The proportion of schizophrenia cases associated with cannabis use disorder in Denmark increased 3- to 4-fold over several decades, a registry-based study found.
The population-attributable risk fraction (PARF) for cannabis use disorder in schizophrenia rose from about 2% in 1995 and became stable at approximately 6% to 8% from 2010 to 2016, reported Carsten Hjorthøj, PhD, of Copenhagen University Hospital, and co-authors in JAMA Psychiatry.
“This increase is in concordance with what would be expected, given observed increases in use and potency of cannabis,” Hjorthøj and colleagues wrote. “These results from longitudinal analyses of the associations over time between cannabis use disorder and schizophrenia lend further support to the hypothesis that cannabis may be involved in the etiology of schizophrenia.”
“An important implication of our study may thus be that both use of cannabis and the potency of cannabis available should be reduced to achieve primary prevention of schizophrenia,” they added.
The researchers analyzed data from 7,186,384 Danish citizens born before Dec. 31, 2000, in nationwide registers to assess schizophrenia diagnosis and estimated PARF of cannabis use disorder in schizophrenia from 1972 to 2016.
Half of the cohort was female. Overall, 30.5% of people in the study were born in 1939 or earlier, and 10% to 12% were born in each more recent decade through the 1990s.
A total of 0.6% of the sample developed schizophrenia and 0.3% had one or more recorded instance of a diagnosis of cannabis use disorder over the course of the study.
Compared with people who did not have a cannabis use disorder diagnosis, individuals with a diagnosis of cannabis use disorder had an adjusted HR for schizophrenia of about 4.0. This HR remained stable over the yearly calculations performed in the study.
“The fact that the hazard ratio did not increase over time was unexpected, because this would have been expected if the association between cannabis use disorder and schizophrenia was primarily driven by high-potency cannabis, as has previously been suggested,” Hjorthøj and colleagues wrote. “This could either indicate that potency of cannabis in Denmark has long been above the threshold for psychogenic effects, or that cannabis use disorder is itself an indicator of severe exposure.”
In an accompanying editorial, Tyler VanderWeele, PhD, of Harvard T. H. Chan School of Public Health in Boston, noted that “estimates from elsewhere suggest the PARF in London, and Amsterdam, the Netherlands, may be considerably higher still.” Estimates like these “may be conservative because of underdiagnosis of cannabis use disorder and only examining cannabis use disorder, rather than cannabis use per se,” he added.
In the Danish analysis, “the RR was relatively constant over time at approximately 4 and it was the prevalence of cannabis use disorder that is increasing,” VanderWeele continued. “This increasing prevalence drove the increasing PARF. While an increasing PARF estimate would be expected under the assumption of causality, it would also be expected if the cannabis-schizophrenia association were entirely confounded or non-causal, since the estimated PARF could be increasing simply because the prevalence of cannabis use disorder is increasing.”
“Cannabis use disorder is not responsible for most schizophrenia cases, but it is responsible for a non-negligible and increasing proportion,” he pointed out. “This should be considered in discussions regarding legalization and regulation of the use of cannabis.”
A 2019 European multicenter case-control study that looked at 901 patients with first-episode psychosis found that daily cannabis use was associated with increased risk of psychotic disorder versus those who had never used cannabis (adjusted OR 3.2, 95% CI 2.2-4.1), with “striking variation in the incidence of psychotic disorder across the 11 studied sites” attributed to differences in patterns of use and use of high potency cannabis.
A 2019 review on the potency and price of European cannabis between 2006 and 2016 found that the mean percent tetrahydrocannabinol in European samples increased from 5% in 2005 to 10.22% in 2016.
“Cannabis on the Danish market is noted to be among the most potent variants in Europe and has increased from approximately 13% Δ9-tetrahydrocannabinol in 2006 to nearly 30% in 2016,” VanderWeele observed.
In the current study, adjusted analysis included potential confounders of alcohol use disorder, other psychiatric disorders, parental schizophrenia, parental other psychiatric disorder, parental alcohol or substance use disorder, parental educational attainment, sex, and age.
Limitations of the analysis included the inability to determine causality due to its observational nature. “The PARF is an estimate of the proportion of cases of schizophrenia that would have been prevented if no individuals had been exposed (in this case to cannabis use disorder), under the assumption that the association between cannabis and schizophrenia may be causal,” Hjorthøj and co-authors noted.
“In light of this assumption, the PARF cannot confirm whether an association is truly causal,” they wrote. “However, an increase in the PARF co-occurring alongside an increase in either the proportion using cannabis or in the potency of cannabis would be expected if the association was indeed causal.”
The proportion of schizophrenia cases associated with cannabis use disorder in Denmark increased 3- to 4-fold over several decades.
The population-attributable risk fraction for cannabis use disorder in schizophrenia rose from about 2% in 1995 and became stable at approximately 6% to 8% from 2010 to 2016.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was supported by a grant from Lundbeckfonden.
Hjorthøj reported no conflicts of interest.
VanderWeele reported grants from National Cancer Institute and John Templeton Foundation.
Cat ID: 146
Topic ID: 87,146,730,192,146,57,925