Disclosures: The study authors report no relevant financial disclosures. VanderWeele reports receiving grants from John Templeton Foundation and National Cancer Institute.
July 22, 2021
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Cannabis ‘not harmless’ given link between overuse, schizophrenia

Disclosures: The study authors report no relevant financial disclosures. VanderWeele reports receiving grants from John Templeton Foundation and National Cancer Institute.
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The proportion of schizophrenia cases linked to cannabis use disorder increased three- to fourfold in the past 2 decades, according to results of a nationwide prospective cohort study published in JAMA Psychiatry.

“Several studies have previously shown that cannabis use is associated with an increased risk for schizophrenia or related psychoses,” Carsten Hjorthøj, PhD, of the Copenhagen Research Center for Mental Health–CORE at the Mental Health Center Copenhagen in Denmark, told Healio Psychiatry. “However, one often-encountered counter argument is that, if the association is truly causal, then one would have expected an increase in the incidence of schizophrenia. Proponents of the hypothesis of causality claim that this has not occurred, but this is actually not known.”

infographic with Hjorthoj quote about dangers of cannabis use

According to Hjorthøj and colleagues, the population-attributable risk fraction (PARF), which, for the purposes of this study, was the proportion of cases of schizophrenia considered attributable to cannabis, would reflect an increase if the link between cannabis use and schizophrenia was causal. The researchers aimed to assess this potential causality by conducting a nationwide, register-based historical prospective cohort study that included all individuals (n = 7,186,834; 50% women) in Denmark prior to Dec. 31, 2000, who were alive and aged 16 years or older at some point between Jan. 1, 1972, and Dec. 31, 2016. Cannabis use disorder diagnosis served as the exposure. Schizophrenia diagnosis, with estimated PARF of cannabis use disorder in schizophrenia from 1972 to 2016, served as the main outcome.

Results showed the adjusted HR for schizophrenia fluctuated at approximately four during most of the study period when individuals with a cannabis use disorder diagnosis were compared with those without this diagnosis. The cannabis use disorder in schizophrenia PARF fluctuated as well; however, the researchers noted significant evidence of an increase from approximately 2% in 1995 to a level of some stability between 6% and 8% since 2010.

“These findings are exactly what would be expected in a situation where we see increasing potency of cannabis and increasing population use of cannabis,” Hjorthøj said. “We also find that these findings are very robust to unaccounted-for competing risk factors. While not a definite ‘proof’ of causality, it is probably as close as we are going to get for a while, and the clinical relevance of our findings is thus that there is no reason to consider cannabis to be a harmless substance, something that is increasingly the case, unfortunately.”

In a related editorial, Tyler J. VanderWeele, PhD, of the Harvard T.H. Chan School of Public Health, noted that the increasing proportion of schizophrenia cases attributable to cannabis use disorder should be considered when discussing cannabis legalization and regulation.

“As noted by Hjorthøj [and colleagues], the estimates may be conservative because of underdiagnosis of cannabis use disorder and only examining cannabis use disorder, rather than cannabis use per se,” VanderWeele wrote. “If such underdiagnosis were 50%, and only half of schizophrenia incidence arising from cannabis use involved cannabis use disorder, then the cannabis use PARF instead would be 32%. If 32% (or even just 8%) of cases of schizophrenia in Denmark are attributable to cannabis use, this is important, and moreover, as noted by Hjorthøj [and colleagues], this PARF has been increasing.”