A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol

Cannabis is the third most widely used drug in the world, after tobacco and alcohol, with an estimated 209 million persons, or 4.1% of the global adult population having used cannabis in the previous year (2020), Cannabis use has increased by 23 per cent between 2010 and 2020 [1]. Worryingly, between 9 and 22% of people who use cannabis will develop moderate or severe cannabis use disorder (CUD) [2] signifying ongoing cannabis use despite clinically significant impairment in health and social function [2]. The most recent global estimate suggests approximately 22.1 million persons met diagnostic criteria for CUD in 2016 (289.7 cases per 100,000 people) [3, 4].

CUD is associated with an increased risk of numerous psychosocial outcomes, including: (i) mental health problems (e.g., anxiety, depression, psychosis, suicide); (ii) physical illness (e.g. respiratory, cardiovascular disease, cancer); (iii) cognitive impairment (e.g., verbal learning, memory and attention); (iv) impaired brain development with prenatal or adolescent exposure; (v) social harms (e.g. crime, employment, parenting, financial impacts); and (vi) motor vehicle accidents [5].

Existing treatments for CUD have modest outcomes. Reviews of psychosocial interventions (e.g. cognitive behavioural therapy (CBT), motivational enhancement therapy) [6] and acute withdrawal management [7] indicate that over 80% of patients relapse within 1–6 months of attempting treatment [8‐11]. In substance use disorders other than CUD, treatment outcomes are generally optimised when combining medications with psychosocial interventions [12]. Despite examining a wide variety of medications, there are no registered pharmacotherapies for treating CUD [13‐15].

There is increasing interest in the use of cannabinoid medications to treat CUD. Promising results have emerged in RCTs with delta-9-tetrahydrocannabinol (THC)-based medications (e.g., nabiximols [16], a 1:1 ratio of THC and CBD) and synthetic THC-based medications (e.g., dronabinol, nabilone) [16, 17]. However, many individuals may not be attracted to cannabinoid ‘agonist’ therapy with THC-based medications as they may have intoxicating, psychotogenic, anxiogenic and addictive properties. Thus, there is growing interest in the potential of non-intoxicating cannabinoids, such as CBD, in the treatment of CUD.

Cannabidiol (CBD) is one of the many cannabinoids found in the Cannabis sativa plant. It has diverse and multiple molecular targets [18] and anti-inflammatory, anxiolytic, anticonvulsant and antipsychotic properties [18‐24]. Importantly in the context of CUD, CBD is a negative allosteric modulator of the activity of cannabinoid type 1 receptors within the central nervous system, restricting the ability of THC to bind to these receptors, thus reducing THC action [25]. CBD does not cause intoxication, dependence, or withdrawal on discontinuation, and does not result in positive results in urine or saliva tests used to detect cannabis use [26, 27]. Meta-analyses of clinical trials indicate CBD has a good safety profile [28], including in cannabis-using populations [29], and low oral bioavailability (approximately 6%) with a half-life of 18–32 h that permits once daily dosing [30].

CBD has shown promise in animal studies modelling addiction to a range of other substances, with reductions in self-administration of alcohol, opioids, cocaine, and methamphetamine [31]. Endocannabinoids are important regulators of the brain pathways that mediate neurodevelopment, drug-reward and addiction[32, 33]. In human studies examining other addictive drugs, CBD has been found to significantly reduce cue-induced craving and anxiety during abstinence from heroin [34] and cigarette use among tobacco smokers [35], but was not effective in reducing relapse or cravings in a placebo-controlled randomised trial for cocaine dependence [36].

There has been considerable scientific discussion in recent years about the promise of CBD as a treatment for CUD [37, 38], summarised in a recent review: “According to the previous evidence, it seems that CBD could play a crucial role in the management of CUD [38]”. Preclinical studies suggest that CBD administered to cannabis-dependent rodents reduces the severity of spontaneous withdrawal from THC [39‐41]. Despite this, there has been little rigorous clinical research to date examining CBD as a treatment for CUD in humans. Early open-label case studies involving 10 participants with severe CUD indicate that CBD may ameliorate cannabis withdrawal severity and improve anxiety and sleep [39, 42, 43]. These studies used doses varying from 18 to 1200 mg daily but had methodological limitations that limit conclusions regarding efficacy.

