Background and Aims
While epidemiological studies support a role for heavy, high‐potency cannabis use on first‐episode psychosis, genetic models of causation suggest reverse causal effects of ...schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking.
Design
This study used summary statistics from published genome‐wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever‐use, ever‐smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ.
Setting
Genome‐wide association studies were published previously as part of international consortia.
Participants
Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry.
Measurements
Genome‐wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever‐use, ever‐smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses.
Findings
Genetic liability to CUD was significantly associated with SCZ β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001, even when accounting for cannabis ever‐use, ever‐smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = −0.08, 95% CI = −0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk‐increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever‐use, ever‐smoked tobacco regularly and nicotine dependence).
Conclusions
Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever‐use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.
Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there ...is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.
IMPORTANCE: Cannabis use after first-episode psychosis is associated with poor outcomes, but the causal nature of this association is unclear. OBJECTIVE: To examine the precise nature of the ...association between continued cannabis use after the onset of psychosis and risk of relapse of psychosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services in South London, England, from April 12, 2002, to July 26, 2013, with first-episode psychosis. Longitudinal modeling (fixed-effects analysis, cross-lagged path analysis) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use, psychosis increasing the risk of cannabis use (reverse causation), or a causal effect of cannabis use on psychosis relapse. INTERVENTIONS: Exposure to cannabis within the first and second years after onset of psychosis. MAIN OUTCOMES AND MEASURES: The main outcome measure was relapse of psychosis, defined as subsequent hospitalization for psychosis. Effect of cannabis use status in the first year (Ct1) and second year (Ct2) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year (Rt1) and risk of relapse in the second year (Rt2) after psychosis onset. RESULTS: A total of 220 patients with first-episode psychosis were included in the analysis (mean SD age, 28.62 8.58 years; age range, 18-65 years; 90 women 40.9% and 130 men 59.1%). Fixed-effects models that adjusted for time-variant (other illicit drug use, antipsychotic medication adherence) and time-invariant (eg, genetic or premorbid environment) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use (odds ratio, 1.13; 95% CI, 1.03-1.24). Change in the pattern of continuation significantly increased the risk (odds ratio, 1.07; 95% CI, 1.02-1.13), suggesting a dose-dependent association. Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse (Ct1→Rt2: β = 0.44, P = .04) rather than an effect of relapse on subsequent cannabis use (Rt1→Ct2: β = −0.29, P = .59). CONCLUSIONS AND RELEVANCE: These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding.
Cannabis has been known for at least 4,000 years to have profound effects on the mind--effects that have provoked dramatically divergent attitudes towards it. Some societies have regarded cannabis as ...a sacred boon for mankind that offers respite from the tribulations of everyday life, whereas others have demonized it as inevitably leading to 'reefer madness'. The debate between the protagonists and prohibitionists has recently been re-ignited, but unfortunately this debate continues mainly in ignorance of our new understanding of the effects of cannabis on the brain and of studies that have quantified the extent of the risks of long-term use.
Background and aims
Cannabis products with high delta‐9‐tetrahydrocannabinol (THC) concentrations carry an increased risk of addiction and mental health disorders, while it has been suggested that ...cannabidiol (CBD) may moderate the effects of THC. This study aimed to systematically review and meta‐analyse changes in THC and CBD concentrations in cannabis over time (PROSPERO registration: CRD42019130055).
Design
Embase, MEDLINE® and Epub Ahead of Print, In‐Process and Other Non‐Indexed Citations and Daily, Global Health, PsycINFO and Scopus were searched from inception to 27/03/2019 for observational studies reporting changes in mean THC and/or CBD concentration in cannabis over at least three annual time points. Searches and extraction were conducted by two independent reviewers. Random effects meta‐regression models estimated annual changes in THC and CBD for each product within each study; these estimates were pooled across studies in random effects models.
Results
We identified 12 eligible studies from the USA, UK, Netherlands, France, Denmark, Italy and New Zealand. For all herbal cannabis, THC concentrations increased by 0.29% each year (95% CI: 0.11, 0.47), P < 0.001 based on 66 747 cannabis samples from eight studies, 1970–2017. For cannabis resin, THC concentrations increased by 0.57% each year (95% CI: 0.10, 1.03), P = 0.017 based on 17 371 samples from eight studies, 1975–2017. There was no evidence for changes in CBD in herbal cannabis −0.01% (95% CI: −0.02, 0.01), P = 0.280; 49 434 samples from five studies, 1995–2017 or cannabis resin 0.03% (95% CI: −0.11, 0.18), P = 0.651; 11 382 samples from six studies, 1992–2017. Risk of bias was low apart from non‐random sampling in most studies. There was evidence of moderate to substantial heterogeneity.
Conclusions
Concentrations of delta‐9‐tetrahydrocannabinol (THC) in international cannabis markets increased from 1970 to 2017 while cannabidiol (CBD) remained stable. Increases in THC were greater in cannabis resin than herbal cannabis. Rising THC in herbal cannabis was attributable to an increased market share of high‐THC sinsemilla relative to low‐THC traditional herbal cannabis.
Cannabis is known to produce acute, transient psychotic-like experiences. However, it is unclear whether cannabis disproportionately increases the risk of specific types of psychotic experiences and ...whether genetic predisposition influences the relationship between cannabis use and psychotic experiences. In this cross-sectional study of 109,308 UK Biobank participants, we examined how schizophrenia polygenic risk modulates the association between self-reported cannabis use and four types of self-reported psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, and delusions of reference). Cohort-wide, we found a strong, dose-dependent relationship between cannabis use and all four types of psychotic experiences, especially persecutory delusions. Cannabis users' psychotic experiences tended to be earlier-onset and cause greater distress than non-users', but were not more likely to lead to help-seeking. Participants with high schizophrenia polygenic risk scores showed stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall. For instance, cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of polygenic risk, but only 7% greater adjusted odds among the bottom fifth. Our results suggest that cannabis use is a predictive risk factor for psychotic experiences, including early-onset and distressing experiences. Individuals genetically predisposed to schizophrenia may be especially vulnerable to psychotic experiences as a result of using cannabis, supporting a long-postulated hypothesis. This study exemplifies the utility of population-scale biobanks for elucidating gene-by-environment interactions relating substance use to neuropsychiatric outcomes and points to the translational potential of using polygenic risk scores to inform personalized harm reduction interventions.
People who use cannabis have an increased risk of psychosis, an effect attributed to the active ingredient Delta 9-tetrahydrocannabinol (Delta 9-THC). There has recently been concern over an increase ...in the concentration of Delta 9-THC in the cannabis available in many countries.
To investigate whether people with a first episode of psychosis were particularly likely to use high-potency cannabis.
We collected information on cannabis use from 280 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust, and from 174 healthy controls recruited from the local population.
There was no significant difference between cases and controls in whether they had ever taken cannabis, or age at first use. However, those in the cases group were more likely to be current daily users (OR = 6.4) and to have smoked cannabis for more than 5 years (OR = 2.1). Among those who used cannabis, 78% of the cases group used high-potency cannabis (sinsemilla, 'skunk') compared with 37% of the control group (OR 6.8).
The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.
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