Eden Evins

It is clear that THC can cause acute psychotic symptoms, such as paranoia, in a dose-dependent manner (D'Souza et al, 2004; Murray et al, 2013), and those with a psychotic illness who do not stop using cannabis have a poorer prognosis on average than those who do (Tarricone et al, 2014; Alvarez-Jimenez et al, 2012), controlling for other substance use (Foti et al, 2010). What is somewhat controversial is whether to draw causal inference from the now well-replicated finding from large, prospective, longitudinal, epidemiologic studies that cannabis use, particularly heavy adolescent use of high potency cannabis, is associated with increased odds of developing schizophrenia (Andreasson et al, 1987; Arseneault et al, 2002; Di Forti et al, 2009; Fergusson et al, 2003; Giordano et al, 2014; Large et al, 2011; van Os et al, 2002; Zammit et al, 2002; Stefanis et al, 2014). There is a well-replicated dose effect, such that daily use and use of high THC potency cannabis further increase odds of developing a psychotic illness and of earlier onset of psychosis (Di Forti et al, 2009, 2013, 2015). Galvez-Buccollini and colleagues (2012) found a direct association between age of onset of cannabis use and age of onset of psychosis.

While presence of schizophrenia prodrome confounds establishment of precise onset of schizophrenia illness, and those in the prodrome may be more likely to use intoxicants (Giordano et al, 2014; DeLisi et al, 1991), strong evidence that cannabis exposure preceded onset of psychosis by up to 7 years has been reported in several large studies, controlling for or removing those with other drug use (Andreasson et al, 1987; Di Forti et al, 2009; Fergusson et al, 2003). Control for familial risk of schizophrenia attenuates but does not eliminate the association between cannabis use and schizophrenia, further supporting the hypothesis that cannabis exposure, particularly early, frequent exposure to high THC potency cannabis is a causal factor in the development of schizophrenia (Giordano et al, 2014).

Interactive effects between genotype, cannabis use, and psychosis suggest that cannabis use confers far greater risk of psychosis for some, in some cases a five- to sevenfold greater risk among daily users. Among cannabis users and daily cannabis users, respectively, carriers of the DRD2, rs1076560, T allele had three- and fivefold increased odds of developing a psychotic disorder compared with cannabis users who were GG carriers (Colizzi et al, 2015). Carriers of the COMT valine158 (Val) allele were more likely to develop schizophreniform disorder if they used cannabis in adolescence, although cannabis use had no influence on individuals homozygous for the methionine (Met) allele (Caspi et al, 2005). In a randomized clinical trial, COMT Val allele carriers experienced greater cognitive impairment with THC (300 μg/kg), and more psychotic symptoms in those prone to psychosis compared with placebo than Met allele carriers (Henquet et al, 2006). An AKT1 genotype by cannabis use interaction has also been reported, with those with C/C rs2494732 genotypes who used cannabis having twofold odds of having a psychotic disorder (van Winkel and Genetic R, Outcome of Psychosis I, 2011). In another study, those with AKT1 C/C genotype with prior cannabis use and daily use, respectively, showed two- and sevenfold increased likelihood of a psychotic disorder compared with users and daily users who were T/T carriers (Di Forti et al, 2012).

There is evidence that individuals with or vulnerable to psychosis have a neurobiological response to THC that renders them more vulnerable to psychotogenic effects of cannabis. Those with psychotic disorder and their siblings are more sensitive than matched controls to the psychotogenic effects of acute THC administration (D’Souza et al, 2005; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). This may explain why even among those taking medications for psychotic disorders, cannabis use is associated with an increased risk of relapse into psychotic symptoms (Alvarez-Jimenez et al, 2012). Inhalation of vaporized THC (8 mg) by cannabis users with a psychotic disorder (not on medication) and those with first-degree relatives with a psychotic disorder showed significantly greater striatal DA release following THC administration than control cannabis users without psychiatric illness, despite having a similar subjective response to THC (Kuepper et al, 2013). Therefore, although a common argument against causality is that cannabis use has risen considerably in the past 40 years, whereas rates of schizophrenia have not (eg, Frisher et al, 2009; Degenhardt et al, 2003; but see Hickman et al, 2007), its impact in the general population would be expected to be modest if cannabis precipitates psychosis preferentially in those with specific genetic vulnerability (Hall, 2014).

Thus, although schizophrenia etiology is multifactorial, and the majority of people who use cannabis do not develop schizophrenia, these findings, taken together, support the hypothesis that cannabis use, particularly frequent use of high THC content cannabis, increases the risk for development of psychosis, particularly in those with genetic susceptibility that influences vulnerability to environmental exposures. This warrants serious consideration from the point of view of public health policy (Radhakrishnan et al, 2014).

Meg Haney

Although heavy cannabis use by individuals with a psychotic disorder or vulnerable to one is largely associated with a poorer prognosis, there are sufficient reasons to question the causality of this relationship. To start, it is important to emphasize that although meta-analyses show a consistent association between cannabis use and psychotic disorders, the odds ratio is small. For those ever using cannabis, the association with psychotic disorders is 1.41 (95% CI 1.20–1.65), whereas the odds ratio is 2.09 (95% CI 1.54–2.84) for those using cannabis frequently (Moore et al, 2007). As noted by Moore et al (2007), larger effect sizes have been reported in other analyses, but these were based on cross-sectional data or were not adjusted for factors such as cumulative cannabis use, presence of psychiatric illness at baseline, other concurrent drug use, or cannabis use at least once vs dependence (Arseneault et al, 2002; Henquet et al, 2005, Semple et al, 2005). Thus, an association between cannabis and psychosis exists, but, at best, it is only one small factor in a much larger constellation of factors associated with this disorder.

