Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38–4.96) or due to adverse events (OR 2.65, 95% CI: 1.04–6.80), any serious adverse event (OR 2.30, 95% CI: 1.18–4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09–60.02) or pneumonia (OR 5.37, 95% CI: 1.17–24.65), any adverse event (OR 1.55, 95% CI: 1.03–2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94–6.53), diarrhoea (OR 2.61, 95% CI: 1.46–4.67), somnolence (OR 2.23, 95% CI: 1.07–4.64) and sedation (OR 4.21, 95% CI: 1.18–15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44–17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.

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Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a doseresponse relationship between the level of use and the risk of later psychosis. High-potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co-administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high-potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids.Key words: Cannabis, psychosis, marijuana, synthetic cannabinoids, cognitive function, brain structure, genetic predisposition, early adolescence (World Psychiatry 2016;15:195-204) The use of cannabis has been illegal in most countries since the 1930s, but this has not deterred use 1 . Currently, cannabis is used by around 180 million people globally 2 . The tensions produced by this unsatisfactory situation have resulted in much attention being paid to the legal status of cannabis.Possession of the drug in small quantities has been decriminalized officially in countries such as Portugal and the Netherlands, and unofficially in many more. In 2013, Uruguay became the first nation to legalize the sale, cultivation and distribution of cannabis 3 . Four US states have also legalized recreational use, and another twenty-five US states as well as Canada permit so-called "medicinal marijuana". While Uruguay has strict rules concerning access, laws vary state by state in the US, with policy being increasingly driven by entrepreneurs in search of profit, and law makers in search of taxes.Given the above, it seems likely that consumption of cannabis will increase rather than decrease. This makes it imperative to understand the possible adverse consequences of use, even if they only affect a minority of users. In this paper we start by reviewing cannabinoids and the endocannabinoid system. We then focus on cannabis use and risk of psychiatric disorder, particularly psychosis, before touching on the effects on cognition and brain structure. CANNABINOIDS AND THE ENDOCANNABINOID SYSTEMCannabis contains over one hundred cannabinoids 4 , the most important of which are tetrahydrocannabinol (THC) and ...

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