Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users

Camilla Beale, Samantha J Broyd, Yann Chye, Chao Suo, Mark Schira, Peter Galettis, Jennifer H Martin, Murat Yücel, Nadia Solowij, Camilla Beale, Samantha J Broyd, Yann Chye, Chao Suo, Mark Schira, Peter Galettis, Jennifer H Martin, Murat Yücel, Nadia Solowij

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).

Keywords: CA1; cannabidiol; cannabis; hippocampal subfields; hippocampus; subiculum.

Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Cross-sectional slices of a T1-weighted image from one participant with automated segmentation of hippocampal subfields overlaid. Coronal (top), axial (middle), and sagittal (bottom) views. CA, cornu ammonis; GC-ML-DG, granule cells in the molecular layer of the dentate gyrus; HATA, hippocampal-amygdala transition area; ML-DG, molecular layer of the dentate gyrus.
FIG. 2.
FIG. 2.
Time by group interaction for (a) left presubiculum (*p=0.015) and (b) right CA1 (*p=0.012) volume, controlling for intracranial volume and cumulative cannabis use (cones smoked) across the trial. Error bars represent standard error.
FIG. 3.
FIG. 3.
Significant associations in heavy users between (a) mean plasma CBD concentration and right presubiculum volume change; (b) mean plasma CBD concentration and right subicular complex volume change; and (c) final week CBD plasma concentration and right total hippocampal volume change. CBD, cannabidiol.

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