How does cannabis use affect teenagers' brains, cognitive functions and psychological well-being? (CANN-TEEN)

How does cannabis use affect the teenage brain, cognitive function and psychological well-being? This is an important question for several reasons. 1. Across the globe, more people use cannabis than any other illicit drug and roughly half of them start using it before they are 18 years of age. 2. The active ingredient in cannabis - THC - causes more profound and persistent harms to adolescent rats and monkeys than it does in adult animals. 3. The brain's 'own cannabis' system - the endocannabinoid system - is critically important to brain development in adolescence and can be disrupted by cannabis use. 4. The strength of cannabis has increased dramatically over recent years so very high potency varieties (15% THC or more) are what most teenagers get when they start using. 5. The high potency varieties contain virtually no cannabidiol (CBD) - an ingredient in cannabis which can protect adults against some of the harms caused by THC. 6. Across Europe, the proportion of people who become addicted to the drug is six times higher in 14-17 year olds than in adults and younger use is associated with greater risk of developing a psychotic disorder like schizophrenia. 7. Earlier cannabis use is also associated with greater risk of cognitive impairment and poorer achievement at school so can seriously affect an individual's life trajectory.

We recently completed the first ever study to directly compare the effects of a single dose of cannabis in human adolescents (16-17 year old boys) with adults. Compared with adults, the teenagers showed greater impulsiveness and wanted more of the drug even when they had consumed cannabis rather than placebo. Whilst the adults showed increases in anxiety the teenagers did not, and the teenagers experienced significantly fewer negative effects including reduced physiological response and psychotic-like symptoms than adults. The teenagers' 'stop' mechanism therefore appeared switched to a 'go' profile: once they were 'stoned' they were more impulsive and wanted more cannabis. The teenagers' different pattern of response to acute cannabis could be a key mechanism mediating their increased risk compared with adults of transitioning to addiction or other mental health problems, and experiencing difficulties in cognitive functioning and educational achievement. We now need to find out how the use of cannabis affects human adolescents compared with adults over an extended period of time whilst using objective measures of cannabis (THC and CBD), alcohol, tobacco and other drug use, monitoring changes in the markers of the endocannabinoid system. This project will do this in 3 related studies. Study 1 will determine how cannabis use over a 12 month period affects psychological well-being, cognitive function and markers of endocannabinoids in 16-17 year olds compared with 26-27 year old adults. Study 2 will determine the extent to which there are differential changes in markers of brain structure and function in teenage and adult cannabis users over this same 12 month period. Study 3 is the first experiment to examine the causal effects of cannabis on the adolescent brain. It will build on the discovery in adults of the protective effects of CBD, to determine whether teenagers and adults respond differently to the acute effects of cannabis and whether this varies depending on whether the cannabis contains CBD or not.

Although virtually all cannabis users experience at least transient cognitive impairments, only around 9% of adults become addicted and a smaller minority ever develops psychosis. We will also analyse our data to address this question: what factors predict vulnerability/resilience to the negative consequences of use and do these differ in teenagers and adults? Crucially, this project will enhance our theoretical and clinical understanding and provide vital information to young cannabis users, to their families, friends and those professionals who interact with them.

