Abstract
Introduction: Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. While adverse impacts of cannabis use are generally attributed to Δ9-tetrahydrocannabinol, emerging naturalistic evidence suggests cannabidiol (CBD) is neuroprotective and may ameliorate brain harms associated with cannabis use, including protection from hippocampal volume loss. This study examined whether prolonged administration of CBD to regular cannabis users within the community could reverse or reduce the characteristic hippocampal harms associated with chronic cannabis use.Materials and Methods: Eighteen regular cannabis users participated in an ∼10-week open-label pragmatic trial involving daily oral administration of 200 mg CBD, with no change to their ongoing cannabis use requested. Participants were assessed at baseline and post-CBD treatment using structural magnetic resonance imaging. Automated longitudinal hippocampal segmentation was performed to assess volumetric change over the whole hippocampus and within 12 subfields.Results: No change was observed in left or right hippocampus as a whole. However, left subicular complex (parasubiculum, presubiculum, and subiculum) volume significantly increased from baseline to post-treatment (p=0.017 uncorrected) by 1.58% (Cohen's d=0.63; 2.83% in parasubiculum). Heavy cannabis users demonstrated marked growth in the left subicular complex, predominantly within the presubiculum, and right cornu ammonis (CA)1 compared to lighter users. Associations between greater right subicular complex and total hippocampal volume and higher plasma CBD concentration were evident, particularly in heavy users.Conclusions: Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis. While replication is required in a larger, placebo-controlled trial, these findings support a protective role of CBD against brain structural harms conferred by chronic cannabis use. Furthermore, these outcomes suggest that CBD may be a useful adjunct in treatments for cannabis dependence and may be therapeutic for a range of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer's disease, and major depressive disorder).
Highlights
Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus
We have recently shown apparent normalization of hippocampal volume and n-acetylaspartate (NAA; a marker of hippocampal neuronal integrity) levels in cannabis users regularly smoking cannabis containing CBD, such that they were indistinguishable from controls, while those exposed to THC but not CBD, showed 11% smaller hippocampal volumes and 15% lower NAA concentrations than controls.[8]
Participants reported experiencing less euphoria when smoking cannabis at post-treatment compared to baseline ( p = 0.001)
Summary
Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. Regular and prolonged cannabis use has been associated with morphological[1,2] and functional brain changes,[2,3,4] cognitive impairment,[5] and increased risk of adverse mental health outcomes, including the precipitation of psychotic symptoms and disorders.[6,7] Neuroimaging evidence has consistently identified the hippocampus, a subcortical brain region critically involved in learning and memory and implicated in psychopathology, as a particular locus of compromise.[1,2] Long-term heavy cannabis users have demonstrated reduced hippocampal volume[8,9] and gray matter density[10] compared to nonuser controls, with some evidence for greater volume loss resulting from greater exposure to cannabis.[1] Alterations to hippocampal shape,[11] neurochemistry,[8] and structural[12] and functional connectivity[13] in chronic cannabis users have been reported. Precise neurobiological mechanisms by which CBD may promote neurogenesis remain unclear, modulation of endocannabinoids such as anandamide through CB1Rs has been implicated.[29,31]
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