A recent Phase 2a adaptive Bayesian RCT [44] demonstrated the promise of CBD for moderate-to-severe CUD and determined suitable doses for further investigations. 82 outpatients diagnosed with moderate-to-severe CUD were randomised to four-weeks of oral placebo (n = 23), 200 mg CBD (n = 12), 400 mg CBD (n = 24), or 800 mg CBD (n = 23), each receiving six sessions of motivational interviewing The 200 mg dose arm was eliminated as it was not efficacious following interim analyses. Both 400 mg and 800 mg groups were more efficacious than placebo in reducing cannabis use indicated by self-reported cannabis-free days and urinary carboxy-THC (THC-COOH), the inactive metabolite of THC excreted in urine. Doses were well tolerated with no serious adverse events. Reductions in cannabis use persisted 20-weeks after the four-week intervention in the 400 mg, but not the 800 mg group suggesting that further exploration of the 400 mg dose is warranted. However, the study was not powered to demonstrate efficacy, so larger RCTs are also necessary. The relatively high rates of relapse to heavy cannabis use at follow-up may be attributed to the brief treatment duration (4-weeks) examined in the phase 2a RCT. Indeed, in our previous 12-week RCT of nabiximols, we demonstrated that the full extent of reductions in cannabis use were not achieved until at least week 8 [16]. This suggests a prolonged duration, such as, 12-weeks of CBD and counselling may achieve better outcomes.

In their recent 12-week exploratory, observational, non-randomised, open-label study, Cleirec and colleagues [45] investigated the therapeutic potential of inhaled CBD amongst 20 patients, administered through an electronic vaping device, for the treatment of moderate-to-severe CUD. The average daily dose of inhaled CBD was 216 mg (equivalent to approximately 600–700 mg oral CBD). With a flexible dosing regimen and no formal counselling, the study demonstrated promising outcomes, including a notable 30% (n = 6) of participants achieving a 50% reduction in days of cannabis use, and 15% (n = 3) reporting complete abstinence by the end of the intervention. The absence of significant adverse events or the need for rescue medications further supports rigorous clinical trials examining the efficacy of CBD for CUD.

Fortin and colleagues [46] recently reported findings from an online anonymous survey of French residents who reported having used CBD within the past month. Respondents reported using CBD primarily to reduce their use of (illicit) cannabis. Of these, 59% (61/105) reported that their CBD use led to a large reduction in illegal cannabis consumption, 35% a moderate reduction, 6% no reduction, and 1% a moderate increase. While the study is limited by the self-report nature of the data and the inherent sampling biases of online surveys, the study provides a consumer perspective of the promise of CBD for treating CUD, complementing findings from the aforementioned preclinical and clinical studies.

In addition to CBD’s potential to facilitate a reduction in cannabis use, prolonged high-dose CBD usage in individuals with CUD may offer an additional advantage—potentially mitigating the adverse cognitive and mental health effects of long-term THC exposure [40, 41]. Animal studies indicate CBD reverses THC-induced memory deficits, conditioned place aversion and decreased social interaction [26]. In a human laboratory study, pre-treatment with CBD reduced acute THC-induced persecutory symptoms and hippocampal-dependent memory impairment [40]. In an open-label study, 10-weeks of daily oral CBD (200 mg) was associated with reduced cognitive deficits, psychotic-like and depressive symptoms and increased hippocampal volumes in chronic cannabis users (daily or near-daily use) (despite continued cannabis use), with the greatest benefits seen in those with cannabis dependence [47]. In the same trial, hippocampal and amygdala functional connectivity with other cortical regions (precentral and lingual gyrus, respectively), changed from pre-to-post intervention, with strong effect sizes (d > 1) [48]. However, in a Phase 2a RCT, CBD was not found to significantly impact cognition relative to placebo, except in the 800 mg group [49], although the study was underpowered. Nevertheless, the above studies suggest that the anxiolytic, antipsychotic and neuroprotective effects of CBD may improve the psychological, cognitive and brain health commonly related to long-term cannabis use [24]. This may be an added benefit of using high-dose CBD in people seeking treatment for CUD and identifies potential ‘secondary outcomes’ for future studies.

