Therapeutic Effects of Prolonged Cannabidiol Treatment on Psychological Symptoms and Cognitive Function in Regular Cannabis Users : A Pragmatic Open-Label Clinical Trial
Nadia Solowij, Samantha J. Broyd, Camilla Beale, Julie-Anne Prick, Lisa-marie Greenwood, Hendrika van Hell, Chao Suo, Peter Galettis, Nagesh Pai, Shanlin Fu, Rodney J. Croft, Jennifer H. Martin, and Murat Yücel
Cannabis and Cannabinoid Research, 2018, 3, 1,21-35
Doi : 10.1089/can.2017.0043
Introduction : Chronic cannabis use has been associated with impaired cognition and elevated psychological symptoms, particularly psychotic-like experiences. While D9-tetrahydrocannabinol (THC) is thought to be primarily responsible for these deleterious effects, cannabidiol (CBD) is purported to have antipsychotic properties and to ameliorate cognitive, symptomatic, and brain harms in cannabis users. However, this has never been tested in a prolonged administration trial in otherwise healthy cannabis users. Here, we report the first study of prolonged CBD administration to a community sample of regular cannabis users in a pragmatic trial investigating potential restorative effects of CBD on psychological symptoms and cognition.
Materials and Methods : Twenty frequent cannabis users (16 male, median age 25 years) underwent a 10-week open-label trial of 200mg of daily oral CBD treatment, while continuing to use cannabis as usual. The majority of participants were daily cannabis users who had used cannabis for several years (median 5.5 years of regular use). Participants underwent psychological and cognitive assessments at baseline (BL) and post-treatment (PT) and were monitored weekly throughout the trial.
Results : CBD was well tolerated with no reported side effects; however, participants retrospectively reported reduced euphoria when smoking cannabis. No impairments to cognition were found, nor were there deleterious effects on psychological function. Importantly, participants reported significantly fewer depressive and psychotic-like symptoms at PT relative to BL, and exhibited improvements in attentional switching, verbal learning, and memory. Increased plasma CBD concentrations were associated with improvements in attentional control and beneficial changes in psychological symptoms. Greater benefits were observed in dependent than in non-dependent cannabis users.
Conclusions : Prolonged CBD treatment appears to have promising therapeutic effects for improving psychological symptoms and cognition in regular cannabis users. Our findings require replication given the lack of a placebo control in this pragmatic trial, but suggest that CBD may be a useful adjunct treatment for cannabis dependence.
Keywords : cannabidiol; cannabis; attention; memory; psychological symptoms
The global trend toward legalization of cannabis for medicinal and recreational use highlights an urgent need for scientific investigation of the potentially harmful and beneficial effects of its constituent compounds, particularly in light of ongoing concerns regarding cannabis exposure effects on health.1,2 Prolonged frequent use of cannabis, particularly of high potency, has been associated with deleterious effects on psychological function, including increased risk of developing psychosis,3,4 impaired cognition,5,6 and alterations to brain structure7 and function.8,9 These adverse outcomes have been associated with the action of D9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and partial agonist at central cannabinoid (CB1) receptor sites.10 In contrast, the second most abundant constituent within cannabis, cannabidiol (CBD), is thought to have a broad range of therapeutic properties, including amelioration of the adverse psychological and cognitive effects of THC.11 Unlike THC, CBD is a low-affinity CB1 and CB2 receptor ligand and negative allosteric modulator of CB1, which reduces the binding of CB1 agonists, while augmenting endocannabinoid tone in an indirect manner.12,13
Therapeutic effects of CBD have been reported across a range of study designs and in different populations. In studies examining naturalistic exposure to CBD through hair analysis in regular cannabis users, greater concentrations of CBD have been associated with better cognitive performance, especially memory,14 fewer psychotic symptoms,15,16 and increased gray matter in the hippocampus. 17 We recently demonstrated that naturalistic exposure to CBD in cannabis users is associated with normal hippocampal volumes relative to users exposed to THC, but not CBD.18 This suggests that CBD may
be neuroprotective, perhaps through its role in synaptic plasticity and/or neurogenesis. Animal studies have also shown CBD to reverse THC-induced spatial memory deficits,19 conditioned place aversion,20 and decreased social interaction (for a review, see Refs.12,21), and importantly, to increase hippocampal cell survival and neurogenesis. 22 Administration of pure compounds to humans showed that CBD produces opposite effects to THC in the nature of regional brain activation23 and acute exposure to CBD ameliorates cognitive and psychotic-like symptoms induced by THC in cannabis users.24 Despite promising evidence of the therapeutic effects of CBD, no study to date has examined the potentially
restorative effects of prolonged CBD administration to cannabis users.
This study is the first investigation of potential therapeutic effects of prolonged daily administration of CBD to regular cannabis users using a pragmatic open-label design, wherein cannabis users maintained their naturalistic use of cannabis. On the basis of reviewed literature, we focused on symptoms of depression, trait anxiety, and psychosis-proneness,4,25,26 and cognitive performance within the domains of attention/executive function and learning andmemory, being the most sensitive to the deleterious effects of chronic cannabis use.5 We hypothesized that prolonged administration of CBD would improve psychological functioning and cognitive performance in regular cannabis users. We had no a priori hypothesis regarding the effects of prolonged CBD exposure on ongoing patterns of cannabis use, since potentially diminished effects of THC could either result in a reduction or an increase in cannabis use if its rewarding effects are mitigated.