Cannabidiol: a novel treatment for cannabis dependence?

In Europe, 1% of all adults and nearly 2% of 14-17 year olds are addicted to cannabis. Rates of cannabis dependence have increased markedly over recent years alongside changes in the ingredients of cannabis available on the market (increasing skunk or sinsemilla with high THC and lacking CBD). Among UK first-time drug treatment clients, cannabis is now the primary addiction in 28% of those entering drug treatment, second only to heroin (41%). At present, clinicians rely on psychological treatments which have very limited effectiveness. There is no pharmacological treatment for cannabis addiction. If we found a safe, effective medicine this could improve treatment in a similar way that various medicines have improved rates of stopping tobacco use. It would also impact on educational/vocational achievement and illegal behaviour, and reduce young people's risks of cannabis-associated mental health problems (e.g. schizophrenia, depression).
Converging preclinical and human research suggests cannabidiol (CBD) to be a highly promising treatment, with excellent tolerability and safety. One of the key consequences of cannabis withdrawal is anxiety and CBD reduces anxiety. CBD has shown promising pro-cognitive and neuroprotective effects which may reverse some of the cognitive deficits associated with cannabis dependence. Our recent research has shown that cannabis dependence is more common in those using 'skunk'. Other data suggest a mechanism by which CBD may be protective against cannabis dependence. A key feature of addiction is that an addict's attention is strongly drawn to cues related to the drug abused over and above other cues and this makes it hard to stop use. Animal evidence suggests that CBD can reduce the ability of drug cues to cause relapse to heroin. In people dependent on cannabis, we have found that CBD reduced attention grabbing by cannabis-related pictures. After CBD, cannabis users rated cannabis pictures as less pleasurable. Thus CBD may reduce the motivating power of drug cues. Overall, evidence now suggests that CBD is a logical treatment for cannabis dependence, by targeting key mechanisms both in dependence and equally importantly, cannabis withdrawal symptoms.
This project's objectives are first to determine the optimal dose of CBD and then to evaluate its efficacy in treating cannabis dependence.
Design: participants will be 16-26 year olds who meet clinical criteria for cannabis dependence. Stage 1 is a dose-finding study comparing 28 days' treatment with CBD 200, 400, 800mg or matched placebo. Data will be independently reviewed during interim analyses to identify the Most Effective Dose based on measures of changes in cannabis use and withdrawal symptoms. Stage 2 will then expand existing group numbers by allocating new participants to either MEDmg or placebo until there are 60 in each group. Success criteria at Stage 2 include more individuals in the CBD than the placebo group being abstinent or non-dependent and significantly reduced intensity of cannabis withdrawal symptoms. We also predict that those given CBD treatment will show improvements in memory, psychological well-being and days in work/education.
Application: More people are dependent on cannabis than any other illicit drug - at least 18 million worldwide. The demand for cannabis treatment has more than doubled since 2001 (UNODC World Drug Report 2010). An effective pharmacological treatment would therefore be a major benefit to mental and physical health. It would also impact upon associated psychological and social consequences of cannabis addiction. Benefits would additionally accrue in a reduction of the acute harms associated with cannabis (e.g. anxiety, psychosis-like effects, increased risk of road traffic accidents). The success of this study would provide a very strong impetus for a large scale clinical trial.

Background: In Europe 1% of all adults and nearly 2% of 14-17 year olds are addicted to cannabis and 28% of all new drug treatment admissions are now for primary cannabis dependence. There is no medication for cannabis dependence. An effective treatment would impact significantly on medical and legal costs, on young people's educational achievement and their risk of mental health problems.
Proposed solution: Based on a strong preclinical rationale, our own extensive human data and the importance of the endocannabinoid system in reward and addiction, cannabidiol (CBD) is a highly promising treatment which has excellent tolerability and safety.
Objectives: To determine the optimal dose of CBD and its efficacy in the treatment of cannabis dependence.
Design: Stage 1 (dose-finding study) will randomly allocate 16-26 year olds who meet DSM criteria for cannabis dependence to parallel groups administered oral CBD 200, 400, 800mg or matched placebo for 28 days. Independent data review at specified recruitment points will identify doses of interest based on significant reductions in urinary THC-COOH, self-reported cannabis use and withdrawal intensity. If Stage 1 successfuly identifies a Most Effective Dose (MEDmg) of CBD, Stage 2 will expand existing group numbers by allocating new participants to MEDmg or placebo (total N=120). Primary success criteria include: more abstinent cannabis users (ideal criterion), more non-dependent users (acceptable criterion) and reduced withdrawal intensity in the CBD than placebo group. Secondary criteria include improved memory, psychological well-being and days in work/education.
Application/exploitation: The findings would have broad application given the world wide prevalence of dependent cannabis use and associated medical, psychological and social consequences. The success of this study would provide a very strong impetus for a large scale clinical trial.

Who will benefit from this research?

Policy makers: currently there are reviews of drug policy occurring in both the House of Commons and the House of Lords. A pharmacological treatment for cannabis dependence may well influence drug policy in terms of debates about decriminalisation or licensing cannabis use. In the USA, policy makers may use this research in debating the continuation or not of medical uses of marijuana. Within the UK, users of this research would be the government's Advisory Council on the Misuse of Drugs and the Independent Scientific Committee on Drugs.

Wider public: cannabis is a public health issue across the world and so the findings of this project have potential for global impact. Those addicted to cannabis will be the major users of this research. Dependent cannabis use by younger people can impact negatively upon their families and their schools/colleges and these may be indirect beneficiaries. Cannabis remains a large problem for policing and the legal system. The probationary/legal system could be users of this research in terms of advocating more effective treatment orders.

Charities: there are various charities concerned with the use of drugs who will use outputs from this project. For example, the charity DrugScope provides educational materials for school pupils and their teachers and these could encourage more problematic cannabis users to seek help given an effective pharmacological treatment.

Commercial private sector: companies manufacturing cannabidiol would be users of this research. They would also benefit in terms of increased understanding of the effects of CBD treatment on the brain's endogenous cannabinoid system which would be very important to the development of new cannabinoid targets, some of which are now in the early stages of development.


How might they benefit?
Potential to contribute to the nation's health and wealth: the marked prevalence of cannabis use makes it a public health issue and if successful this project will make a significant contribution to the nation's health. It will also have impact on wealth in terms of fewer days absent from education/work and this combined with improved neurocognitive function should enhance achievement and productivity. Quality of life of individuals with the addiction and their families would be improved by successful pharmacological treatment.

Increasing the effectiveness of public services and policy: the main users will be NHS Drug Treatment Services and treatment provision within the charitable and private sectors.
Timescales for the benefits to be realized: the success of this project would lead to a large scale randomized clinical trial which, if also successful, would mean that benefits to the target population of cannabis dependent individuals could be realized within 3 years following completion of the present project.

What research and professional skills of staff working on the project will be gained? We anticipate a wide range of generic research skills will be acquired by the post-doc and RA as well as generic communication skills (via peer-reviewed articles, conference abstracts, oral presentations to a range of academic and non-academic audiences).