Reducing the harmful effects of cannabis use: finding the optimal CBD:THC ratio

Cannabis is used by an estimated 182 million people globally. There are indications that this number is on the rise and an estimated 30% of the UK public have tried it. There is a dominance of high-potency cannabis, high in its main active compound delta-9-tetrahydrocannabinol (THC) and with little or none of the protective compound cannabidiol (CBD).

Large studies of the general population consistently show that people who use cannabis are more likely to develop psychosis later in life. People with psychosis experience unpleasant symptoms such as delusions and hallucinations, which are difficult to treat and can persist for years or even a whole lifetime.

Importantly, studies comparing different types of cannabis have found that stronger cannabis poses an even greater risk to psychosis compared to weaker types. Experiments in healthy volunteers suggest that this might be due to both high levels of THC and low levels of CBD. THC can cause short-lived anxiety and psychotic symptoms, whereas CBD has can help to treat people suffering from anxiety or psychosis.

It is therefore likely that cannabis with greater CBD would be less harmful. However, most previous studies have not been able to separate the effects of THC from CBD. Furthermore, it is unclear exactly how much CBD is needed to reduce the harmful effects of THC. Answering this question could allow cannabis users to reduce their risk of developing mental health problems like psychosis, addiction and memory problems.

In this study we aim to explore how much CBD is needed to offset the harmful effects of THC in 45 volunteers. Participants will be assessed to make sure they are physically and psychologically healthy before taking part. They will then be invited for 4 separate study visits, each separated by a minimum of 2 weeks, in which they will be administered inhaled cannabis vapour of 4 different potencies. The standardised cannabis material will be provided by Bredrocan BV, Holland (http://www.bedrocan.nl/), and the inhalation device will be provided by Storz & Bickel GmbH, Germany (http://www.storz-bickel.com/shop_eu/en/). On each study visit, participants will be given vaporised cannabis with a CBD:THC ratio of 0:1, 1:1, 2:1 and 3:1 in a random order. Both the participants and researchers will be unaware of which CBD:THC ratio is being administered on a given study visit.

Following the inhalation of cannabis vapour, the participants will complete a series of tests examining their cognitive functioning, such as remembering a list of words. The participant will then take a short walk from the research facility at King's Hospital to the hospital canteen - this has previously been found to increase anxiety and paranoia while under the influence of THC. Lastly, the participants will fill out questionnaires relating to their mood states and a trained interviewer will perform a short clinical interview to see if the participant has experienced any psychotic symptoms. Throughout the day, participants will provide 3 blood samples, which will be analysed for levels of CBD and THC.

We expect that the greater the CBD:THC ratio is - the less pronounced the cognitive, paranoid and psychotic effects will be for the participants. We also predict that higher doses of CBD will not influence the pleasurable effects of the inhaled cannabis, nor will CBD influence the amount of THC which reaches the blood.

The legislative landscape of cannabis has been changing recently; all while prevalence and negative cannabis related outcomes have been on the rise. Interventions to prevent or reduce cannabis use have been unsuccessful to date. Therefore, manipulation of CBD levels in cannabis may be a viable way to minimise cannabis related harms, in places where cannabis is regulated.
This will be a randomised, double-blind, 4-arm, cross-over, within-subjects design study in healthy volunteers being administered different intra-pulmonary cannabis preparations with varying CBD:THC ratios. Forty five female and male volunteers, aged between 21-50, and who have used cannabis at least once and no more than once per week on average in the last year will be invited for a screening/baseline visit. Participants will be excluded if they have a past history of major mental or physical illness, a first degree family member with psychosis, history of drug or alcohol dependence, current pregnancy or lactation in women, currently taking prescription medication (except oral contraceptives), positive urine drug screen at any study visit, alcohol use within the last 24h hour, and weekly use over recommended limits.
At each experimental visit, participants will be administered a vaporised cannabis preparation containing CBD:THC ratios of 0:1, 1:1, 2:1, and 3:1 (CBD: 10-30mg, THC: 10mg, loaded). This will be followed by a social interaction task (purchase item in hospital shop), a comprehensive cognitive test battery and clinical assessment of psychopathology. Blood samples and vital signs will be collected at 5min, 15min and 1h post-inhalation to analyse plasma THC and CBD levels, as well as their relevant metabolites. We predict that CBD will in a dose dependent manner reduce the negative impact of THC on cognition and psychopathology, while not influencing its intoxicating properties. We expect these effects to be due to the CBD:THC ratio and not due to changes in THC plasma levels.

Most of the harmful effects of cannabis use are attributable to THC, and there is now clear evidence that CBD can protect against these effects. A key outstanding issue is that it is not known what ratio of CBD:THC in cannabis confers the greatest protection. The present study aims to be the first to determine this experimentally, which is critical for the development of harm-reduction interventions.

Cannabis use poses a significant risk to society. These include a risk of psychiatric symptoms and disorders, impaired cognitive and intellectual functioning, addiction and associated criminal activity, and increased risk of industrial and road-traffic accidents. Furthermore, cannabis use is particularly harmful for people with schizophrenia, as it exacerbates psychotic symptoms. It also increases the likelihood of relapse, hospital admission, and risk of violence. All of these harms are associated with significant health economic costs, both to society and to healthcare systems.

In recent years, the type of cannabis available to users is increasingly likely to have an extremely low CBD:THC ratio. Determining the CBD:THC ratio that minimises harmful effects without losing the desirable effects of cannabis to the user is fundamental to the development of a 'safe' pharmaceutical form of cannabis that could be used as an alternative to illicit cannabis, as part of a harm-reduction strategy. Our discussions with problem users have highlighted that they are unable or unwilling to stop using cannabis in spite of it causing serious problems. It is therefore vital to explore all alternatives to reduce harm for this vulnerable group. This is analogous to the use of electronic cigarettes as a means of reducing the harmful effects of smoking tobacco.

Many cannabis users experience significant adverse effects from the drug, but are unwilling to stop using it. If these individuals used a "safe' form of cannabis (with a high CBD:THC ratio) instead of illicit cannabis (with a low CBD:THC ratio), they would be less likely to experience harmful effects. The findings of this study will also be of significant importance to the pharmaceutical industry. The development of new cannabis-based medicines is an important area of activity and the UK already has a licensed medicine named Sativex, which contains CBD and THC (1:1 ratio). This study will inform pharmaceutical industry work in this field by clarifying the extent to which unwanted effects of cannabinoids can be minimised by manipulating the proportions of CBD and THC. Furthermore, understanding the ability of CBD to reduce the induction of psychiatric symptoms will inform ongoing work aimed at developing psychotropic medicines based on CBD.

In 2007, in the light of a body of research indicating the adverse effects of cannabis use, particularly on mental health, the UK government changed the status of cannabis from a C-class to a B-class drug. The recent advent of high potency forms of cannabis may lead national governments to introduce new legislation that differentiates between types of cannabis according to their THC concentration. In Uruguay, where cannabis use is legal, there is a proposal to make cannabis with a THC concentration of more than 15% illegal, and similar propositions have been made in the Netherlands. These measures are intended to minimise cannabis related harm by reducing exposure to THC. However our research suggests that the ratio of CBD:THC is a crucial factor, and these proposals do not to take CBD into consideration. The findings of the present study are likely to highlight this issue, and may thus critically influence future legislation on cannabis use. For example, in countries or states where cannabis use is legal, governments may require that cannabis products sold to the public contain adequate amounts of CBD. In countries where cannabis use is illegal, the use of cannabis with a high CBD:THC ratio might be associated with less severe penalt