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

Cannabis and Cannabinoid Research, 2018, 3, 1, 94-107.

Doi : 10.1089/can.2017.0047

Regular and prolonged cannabis use has been associated with morphological1,2 and functional brain changes,2–4 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-termheavy cannabis users have demonstrated reduced hippocampal volume8,9 and gray matter density10 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 structural12 and functional connectivity13 in chronic cannabis users have also been reported. Recently, we showed that volumetric reduction of specific hippocampal subfields (cornu ammonis [CA]1–4 and dentate gyrus [DG]) was sensitive to cannabis dependence, with an inverse correlation between greater lifetime cannabis exposure and subfield volumes in dependent, but not nondependent users.14

Cannabinoid type 1 receptors (CB1Rs) are abundant throughout the brain, but occur in high density in specific regions, including the hippocampus.15 Cannabis-related neurobiological, cognitive, and psychological harms are generally ascribed to D9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, which is a partial agonist at CB1Rs.16,17 Acute administration of THC to humans dose-dependently transiently increases anxiety, impairs cognition, and induces a range of positive and negative psychoticlike symptoms, including paranoia, delusions, and conceptual disorganization.18–20 While the precise mechanisms underlying these effects are not well understood, animal studies have shown that THC accumulates in neurons,21 with long-term exposure to THC resulting in neurotoxic changes in hippocampal microstructure.22 Conversely, cannabidiol (CBD) is the second most abundant cannabinoid in cannabis and has purported neuroprotective,23 anxiolytic,24
and antipsychotic25 properties. Acutely administered, CBD exerts opposing effects to THC upon activation of specific brain regions, including the hippocampus, 26 and ameliorates the induction of hippocampaldependent cognitive impairment and psychotic-like symptoms by THC in healthy volunteers.27 CBD has a low affinity for CB1Rs, yet demonstrates the capacity to antagonize CB1R agonists, which may underlie its functional antagonism of THC.28 Preclinical studies have shown CBD to induce synaptic plasticity and facilitate hippocampal neurogenesis,29,30 with some evidence suggesting that the proneurogenic action of CBD via the hippocampus may underlie its anxiolytic
effects.30 Although precise neurobiological mechanisms by which CBD may promote neurogenesis remain unclear, modulation of endocannabinoids such as anandamide through CB1Rs has been implicated.29,31

In recent years, increasingly potent strains of cannabis containing high levels of THC and decreasing levels of CBD have dominated the market, raising concerns for greater THC-related harms in the community.7,32 Naturalistic studies examining proportional exposure to THC and CBD by hair analysis of chronic cannabis users found that the presence of CBD in cannabis was associated with fewer psychotic-like symptoms,33,34 improved recognition memory,34 and increased hippocampal gray matter concentration.10 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 fromcontrols, while those exposed to THC but not CBD, showed 11% smaller hippocampal volumes and 15% lower NAA concentrations than controls. 8 These findings indicate CBD may protect against neurobiological and psychological harms of regular cannabis use; however, the cross-sectional nature of these studies precludes any inferences about directionality.

The possibility that prolonged administration of CBD to cannabis users may protect against or reduce
THC-induced harms is intriguing. The hippocampus is highly neuroplastic and volume growth has been demonstrated following relatively brief interventions (e.g., increase in hippocampal volume by 12% in patients with schizophrenia and 16% in healthy controls following 12 weeks of aerobic exercise,35 indicating this is an adequate timeframe to observe discernible treatment effects in the hippocampus). Hence, this study aimed to investigate whether prolonged administration of CBD may reverse hippocampal volumetric reduction typically observed in long-term, heavy cannabis users, but recruitment was broadened to enable examination of effects of CBD treatment in a sample with a range of cannabis experience. An *10-week pragmatic, open-label trial was undertaken, in which cannabis users within the community consumed 200mg CBD in capsule form daily, in the context of their ongoing cannabis use. Structuralmagnetic resonance imaging (MRI) scans were completed at baseline and post CBD treatment. It was hypothesized that prolonged CBD administration would result in increased hippocampal volume at post-treatment, as subserved by growth in specific subfields such as CA1, subiculum, and DG, due to the high concentration of CB1Rs in these subregions15 and their involvement in neurogenesis.36

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