In line with preclinical research on adolescent rats and monkeys, and the known importance of the endocannabinoid system in adolescent neurodevelopment, we recently found that teenage humans (16-17 year olds) show a markedly different response profile from adults to acute cannabis: more impulsivity, less satiety (wanting more cannabis) whilst also experiencing significantly fewer negative effects than adults. This project aims to address the following questions: how does cannabis use over a 12 month period affect the brain, cognitive function, symptoms of addiction and of psychosis in 16-17 year olds compared with adults? And can CBD lessen the harms induced by THC in teenagers as it has been found to in adults? Study 1 recruits 360 individuals aged - 16-17 and 26-27 who do and do not use cannabis frequently - and assesses them every 3 months for a year, taking objective measures of cannabis (THC, CBD), alcohol & other drug use in hair, urine and saliva, serum anandamide, and cognitive function & psychological well-being. Study 2 uses s/fMRI to compare a sub-set of the same groups at baseline and +12 months. Study 3 uses pharmacological fMRI to compare teenagers and adults who use cannabis in their acute response to different cannabis strains (THC+CBD, THC-CBD, matched placebo). Motivations to use cannabis and beliefs about the drug/strains will be explored in interviews, and analyses will examine why some individuals are vulnerable and others resilient to its harmful effects. If we show differential effects in teenagers and adults then this would be a clear evidence-base for prevention messages (e.g. avoid or delay initiation of cannabis use to adulthood; only use strains with significant CBD content or take CBD supplements). This could lead to a new era of safer cannabis use. Importantly, it could significantly reduce the numbers of young people in the UK currently in treatment for addiction or psychosis who may not have become ill had they not used this drug.

The people who will benefit from this research project are firstly teenagers and young people who use cannabis and significant others in their lives such as family, partners and friends. Of the ~180 million cannabis users worldwide, around 19.5 million meet criteria for dependence; in Europe, an estimated 3.2 million people are clinically dependent.These individuals are also at increased risk of psychosis, especially if they use highly potent varieties that lack CBD (Di Forti et al 2015). All cannabis users are exposed to at least transient cognitive impairments, which can impact negatively on educational achievement. Users may also become less motivated to attend school/college, exacerbating underachievement and often leading to isolation from peers, teachers and other protective environments.

Other non-academic beneficiaries include those who work with teenage cannabis users including teachers, professionals in Child and Adolescent Mental Health Services, drug services and early intervention in psychosis. Further, as more people are addicted to cannabis than any other illicit drug, there will be broader societal impacts as addiction costs the UK more than £40 billion per year (Centre for Social Justice, 2013).

An additional benefit is having greater knowledge about safer cannabis use. If we confirm our hypotheses about age differences in the effects of cannabis then we can give strong, evidence-based advice to teenagers to avoid cannabis, or delay starting cannabis use until adulthood - a crucial preventative message for adolescent mental health. Our identification of what factors make some more resilient will help us to provide tailored guidance to more vulnerable individuals. Further, if we show strains containing CBD are less damaging for teenager's mental health, cognitive function and/or neural integrity, this could allow the adverse consequences of THC to be offset with novel harm reduction strategies: i) if teenagers are unable or unwilling to stop using cannabis, they could be encouraged limit their use to cannabis with adequate levels of CBD (this might be assessed by the development of a testing kit) or ii) by CBD being made available to vulnerable cannabis users (e.g. oral spray) so that inadequate CBD levels may be counteracted by taking CBD alongside cannabis use.

This project will also produce important novel findings about the social and economic context of cannabis use by teenagers and adults: how do they obtain cannabis (e.g. friends, internet, dealers, home-grown), the costs and the social context of use. Have they been exposed to synthetic cannabis (e.g. Spice) and do they know how this is covered in the Government's recent law (the New Psychoactive Substances Bill, coming into force May 26 2016)? When and why did they start use, what are the drug's benefits and what might influence their decision to stop in the future? What are their parents' views of the drug and what did their parents tell them about it? This information will enhance impact by helping target public health messages more appropriately to different age groups and different at-risk groups, and will provide invaluable insight to professionals working with young users in the clinic.

Cannabis now stands poised to join alcohol and tobacco as a legal drug. For example, two-thirds of Americans can now legitimately access medical marijuana. In some US states, all of Canada and several European countries, recreational use of cannabis has been decriminalised or made a legal activity and the number of users is rapidly increasing (Volkow et al, 2016). In the UK the Liberal Democrats now openly support legalisation. This project will therefore provide important scientific evidence to inform political debate. The high prevalence of cannabis use, especially among the young, means that the findings of this project will impact significantly on public health not only in the UK but throughout Europe, North and South America and beyond.