A challenge in embarking on clinical trials for substance use disorder is choosing a primary endpoint. Whilst historically abstinence (cessation of all use) has often been used in cannabis treatment research, there is increasing recognition that abstinence may not be the primary goal of treatment for patients who use cannabis. A recent consensus expert panel identified suitable outcomes when undertaking clinical trials for the treatment of CUD [50], recommending primary outcomes of (a) self-reported frequency of use, using the Time Line Follow Back (TLFB) method [51]; (b) biological assessment of cannabis use, with urinalysis of the metabolite THC-COOH or oral fluid detection of THC; and (c) severity of CUD, using a structured instrument measuring DSM-5 Criteria (e.g. Mini-International Neuropsychiatric Interview (MINI) [52]). In line with these recommendations, and consistent with the previous Phase 2a RCT, we propose to use two primary endpoints to measure illicit cannabis use: (1) self-reported ‘cannabis-free days’ and (2) urinary THC-COOH, across the 12-week treatment period of the study, alongside a range of secondary outcome measures.

Cannabis use is more prevalent among Aboriginal and Torres Strait Island people than non-Indigenous Australians. Data from the 2019 National Aboriginal and Torres Strait Islander Health Survey [53] indicated 24% (31% males, 18% females) of Indigenous people aged ≥ 15 years reported cannabis use in the past year, an increase from 19% in the corresponding 2012–2013 survey, and 30% higher than non-Indigenous Australians [53]. The elevated prevalence of illicit drug use among Indigenous Australians could be attributed to personal and familial factors, including intergenerational trauma from colonisation and experiences of racism. Societal-level influences such as persistent social and economic marginalisation contribute significantly to the increased likelihood of substance use amongst Indigenous Australians [1, 2].

Not only are prevalence rates of CUD higher, but the harms also resulting from cannabis use are greater in Indigenous Australian communities. Indigenous Australians are five times more likely to be hospitalised for CUD than non-Indigenous Australians [54] and six times more likely to seek treatment for cannabis use than non-Indigenous Australians when adjusted for age [2].

Yet despite the high prevalence of cannabis use and related harms in Indigenous Australians, to date, there have been no clinical treatment trials for CUD among Indigenous Australian populations. This study aims to ensure that a representative proportion of Indigenous Australian participants, with a target of 20% of the total sample, are recruited to the study. The target reflects the proportion of Indigenous Australian clients attending for cannabis treatment in participating study sites, with representation of Aboriginal researchers, health workers and consumers at all levels of the project governance (see Methods).

Cannabis Use Disorder poses significant health and social risks. Existing psychosocial treatments for CUD have modest effects, prompting the exploration of effective medications. CBD has emerged as a promising treatment for CUD, backed by preclinical evidence, and pilot data from a recent Phase 2a RCT. CBD offers additional advantages by potentially alleviating the mental health, and cognitive impairments associated with prolonged cannabis use.

The study is a parallel group prospective double-blind Phase 3 randomised controlled trial comparing a 12-week treatment period of oral CBD (400 mg daily) (Experimental) to placebo (Control), with both groups receiving 4 sessions of manualised CBT-based counselling. Research interviews will be conducted at baseline (week 1), 3-weekly during the study intervention (weeks 4, 7, 10 and 13) and 12-weeks after the end of treatment (week 25) (Fig. 1). The study will use a modified intention-to-treat analysis. The expected number of participants is 250, of which we estimate approximately 20% (n = 50) will be of Indigenous background. The study will also include qualitative interviews with Indigenous Australian participants in both control and intervention groups (a total of n = 15–25 Indigenous Australian participants) to examine their experiences in the study.

