of the world population aged 15–64 used marijuana (United Nations Office on Drug and Crime, 2013). In the US, the rate of past month marijuana use among adolescents aged 12–17 years increased from 6.7% to 7.9% between 2007 and 2011 (SAMHSA, 2013). It is expected that the prevalence of marijuana use will continue to escalate at a rapid rate in the US across all age groups, given the recent legalization of medical and recreational use, and a decrease in public perception of harm associated with MJ use (Palamar et al., 2014, Schuermeyer et al., 2014). Accordingly, 54.6% of adolescents aged 12–17 perceived smoking marijuana once or twice a week as a “great risk” in 2007, which has decreased to 44.8% in 2011 (SAMHSA, 2013). Therefore, a better understanding of the long-term effects of marijuana on the brain, particularly the developing brain, as young adolescent users transition into emerging adulthood (ages 18–24), is an increasingly important public health endeavor. To this end, previous studies show that when marijuana use was initiated before age 17, the negative impact of chronic marijuana use on cognitive function and brain morphology can last several years and may even be permanent (Gruber et al., 2011, Jacobus et al., 2009, Jacobus et al., 2014, Meier et al., 2012, Schweinsburg et al., 2008b, Wilson et al., 2000). As such, investigating the effects of marijuana exposure initiated during adolescence and continuing during emerging adulthood on vulnerable prefrontal and subcortical regions will offer unique insight into structural consequences of short-term persistent marijuana use in emerging adults.
The major psychoactive component in marijuana (MJ) is delta-9-tetrahydrocannabinol (THC). The main cannabinoid receptor in the brain is the CB1 receptor, which is a G-coupled protein that is widely distributed throughout the central nervous system (CNS), with greatest densities in the associational areas of frontal and limbic lobes, cerebellar cortex, thalamus, pallidum, amygdala, hippocampus and substantia nigra pars reticulata (Glass et al., 1997). Marijuana use can broadly affect cognitive processes, and prior research demonstrates MJ-related alterations in executive functioning, attention, memory, learning, decision-making, and processing speed (Becker et al., 2014, Lisdahl et al., 2014, Meier et al., 2012, Swift et al., 2008). Moreover, MJ use has been associated with mental health issues, including co-morbid mood symptoms, especially depression and anxiety (Weinstein et al., 2013), lower age of onset of psychosis, mania, increased risk of suicide attempts and a more severe course of illness (Kvitland et al., 2014). The effects of MJ on mood and other psychiatric symptoms has been linked to the ability of the endocannabinoid system to modulate the activity of other neurotransmitter systems, energy metabolism and immune functions (Leweke and Koethe, 2008).
Findings from neuroimaging studies of MJ users, often focused on either adolescent users or adult users, document significant associations between marijuana use and alterations in neurobiology, including brain structure, function and neurochemistry (for review, see Batalla et al., 2013, Martin-Santos et al., 2010, Sneider et al., 2013b). Findings of alterations in brain structure reported using magnetic resonance imaging (MRI) are somewhat heterogenous, however, and the significance of the changes identified using this technology remains controversial because of conflicting findings among existing studies. For instance, while some studies report alterations in whole brain and regional volumes, and in cortical thickness and subcortical volumes (Ashtari et al., 2011, Cousijn et al., 2012, Matochik et al., 2005, Yucel et al., 2008), other investigations fail to report significant differences in brain structure between adult MJ users and comparison subjects (Block et al., 2000, Jager et al., 2007, Tzilos et al., 2005). Importantly, there is mounting evidence that MJ use, particularly exposure to THC, may be more deleterious during adolescence, a time when cognitive development and brain maturation are rapidly ongoing (Lisdahl et al., 2013). For instance, adolescent MJ users exhibit altered frontal region and insula cortical thickness, suggestive of aberrant gray matter (GM) development or maturation that could persist beyond adolescence (Lopez-Larson et al., 2011), and also exhibit alterations in prefrontal cortex, amygdala and cerebellum, some of which are sex-specific (McQueeny et al., 2011, Medina et al., 2009, Medina et al., 2010). It also has been reported that smaller orbitofrontal cortex volumes observed at age 12 years predict initiation of MJ use by age 16 years, whereas volumes of other regions such as amygdala, hippocampus, and anterior cingulate cortex were not predictive of later MJ use (Cheetham et al., 2012). Furthermore, in a longitudinal study of adolescent MJ users, greater lifetime exposure to MJ predicted greater cortical thickness in the left and right superior frontal gyri, left pars opercularis, right pars triangularis, right supramarginal, and left inferior parietal cortex after adjusting for baseline cortical thickness, suggesting that heavy MJ use during adolescence alters the trajectory of cortical GM development (Epstein and Kumra, 2015).
