Does regular cannabis use affect neuroanatomy ? An updated systematic review and meta-analysis of structural neuroimaging studies, Valentina Lorenzetti et al., 2019

Does regular cannabis use affect neuroanatomy ? An updated systematic review and meta-analysis of structural neuroimaging studies

Valentina Lorenzetti, Yann Chye, Pedro Silva, Nadia Solowij, Carl A. Roberts

European Archives of Psychiatry and Clinical Neuroscience, 2019

Doi : 10.1007/s00406-019-00979-1


Regular cannabis use is associated with adverse cognitive and mental health outcomes that have been ascribed to aberrant neuroanatomy in brain regions densely innervated with cannabinoid receptors. Neuroanatomical differences between cannabis users and controls have been assessed in multiple structural magnetic resonance imaging (sMRI) studies. However, there is heterogeneity in the results leading to cautious interpretation of the data so far. We examined the sMRI evidence to date in human cannabis users, to establish more definitely whether neuroanatomical alterations are associated with regular cannabis use. The regional specificity and association with cannabis use indices (i.e. cumulative dosage, duration) were also explored. We systematically reviewed and meta-analysed published sMRI studies investigating regional brain volumes (cortical, subcortical and global) in cannabis users and non-user controls. Three electronic databases were searched (PubMed, Scopus, and PsycINFO). A total of 17 meta-analyses were conducted (one for each cortical, subcortical and global volume) using the generic inverse variance method, whereby standardised mean difference in volume was calculated between users and non-users. Exploratory meta-regressions were conducted to investigate the association between cannabis use indices and regional brain volumes. A total of 30 articles were eligible for inclusion, contributing 106 effect sizes across 17 meta-analyses. Regular cannabis users had significantly smaller volumes of the hippocampus (SMD = 0.14, 95% CIs [0.02, 0.27]; Z = 2.29, p = 0.02, I2 = 74%) and orbitofrontal cortex {medial (SMD = 0.30, 95% CIs [0.15, 0.45]; Z = 3.89, p = 0.0001, I2 = 51%), lateral (SMD = 0.19, 95% CIs [0.07, 0.32]; Z = 3.10, p = 0.002, I2 = 26%)} relative to controls. The volumes of the hippocampus and orbitofrontal cortex were not significantly associated with cannabis duration and dosage. Our findings are consistent with evidence of aberrance in brain regions involved in reward, learning and memory, and motivation circuits in the regular use of substances other than cannabis, pointing to commonality in neurobiological abnormalities between regular users of cannabis and of other substances.



Cannabis is the most widely used illicit substance globally, with upwards of ~ 180 million users [11]. Regular cannabis use has been perceived as relatively harmless by the general and scientific community [15, 11]. Yet, regular cannabis use has been associated with comorbid psychopathologies or elevated symptoms of depression, anxiety and psychosis [1, 15, 11, 1, 15] and deficits in performance in selected areas of cognition, including reward processing, learning and memory [1, 1, 15]. Adverse mental health outcomes and cognitive deficits in cannabis users have been ascribed to alteration in the neuroanatomy of pathways that underlie emotion, stress, cognitive control and addiction [15]. As such, attempts have been made to assess the neuroanatomical integrity of regular cannabis users with structural magnetic
resonance imaging (sMRI) techniques that allow imaging the brain in vivo at a high resolution (i.e. mm), with somewhat heterogeneous findings.

The most consistent findings suggest neuroanatomical differences between regular cannabis users and non-cannabis using controls, in the hippocampus, amygdala, prefrontal cortex (PFC) and cerebellum [37]. Notably, these brain regions are high in cannabinoid receptors type 1 (CB1) [11], to which delta 9-tetrahydrocannabinol (THC), the psychoactive compound of cannabis, binds [43]. Recent sMRI
evidence indicates that these alterations are correlated with heavier cannabis use or are observed more consistently in samples of heavier cannabis users (e.g. longer duration, higher dosage, more severe problem use) [17–11, 15]. On the other hand, several sMRI studies report a lack of neuroanatomical
differences between cannabis users and controls, and no associations between level of cannabis use and neuroanatomical measures [43, 37, 37]. The heterogeneity of reported findings across studies can, to some extent, be overcome by a meta-analysis, allowing for greater confidence in interpreting the evidence on neuroanatomical changes in cannabis users. This evidence is required to inform debates
on the extent of the potential neurobiological harms associated with regular cannabis exposure.

To our knowledge, only one previous meta-analysis and meta-regression of sMRI studies in cannabis users versus controls exists [11]. This work focused on whole brain, intracerebroventricular, hippocampal, and amygdala volumes as regions of interest (ROIs), finding significant reduction in hippocampal and amygdala volumes in cannabis users. However, they did not examine other cortical and subcortical regions, many of which are densely innervated with CB1 receptors that may mediate the effect of cannabis on the brain. Moreover, since 2013, > 10 additional studies have been published which examined additional brain regions. As such, an updated meta-analysis on the data published to date is warranted.

In this study, we aimed to quantitatively examine the extent of neuroanatomical differences between regular cannabis users and controls, by synthesising the sMRI findings to date in a meta-analysis. To this end, we meta-analysed volumetric data available for cortical (i.e. anterior cingulate (ACC), orbitofrontal (OFC), prefrontal (PFC) and parietal cortices), subcortical (i.e. hippocampus, amygdala, striatum, nucleus accumbens (NAc), caudate, putamen), cerebellum, and global brain areas (i.e. total brain, intracranium, total white matter and total grey matter). Secondly, we explored the association between patterns of cannabis use and the volumetry of regions that differed between cannabis users and controls, informed by our first analysis. This included a series of eight exploratory meta-regressions using either duration or cumulative dosage as predictors, and the volume of select brain regions that differed between groups as dependent variables if > 2 studies assessed either duration or dosage (i.e. the hippocampus and the total, medial and lateral portions of the OFC, but not the nucleus accumbens).