Cannabis Use Disorder Once Again Linked to Psychosis in Observational Study

Cannabis has a long, and contested, relationship with psychosis.

Critics of the drug’s legalization will often point to studies that have linked rising rates of schizophrenia with rising THC levels in illicit products.

Proponents of the plant might then retort and say that such studies observed a correlation, not a causation, and that cannabis is still innocent until proven – through randomized controlled trials – guilty.

Now a new study has reignited this debate.

Published in Psychological Medicine, the study, like many of its kind that preceded it, was observational and so, just like the other studies, didn’t prove any biochemical relationship between cannabis and psychosis.

Nevertheless, it did observe the health records of 6.9 million people in Denmark, making it one of the most comprehensive observational studies of its kind ever undertaken.

So, what did it find? That men with cannabis use disorder (CUD) were more likely to have schizophrenia than women with CUD.

Under the assumption that CUD does contribute to schizophrenia, the researchers behind the study say that around 15% of recent cases of schizophrenia in Denmark among males could have been prevented in the absence of CUD. This figure drops to 4% among females.

And these proportions further fluctuate depending on the age of cannabis consumers and the year they were consuming cannabis, according to the researchers. Men with CUD aged between 21 and 25 supposedly had a population attributable risk fraction (PARF) of almost 30% around the mid-2010s, for instance, while females aged between 16 and 20 had a PARF of barely 2% during the same time period.

Danish data and cannabis psychosis

To begin their study, the researchers – who were from various Danish research centers as well as the US’s National Institute on Drug Abuse – trawled through a national health survey of 6.9 million Danes who were aged between 16 and 49 at some point between 1972 and 2021.

The team then carried out Cox regression analyses by sex of the participants; Cox regression is method for investigating the effect of several variables upon the time a specified event takes to happen. In this case, the variables included CUD status and sex. The relationship with schizophrenia diagnoses was measured later using a statistical software, a joinpoint Regression Program.

In total, the study examined 6,907,859 individuals and 45,327 cases of incident schizophrenia.

While the study’s authors acknowledge its limitations – its observational nature, lack of genetic data of survey participants, etc. – they are confident in the study’s conclusion.

Indeed, they say the true rates of CUD-induced schizophrenia could be even higher than their estimates, given that some cases of CUD and psychosis will have gone undiagnosed and were thus unaccounted for in the patient survey.

“Although CUD is not responsible for most schizophrenia cases in Denmark, it appears to contribute to a non-negligible and steadily increasing proportion over the past five decades,” the researchers wrote in their conclusion.

“In young males (21–30 years, possibly up to 40), the proportion may even be as high as 25–30%.”

Further studies, the research team says, will be needed to probe why cannabis-consuming men seem more likely to develop psychosis than their female counterparts. And, given their findings, the team say initiatives will be needed to regulate cannabis use.

“Our findings underscore the importance of evidence-based strategies to regulate cannabis use and to effectively prevent, screen for, and treat CUD as well as schizophrenia,” they conclude.

The debate goes on

The Danish study marks another entry in the long-running debate over marijuana’s relationship with psychosis.

Does cannabis cause psychosis in otherwise healthy consumers? Does it trigger psychotic episodes in those who are already predisposed to the mental health disorder? Or are those predisposed people simply drawn to use cannabis more often, and there is no biochemical relationship?

This third hypothesis was proposed by two researchers in a review paper published in 2016. But other studies have come out since then, genetic studies that came to a different conclusion.

One study published in Translational Psychiatry in 2021 found that cannabis consumers have higher rates of psychotic experiences than non-consumers, and this difference was more pronounced among those with a high genetic predisposition to schizophrenia.

“These results are significant because they’re the first evidence we’ve seen that people genetically prone to psychosis might be disproportionately affected by cannabis,” Dr Michael Wainberg, lead author of the paper and scientist at the Centre for Addiction and Mental Health, said in a statement at the time.

“And because genetic risk scoring is still in its early days, the true influence of genetics on the cannabis-psychosis relationship may be even greater than what we found here.”

This finding supports the second hypothesis – that cannabis can trigger psychosis in the pre-disposed – but it didn't prove it.

Ultimately, an animal model trial would be needed to prove a causal link between THC and schizophrenia. And, currently, there is no accepted measurement for schizophrenia or equivalent psychosis in animals.