The study will be conducted in accordance with the National Statement on Ethical Conduct in Human Research (2007), the CPMP/ICH Note for Guidance on Good Clinical Practice and consistent with the principles that have their origin in the Declaration of Helsinki. The study was approved by the Sydney Local Health District Human Research Ethics Committee (no 2022/ETH02467) and the Aboriginal Health and Medical Research Council’s Human Research Ethics Committee (no 2110/23). The project has an Aboriginal Reference Group that oversees all aspects of the study, including data collection and analysis as they relate to Indigenous Australians. The study has been registered on the Australian and New Zealand Clinical Trial Registry (ACTRN12623000526673).

The multicenter trial will be coordinated from the Specialty of Addiction Medicine, Faculty of Medicine and Health, University of Sydney (study sponsor). Treatment will be provided at seven specialist addiction outpatient treatment centers: four in Sydney, one in Newcastle and two in Melbourne, Australia.

The primary outcomes are illicit cannabis use during the 12-week intervention period, operationalised using two endpoints:

Secondary outcomes (Table 1) include a range of measures that relate to cannabis use (including rates of abstinence or reduced frequency of cannabis use, cannabis withdrawal and cravings, cannabis related problems, severity of CUD), safety (adverse events), health outcomes (including mental health, physical health, QoL), consumer experience of the medication, cognitive performance, other substance use and post-treatment outcomes (12 weeks after the intervention). The relationship between experiences of racial discrimination (using the modified Everyday Discrimination Scale) and outcomes for Indigenous Australians will also be explored.

Confidentiality of participant data will be secured by removing all identifiable data and replacing it with a unique identifier. The principal investigator and coordinating researcher will have access to key files that link the unique identifier to identifiable data if unblinding is necessary.

Trial data will be electronically entered and stored on REDCap on the research drive of the University of Sydney, with regular data back-up. After the trial, the data will be stored for a minimum of 15 years in a secured study-specific folder on the research drive of the University of Sydney, and access to de-identified data will be considered upon request by the principal investigator.

An independent Data Safety and Monitoring Committee (IDSMC), comprising of an addiction medicine specialist, a statistician and clinical pharmacologist will oversee the safety monitoring of the trial, involving ongoing reviews of any adverse events arising from the administration of CBD (unblinded data). The committee will also monitor aspects of study integrity and design should any protocol changes need to be made.

All data analysis will be performed using Bayesian models instead of frequentist. Bayesian methods can quantify evidence for both effects and the absence of effects, are less prone to non-convergence (due to regularisation), and sample from a joint posterior distribution, hence no family- or experiment-wise correction of regression coefficients for multiple comparisons is necessary [61]. We will use a modified intention-to-treat approach for data analysis, with group membership fixed as the medication type (placebo vs CBD) participants receive on their first study day. Missing data will be imputed via hierarchical multiple imputation [62].

The multisite study will occur across the two most populous states in Australia. It will be coordinated through several governance structures, including an overarching Steering Committee (senior research staff and Study Investigators), a Consumer Advisory Group and an Aboriginal Reference Group.

The Consumer Advisory Group includes a Consumer Researcher (member of project team) and between 8 and 12 people with lived experience of cannabis use and treatment, who advise the project team on the study procedures (including recruitment strategies, treatment, and data collection procedures) and assist in interpretation of findings, and dissemination activities with community groups (e.g., lay summaries of study findings).

The Aboriginal Reference Group includes Aboriginal Investigators, research staff, representatives of Aboriginal Health Workers at participating sites, and representatives of Aboriginal Alcohol and Other Drug (AOD) workers in services not participating in the study (to provide independent community perspectives). The Aboriginal Reference and Consumer Advisory Groups will be consulted to interpret and disseminate study findings.