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Clark CS. 
“High-potency cannabis and incident psychosis: correcting the causal assumption”. 
Lancet Psychiatry. 2019 May 05;6(6):e14.
In their recent paper, Marta Di Forti and colleagues 1 conclude that removing one environmental factor—daily high-potency cannabis use—would reduce the incidence of all psychotic disorders in Amsterdam, the Netherlands, by 50, from 37·9 to 18·8 cases per 100 000 person-years. We think that this is very unlikely given that Sullivan and colleagues 2 confirmed the heritability of schizophrenia to be about 80. Therefore, attributing this complex multifactorial brain disorder to one environmental factor such as high-potency cannabis use seems counterintuitive, especially given that 33·6 of the patients assessed by Di Forti and colleagues had never used cannabis.

The reported 50 population attributable fraction (PAF) for cannabis use in Amsterdam becomes even more questionable with a recent two-sample bidirectional Mendelian randomisation study showing that the causal direction was from schizophrenia to cannabis use and not vice versa.3 Indeed, high-potency cannabis use can lead to drug-induced psychosis and high-potency cannabis use might trigger earlier onset of psychosis in genetically vulnerable individuals who would have developed psychosis anyway.4 But these conclusions are all very different from stating that high-potency cannabis use is responsible for 50 of incident psychosis cases in Amsterdam.

So how can Di Forti and colleagues conclude that 50·3 of incident psychosis cases in Amsterdam are attributable to high-potency cannabis? The answer is simple: they calculated PAFs from the observed odds ratios (ORs) “assuming causality”—ie, that the observed OR is 100 causal. However, case-control studies such as theirs generally suffer from considerable confounding. Moore and colleagues,5 in reviewing studies about the association between cannabis use and psychosis, showed that 10–85 of the observed risk was due to confounding.

Di Forti and colleagues tried to adjust their observations for confounding, but it is very likely that their adjusted ORs and thus their PAFs were still subject to considerable residual confounding due to unmeasured differences between cases and controls in—among other factors—genetic vulnerability for mental disorders and, more specifically, for psychosis. Furthermore, their study used a fairly undefined control group of local individuals without any psychiatric history, instead of healthy siblings or patients with a mental disorder other than psychosis. As a consequence, the ORs and the associated PAFs are very likely to be seriously overestimated.

The authors' data already show this overestimation: Gouda and Voorburg, other Dutch cities close to Amsterdam with access to high-potency cannabis that is very similar to that in Amsterdam, together had a much lower OR (1·5 vs 3·6) and PAF (12·2 vs 50·3) for high-potency cannabis use. Thus, taking actions to prevent incident psychosis is certainly a good idea, but prohibition of high-potency cannabis is unlikely to substantially reduce new cases of psychosis.

We declare no competing interests.


1. Di Forti M Quattrone D Freeman TP et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study.

Lancet Psychiatry. 2019; 6: 427-436

2. Sullivan PF Kendler KS Neale MC Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003; 60: 1187-1192

3. Pasman JA Verweij KJH Gerring Z et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Nat Neurosci. 2018; 21: 1161-1170

4. Dekker N Meijer J Koeter M et al. Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender. Psychol Med. 2012; 42: 1903-1911

5. Moore THM Zammit S Lingford-Hughes A et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007; 370: 319-328
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