Collectively, previous investigations have focused on identifying regions that exhibit structural alterations related to the effects of MJ use measured during adolescence or during adulthood, but there are few investigations specifically examining structural alterations in emerging adults who initiated MJ use in adolescence. Thus, the present study aimed to characterize potential neurobiological consequences of MJ use on cortical thickness and subcortical volumetric differences in emerging adult MJ users compared with age-matched non-user subjects. A priori regions of interest (ROIs) included orbito-frontal, dorsolateral prefrontal, and anterior cingulate cortices (OFC, DLPFC, and ACC respectively), and superior and middle frontal gyri, as well as subcortical amygdala, thalamus and hippocampus regions.
Frontal ROIs were chosen based on previous reports of MJ-related functional alterations in each region during cognitive task performance. Specifically, altered OFC and DLPFC activity is associated with impaired decision-making and poor adaptation to negative consequences (Bolla et al., 2005), and ACC hypoactivity is associated with error awareness and performance monitoring (Hester et al., 2009) and memory retrieval during spatial navigation (Sneider et al., 2013a). Increased activity has been observed in superior and middle frontal gyri in MJ users during inhibitory processing, suggesting inefficient functional responses and potential overcompensation by neighboring tissue to adequately perform the task (Tapert et al., 2007). Given the sub-optimal functional response of these a priori regions in MJ users during cognitive task performance, it is possible that surface-based cortical thickness analyses will reveal corresponding structural changes, with lower cortical thickness related to MJ use in these regions.
Hippocampus, amygdala and thalamus, regions demonstrating high CB1 receptor distribution (Herkenham et al., 1991), also were selected for volumetric analysis based on evidence that MJ users exhibit functional and neurochemical alterations in these regions related to marijuana use (Ashtari et al., 2011, Bolla et al., 2005, Cousijn et al., 2012, Demirakca et al., 2011, Gilman et al., 2014, Glass et al., 1997, Hester et al., 2009, Mashhoon et al., 2013, Matochik et al., 2005, Schacht et al., 2012, Sneider et al., 2013a, Sneider et al., 2013b, Yucel et al., 2008). Clinical measures of mood and impulsivity were examined relative to cortical thickness and brain volume to further probe potential links with neurobiological consequences of marijuana use.
Section snippets
Participants, demographics and procedure
Fifteen marijuana users (MJ; 2 females, age 21.8 ± 3.6) and fifteen non-user controls (NU; 2 females, age 22.3 ± 3.5) were included in this study. Participants were selected from a larger pool of subjects that underwent structural MRI scanning at McLean Hospital as part of two larger functional magnetic resonance (MR) imaging and MR spectroscopy studies (Silveri et al., 2011, Sneider et al., 2013a). All participants were matched on age, education and alcohol use, and underwent a Structured Clinical
Demographics and substance use
There were no significant differences between MJ and NU groups in age, gender distribution, education or amount of alcohol consumed weekly (Table 1). All MJ use variables are also reported in Table 1.
Clinical data
There were no significant differences between MJ and NU groups on total or subscale scores on the POMS or PANAS (Table 1). MJ users did differ significantly from the NU group on multiple BIS measures (Table 1). MJ exhibited higher scores on the BIS motor (F(1,29)=4.21, p = 0.05, ES = .39) and
Discussion
Emerging adult MJ users exhibited cortical thickness and volumetric differences relative to healthy emerging adult NU. Findings revealed less rFG cortical thickness (i.e., rFG cortical thinness), and smaller thalamic volumes in MJ users. Unlike cortical thinning, which is a continuous measure collected with longitudinal data, ‘cortical thinness’ is a descriptive term that has previously been operationally defined (Mashhoon et al., 2014) as indicating less or lower cortical thickness measured
Conflict of interest
No conflict declared.
Contributors
Drs. Sava, Sneider and Silveri conceptualized the study. Drs. Mashhoon and Sava conducted the data processing and analysis. Drs. Mashhoon, Sava and Silveri drafted the manuscript. Drs. Sneider and Nickerson made contributions and edited the manuscript. Dr. Mashhoon consolidated edits from coauthors. All authors approved the final manuscript.
