Rebecca M. Lee1,2, James A. Foulds3, Reza Shoorangiz2, Mustafa M. Almuqbel4, Campbell Le Heron1,2,5, Lana Cleland3, Ross J. Keenan4, Roger Mulder3, Richard J. Porter3, Giles Newton-Howes6, Katie M. Douglas3, Anthony P. H. Butler7, Joseph M. Boden3, and Tracy R. Melzer1,2
1Department of Medicine, University of Otago, Christchurch, New Zealand, 2New Zealand Brain Research Institute, Christchurch, New Zealand, 3Department of Psychological Medicine, University of Otago, Christchurch, New Zealand, 4Pacific Radiology Group, Christchurch, New Zealand, 5Department of Neurology, Christchurch Hospital, Christchurch, New Zealand, 6Department of Psychological Medicine, University of Otago, Wellington, New Zealand, 7Department of Radiology, University of Otago, Christchurch, New Zealand
Synopsis
Keywords: Gray Matter, Brain, Cannabis
This study investigated whether cannabis use during adolescent and early adulthood was associated with long-term brain differences into middle-age, using structural T1-weighted, ASL, and diffusion MRI. Compared to non-using controls, users exhibited significantly less grey matter volume in the hippocampus and amygdala (p < 0.05). We observed no significant between-group differences in cerebral blood flow or white matter integrity. While cannabis may relate to long-term brain changes, prospective longitudinal MRI studies may help to elucidate causality.
Introduction
Cannabis is one of the most widely used illicit drugs in New Zealand and worldwide.1,2 By 21 years old, 80% of New Zealanders will have tried it at least once, with 10% going on to develop a pattern of heavy use or dependence.3
Cannabis use is associated with varying effects on learning, attention, temporary hallucinations, paranoia, disorganized thinking, and short-term memory loss.4,5 MRI studies have also suggested cannabis-related structural and functional changes in temporal regions; however they are often inconsistent and not necessarily associated with the short-term effects of cannabis use.6,7 Knowledge of the long-term effects of cannabis use on the brain is of increasing importance in New Zealand and worldwide as societal attitudes towards the medical and recreational use of cannabis are becoming increasingly tolerant.
In this study, we used MRI to investigate the long-term effects cannabis exposure has on brain volume, cerebral perfusion, and cerebrovascular health at age 43. Methods
Sixty-nine participants, aged 43, were recruited from the Christchurch Health and Development Study (CHDS) – a longitudinal study of people born in Christchurch, New Zealand in 1977, followed from birth. The CHDS has detailed prospective self-report data on cannabis and alcohol use in late adolescence and early adulthood,8,9 which was used to classify participants as cannabis users (n=35) or non-using controls (n=34), matched for sex and tobacco use. Cannabis-exposed participants were defined as having a history of heavy cannabis use or dependence at one or more time-points from age 15 onwards.
All participants underwent MRI scanning using a Siemens Skyra 3T MRI scanner (Siemens Healthcare, Erlangen, Germany). Three imaging acquisitions were used: a T1-weighted MPRAGE (TE/TR/TI=2.85/2000/880ms, flip angle=8°, FOV=256mm, matrix=256 × 256, slices=208, BW=240Hz/pixel, voxel=1 × 1 × 1mm3, total scan time=4:56min); Pseudo-continuous arterial spin labelling (PCASL) to measure perfusion (3D GRASE readout, background suppression, three post-labelling delays (PLD) with Hadamard encoding=1100, 2100, 3100ms, TR/TE=5500/13.08ms, FOV=256mm, matrix=64 × 64, voxel=4 × 4 × 4.5mm3, grappa=2, M0 scans with reversed phase-encoding, scan time ≈ 6min), and measure arterial transit time (7 PLD times starting at 500ms and increasing by 400ms to 2900ms, FOV=256mm, acquisition matrix=64 × 64, voxel=4 × 4 × 4.5mm3, total scan time ≈ 8min); High angular resolution diffusion imaging (HARDI), with diffusion weighting in 150 directions, 25 with b=1000s/mm2, 50 with b=2000s/mm2, 75 with b=2700s/mm2, as well as 10 b=0s/mm2 (TE/TR=106/3600ms, flip angle=90°, matrix=126 × 126, FOV=240ms, voxel=1.9 × 1.9 × 2mm3, multiband factor=3, with inverted phase encoded images to enable distortion correction, total scan time ≈ 9 min). During the PCASL acquisition, participants were instructed to focus on a fixation cross.
T1-weighted images were processed using FreeSurfer (v7.2) and FSL (v6.0.5); PCASL data were processed using oxford_asl (FSL); diffusion data were processed using a tensor fit and constrained spherical deconvolution using MRTrix (v3.0.2).
We tested for brain differences between the cannabis and non-using controls using an ANCOVA model, with sex, tobacco use, and intracranial volume (only for volume comparisons) as covariates. First, we investigated a priori selected subregions of the hippocampus and amygdala (defined using FreeSurfer), which are rich in CB1 cannabinoid receptors. This was followed by exploratory whole brain analyses. Region of interest analyses were performed in R (v4.2.1); whole brain analyses used randomise10 and fixelcfestats11 to carry out non-parametric, voxel-wise cross-subject statistics using 10000 permutations, and threshold-free cluster enhancement to correct for multiple comparisons (p<0.05).Results
Significantly smaller volumes were identified in cannabis users in hippocampal subregions – CA1 (Cohen’s d = 0.66 [0.17, 1.14]), hippocampal fissure, molecular layer, presubiculum, and subiculum – and in the amygdala subregions – lateral, paralaminar, basal, and accessory basal nuclei (Cohen’s d = 0.81 [0.31, 1.3]). No significant group differences (corrected p<0.05) were observed in any perfusion or white matter integrity metrics in the hippocampus or amygdala, or in whole brain analyses.Discussion
Our results of smaller hippocampal and amygdala subregional volumes are consistent with previous short-term follow-up studies, and suggest that volumetric brain differences are still observable in middle-aged adults with a history of cannabis use. Conversely, there was no evidence of differences in cerebral perfusion or white matter integrity amongst people with heavy cannabis exposure.12
Although we identified structural brain changes associated with heavy cannabis use, our study does not conclusively show these changes are causally related to cannabis use. Prospective longitudinal MRI studies may help to elucidate causality.
The lack of detectable cerebral blood flow and white matter tract integrity differences associated with cannabis is interesting. This may suggest that cannabis use has no long-term effect for these properties, or any potential brain changes may be transient and detectable only during periods of use. Additionally, this study may be underpowered so small effects may not be detectable in the current cohort.6Conclusion
Heavy cannabis use in adolescence to early adulthood was associated with volumetric differences in subregions of the hippocampus and amygdala. However, direction of causation and the extent to which these structural brain changes mediate the effect of cannabis on long-term functional outcomes is not clear, but may emerge from longitudinal studies.Acknowledgements
The authors gratefully acknowledge funding support from the Health Research Council of New Zealand, the Canterbury Medical Research Foundation, Pacific Radiology Christchurch, and the MedTech CoRE.
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