Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment
Amir Englund, Paul D Morrison, Judith Nottage, Dominic Hague, Fergus Kane1, Stefania Bonaccorso1, James M Stone, Avi Reichenberg, Rudolf Brenneisen, David Holt, Amanda Feilding, Lucy Walker,
Robin M Murray and Shitij Kapur
Journal of Psychopharmacology, 2012
Doi : 10.1177/0269881112460109
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 600mg (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.
Keywords : Delta-9-tetrahydrocannabinol, cannabidiol, THC, CBD, psychosis
The cannabis plant contains over 60 different cannabinoid molecules (Izzo et al., 2009), but two in particular have relevance for psychiatry. Δ9-tetrahydrocannabinol can induce acute psychotic symptoms, in medicated schizophrenic patients and in healthy controls, whereas cannabidiol (CBD) is showing promise as a possible anti-psychotic (D’Souza et al., 2009; Leweke et al., 2000; Zuardi et al., 2006).
The balance of these two molecules in ‘street cannabis’ appears to have changed over the last decade. For example, in the UK and Holland, cannabis products traditionally contained about 4% THC and 4% CBD, as compared with 16–22% THC and <0.1% CBD content in modern ‘high-potency’ products (Sinsemilla or ‘skunk’) (Slade et al., 2012). There is accruing evidence that sinsemilla carries a greater risk to mental health (Di Forti et al., 2009; Morgan and Curran, 2008; Schubart et al., 2011).
In a highly original design, Morgan and Curran measured trace cannabinoid levels in hair samples from regular cannabis users as well as psychosis proneness as rated by the OLIFE (Oxford Liverpool Inventory of Life Experiences) instrument. Regular users who were grouped as THC-positive/CBD-negative scored higher on scores of unusual experiences than regular users who were positive for both cannabinoids (Morgan and Curran, 2008). In an epidemiological study in South London, Di Forti and colleagues compared patterns of drug use in people presenting with a first episode of psychosis with healthy controls. Patients were approximately seven times more likely than controls to be users of sinsemilla (Di Forti et al., 2009).
In Holland, the most popular types of cannabis sold are measured annually for THC and CBD content. Schubart and colleagues combined this information with data on cannabis use from approximately 1900 people, and found that the THC/CBD ratio was related to subclinical psychotic experiences as rated by the CAPE scale (Community Assessment of Psychic Experiences). Subjects who used products with a high THC/CBD ratio reported significantly higher CAPE-total scores than those using products with a low THC/CBD ratio. In heavy users, higher CBD content was associated with lower scores on the CAPE-positive symptoms dimension (Schubart et al., 2011).
In laboratory-based experimental studies, the acute effects of specific cannabinoid molecules can be measured under tightly controlled conditions. For example, in the early 1980s, Zuardi and colleagues demonstrated that CBD (1 mg/kg) inhibited the anxiety provoked by THC (0.5 mg/kg) (Zuardi et al., 1982). More recently, in a neuroimaging study of 15 healthy volunteers, task-specific blood-oxygen-level-dependent (BOLD) responses were measured following the administration of oral THC (10 mg), CBD (600 mg) or placebo. Relative to placebo, THC and CBD evoked diametrically opposite task-specific BOLD responses in the hippocampus, the amygdala and the occipital cortex (Bhattacharyya et al., 2010), the right superior temporal gyrus (Winton-Brown et al., 2011) and the pre-frontal cortex and caudate nucleus (Bhattacharyya et al., 2012).
Previously we reported preliminary findings that pre-treatment with intravenous (IV) CBD (5 mg) inhibited IV THC (1.25 mg) evoked positive psychotic symptoms, as measured by the Positive & Negative Syndrome Scale (PANSS), although the small sample size (crossover, n=6) prevents definitive conclusions (Morrison et al., 2010). Here we report the first findings from a larger study (between groups, n=48) in which IV THC (1.5 mg) followed pretreatment with either oral CBD (600 mg) or placebo. We hypothesised that, following IV THC, the group who had been pre-treated with CBD would show less positive symptoms and less cognitive impairment than the group that had been pre-treated with placebo.