Role of funding sources
This investigation was supported in part by National Institute on Drug Abuse grants K01DA034028 (YM), R03DA022482 (JTS), and R01DA037265 (LDN), and National Institute on Alcohol Abuse and Alcoholism grant K01AA014651 (MMS).
References (112)
- et al.
Medial temporal structures and memory functions in adolescents with heavy cannabis use
J. Psychiatr. Res.
(2011) - et al.
Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens
Neurobiol. Learn. Mem.
(2002) - et al.
Neural substrates of faulty decision-making in abstinent marijuana users
Neuroimage
(2005) - et al.
Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes
Neurosci. Biobehav. Rev.
(2011) - et al.
Orbitofrontal volumes in early adolescence predict initiation of cannabis use: a 4-year longitudinal and prospective study
Biol. Psychiatry
(2012) - et al.
Developing a cortex specialized for face perception
Trends Cogn. Sci.
(2007) - et al.
Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls
Neuroimage
(2012) - et al.
Cortical surface-based analysis. I. Segmentation and surface reconstruction
Neuroimage
(1999) - et al.
Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol
Drug Alcohol Depend.
(2011) - et al.
An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest
Neuroimage
(2006)
Altered cortical maturation in adolescent cannabis users with and without schizophrenia
Schizophren. Res.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
Sequence-independent segmentation of magnetic resonance images
Neuroimage
Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain
Neuroscience
Differential processing of objects under various viewing conditions in the human lateral occipital complex
Neuron
The primate basal ganglia: parallel and integrative networks
J. Chem. Neuroanat.
Eccentricity bias as an organizing principle for human high-order object areas
Neuron
Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia
Biol. Psychiatry
Functional consequences of marijuana use in adolescents
Pharmacol. Biochem. Behav.
Effects of frequent cannabis use on hippocampal activity during an associative memory task
Eur. Neuropsychopharmacol.
Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS)
Schizophren. Res.
Altered prefrontal and insular cortical thickness in adolescent marijuana users
Behav. Brain Res.
Action-related properties shape object representations in the ventral stream
Neuron
Altered brain tissue composition in heavy marijuana users
Drug Alcohol Depend.
Gender effects on amygdala morphometry in adolescent marijuana users
Behav. Brain Res.
Abnormal cerebellar morphometry in abstinent adolescent marijuana users
Psychiatry Res.
Correlates of intentions to use cannabis among US high school seniors in the case of cannabis legalization
Int. J. Drug Policy
Visual attention: the thalamus at the centre?
Curr. Biol.
Gain control in the visual thalamus during perception and cognition
Curr. Opin. Neurobiol.
Modulation of transmitter release via presynaptic cannabinoid receptors
Trends Pharmacol. Sci.
Temporal trends in marijuana attitudes, availability and use in Colorado compared to non-medical marijuana states: 2003–11
Drug Alcohol Depend.
Abstinent adolescent marijuana users show altered fMRI response during spatial working memory
Psychiatry Res.
A hybrid approach to the skull stripping problem in MRI
Neuroimage
Preliminary evidence for white matter metabolite differences in marijuana-dependent young men using 2D J-resolved magnetic resonance spectroscopic imaging at 4 Tesla
Psychiatry Res.
Adolescent neurodevelopment
J. Adolesc. Health
Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain
Neuroscience
The ontogeny of human gyrification
Cereb. Cortex
Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings
PLoS One
Neurocognition in college-aged daily marijuana users
J. Clin. Exp. Neuropsychol.
Anatomical changes in the emerging adult brain: a voxel-based morphometry study
Hum. Brain Mapp.
Hardwiring the brain: endocannabinoids shape neuronal connectivity
Science
Effects of frequent marijuana use on brain tissue volume and composition
Neuroreport
Dose-related neurocognitive effects of marijuana use
Neurology
Similarity of fMRI activity patterns in left perirhinal cortex reflects semantic similarity between words
J. Neurosci.
Functional diversity on synaptic plasticity mediated by endocannabinoids
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Cannabinoid effects on CB1 receptor density in the adolescent brain: an autoradiographic study using the synthetic cannabinoid HU210
Synapse
The validity of self-reports of alcohol consumption: state of the science and challenges for research
Addiction
Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis
Ann. Neurol.
Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition (SCID-I/NP)
Measuring the thickness of the human cerebral cortex from magnetic resonance images
Proc. Natl. Acad. Sci. U. S. A.
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Co-first authors.