M. Di Forti

Cannabis-associated psychosis: Neural substrate and clinical impact

Abstract Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia‐like psychoses. Early onset of use, daily use of high‐potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk‐increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta‐9‐tetrahydrocannabinol (THC), can produce transient, dose‐dependent, psychotic symptoms, as well as an array of psychosis‐relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”. HighlightsHeavy use of cannabis increases the risk of later psychosis.Administration of THC to volunteers induces transient psychosis and increases release of dopamine in striatum.However in chronic users, synthesis of dopamine in striatum is decreased.The proportion of THC in “street” cannabis is rising.There are plausible biological explanations for the psychotogenic effects of cannabis.

Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders

While acute cannabis use stimulates appetite, general population studies suggest that chronic use is associated with reduced risk of obesity and other cardiometabolic risk factors. In this study we investigated changes in body mass index (BMI), fasting blood glucose and lipids, and rates of metabolic syndrome risk factors in cannabis users vs. non-users in 109 minimally treated patients with first-episode schizophrenia, schizophreniform or schizo-affective disorder who were treated according to a standardized treatment regime with depot antipsychotic medication over 12 months. Participants underwent repeated urine toxicology tests for cannabis and those testing positive at any time during the study (n = 40), were compared with those who tested negative at all time points (n = 69). There was a significant group*time interaction effect (p = 0.002) with the cannabis negative group showing a greater increase in BMI than the cannabis positive group, after adjusting for age, sex, methamphetamine use and modal dose of antipsychotic. There were no group*time interaction effects for fasting blood glucose or lipids. Post hoc tests indicated significant increases in fasting blood glucose and triglycerides and a decrease in high-density lipoprotein cholesterol for the cannabis negative group, with no significant changes in the cannabis positive group. Rates of metabolic syndrome did not differ significantly between groups, although more cannabis negative patients had elevated waist-circumference at endpoint (p = 0.003). It may be that chronic cannabis use directly suppresses appetite, thereby preventing weight gain in users. However, other indirect effects such as dietary neglect and smoking may be contributory and could explain our findings.

Cognitive impairment and subjective time in schizophrenics

Background: The large variation in individual clinical responses to antipsychotic treatment hampers the management of psychotic disorders. Genetic factors are considered a main cause of this variation. Pharmacogenetics studies have demonstrated significant associations between several candidate genes (a.o. D2, D3, 5HTR2A and 5HTR2C, GRM3, COMT and MTHFR) and the response to antipsychotic drugs. The present study investigates the effect of 12 polymorphisms for an association with antipsychotic treatment response in patients with a psychotic disorder. Methods: 335 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 12 SNPs in 7 candidate genes (DRD2: TaqI-A, TaqI-D, -141-C, C957T; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser, -759-T/C; COMT: Val108/158Met; MTHFR: 677-C/T, GRM3: rs274622) using standard protocols. Polymorphisms were based on previous studies showing associations with treatment response. The Clinical Global Impression- Schizophrenia scale was cross-sectionally used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used to test for an association between polymorphisms and improvement in positive symptoms. All polymorphisms were tested in an additive model, with minor allele dose as the dependent variable. Results: Ninety percent of the patients used atypical antipsychotics, with olanzapine (31%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value .029) and 677-C/T of MTHFR (P value .029) were tested significant. Gly carriers and T-carriers, respectively, showed better clinical improvement on the positive scale. All other polymorphisms did not show any association with treatment response (all P values >.10). Conclusion: We were able to replicate only two of the previously reported associations between polymorphisms and treatment response. Heterogeneity in patient samples and outcome variables as well as publication bias and false positive findings may all play a role in lack of replication, found in our study, as in others. The direction of the associations presented here in D3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response.

S26-01 Patients with first episode psychosis take more and stronger cannabis than controls

Epidemiological studies have reported that the increased risk of developing psychosis in cannabis users is dose related. In addition, experimental research has shown that the active constituent of cannabis responsible for its psychotogenic effect is Delta-9-Tetrahydrocannabinol (THC) (Murray et al, 2007). Recent evidence has suggested an increased in potency (% TCH) in the cannabis seized in the UK (Potter et al, 2007). We predicted that first episode psychosis patients are more likely to use higher potency cannabis and more frequently than controls. We collected information concerning socio-demographic, clinical characteristics and cannabis use (age at first use, frequency, length of use, type of cannabis used) from a sample of 191 first-episode psychosis patients and 120 matched healthy volunteers. Cases were more likely to be regular users (p=0.05), to be current users (p=0.04) and to have smoked cannabis for longer (p=0.01). Among cannabis users, 86.8% of 1st Episode Psychosis Patients preferentially used Skunk/Sinsemilla compared to 27.7% of Controls. Only 13.2 % of 1st Episode psychosis Patients chose to use Resin/Hash compared to 76.3% of controls (OR*= 7.4 95% CI 3.4- 17.2, Adjusted for age, gender, ethnicity, level of Education and employment status).The concentration of TCH in these in South East London, ranges between 8.5 and 14 % (Potter et al, 2007). Controls (47%) were more likely to use Hash (Resin) whose average TCH concentration is 3.4% (Potter et al, 2007). Patients with first episode psychosis have smoked higher potency cannabis, for longer and with greater frequency, than healthy controls.