So why might a diagnosis of schizophrenia be associated with higher rates of cannabis use relative to the general population (Foti et al, 2010)? As noted above, the apparent dose–response relationship between amount of cannabis smoked and the likelihood of a disorder is one piece of evidence consistent with causality. The more cannabis used at baseline in large prospective studies, the greater the risk of developing schizophrenia or psychotic symptoms (Zammit et al, 2002; van Os et al, 2002; Fergusson et al, 2003) and the greater likelihood that psychotic symptoms at baseline persist (Henquet et al, 2005).

Yet, psychotic disorders rarely emerge without warning. Even when cannabis use unequivocally predates a diagnosis, schizophrenia is a neurodevelopmental disorder with origins in early development. Those destined to develop schizophrenia exhibit unusual thoughts and behaviors years before they develop delusions and hallucinations (Schiffman et al, 2005). This presents the possibility that, prior to a diagnosis of psychotic disorder and perhaps even prior to the prodrome phase of schizophrenia, those who have unusual thoughts or behaviors smoke more cannabis than those without these features; if this is the case, then a dose–response relationship, ie, heavier cannabis use prior to a diagnosis, does not support a causality association but could reflect heavier use by those neurodevelopmentally vulnerable to developing a psychotic disorder.

Why would individuals at clinical high risk of psychosis or those with schizophrenia smoke cannabis? One reason may be to attenuate negative symptoms (eg, social withdrawal, anhedonia) poorly managed by antipsychotics. This hypothesis of self-medication has been disputed because there is no correlation between early symptoms of the disorder and cannabis use (Malone et al, 2010) or between cannabis use and psychotic symptoms or negative mood (Henquet et al, 2010). Yet, if patients are self-medicating negative or subtle mood symptoms, this correlation could be missed by retrospective reports or prospective monitoring of positive psychotic symptoms.

Another argument levied against the self-medication hypothesis is that individuals seeking treatment for a psychotic episode are more likely to smoke cannabis high in THC and low in CBD, a cannabinoid with potential antipsychotic effects (Leweke et al, 2012) as compared with control volunteers (Di Forti et al, 2013). The authors suggest that since high THC can worsen psychotic symptoms, patients with schizophrenia would not choose a type of cannabis high in THC to self-medicate their symptoms.

Yet, whether cannabis worsens or ameliorates certain symptoms of schizophrenia, it remains a drug of abuse, producing positive subjective and reinforcing effects regardless of psychiatric diagnosis. In fact, there is evidence that cannabis produces greater positive subjective effects in patients with schizophrenia or those prone to a psychotic disorder than in healthy controls. A study tracking mood each day using momentary assessments reported that those with schizophrenia were more sensitive to both the mood-enhancing (lower negative affect) and the psychosis-enhancing (auditory hallucinations) effects of cannabis than healthy controls (Henquet et al, 2010). Similarly, we found that participants who were clinically at high risk for developing schizophrenia showed larger increases in both intoxication and anxiety and paranoia following controlled cannabis administration relative to matched healthy controls (Vadhan et al, 2013). Although symptoms of psychosis were worsened by cannabis, mood was elevated to a greater extent than in controls, and this elevated mood might contribute to the consistent association between psychotic disorders and cannabis use. Thus, evidence that individuals who develop schizophrenia are more likely to smoke cannabis with high THC concentrations than those who do not develop schizophrenia may simply demonstrate that this population favors more potent and reinforcing strains of cannabis, regardless of CBD content.

In terms of the interaction between genetic vulnerability and cannabis use, the link between COMT alleles and vulnerability to psychosis (Caspi et al, 2005; Henquet et al, 2006) has been deemed ‘very weak’ upon subsequent analysis (Moore et al, 2007). A comparison of relatives of individuals with schizophrenia who smoked cannabis versus those relatives who did not did smoke cannabis showed that both groups were more likely to develop the illness compared with relatives of healthy controls regardless of cannabis use (Proal et al, 2014), which does not support the hypothesis that cannabis worsens outcome in individuals genetically vulnerable to psychosis.

It may be that rather than a causal link, there are shared genetic and environmental risk factors for schizophrenia and cannabis use or for drug use in general. An association between schizophrenia risk alleles and cannabis use has been reported (Power et al, 2014), supporting a shared genetic etiology, and there are a number of demographic risk factors in common for cannabis use disorder and schizophrenia, such as being male with low socioeconomic status and educational attainment (DeRosse et al, 2010).

At last, in assessing the interaction between cannabis and psychotic disorder, it is useful to consider tobacco cigarette smoking in this population, as tobacco is more strongly linked to schizophrenia than cannabis. In a meta-analysis assessing tobacco use among patients with first-episode psychosis, there was a strong association (OR=6.04; 95% CI, 3.03–12.02) compared with healthy controls (Myles et al, 2012). Similar to the data with cannabis, patients with first-episode psychosis usually smoked tobacco cigarettes for some years prior to the onset of psychosis, have high prevalence of tobacco use when presenting for treatment, and are more likely to smoke than aged-matched controls (Myles et al, 2012). Also similar to cannabis, some suggest this association reflects the underlying neurobiology of psychotic disorders, which may enhance nicotine reinforcement; or those with schizophrenia use cigarettes to moderate the effects of the illness and the antipsychotic medications (eg, Dalack et al, 1998). Conversely, Kendler and colleagues (2015) recently presented evidence supporting the idea that tobacco use prospectively increases the risk of schizophrenia. These authors thoughtfully considered the same factors argued to support a cannabis–schizophrenia link, but acknowledge that the data support but do not prove causality. They also demonstrate that familial/genetic factors contribute to the association between tobacco use and schizophrenia.

To conclude, public perception and popular media often interpret associations shown in longitudinal studies as demonstrating causation, so the scientific community has to consistently emphasize the distinction between association and causation. Given the low odds ratio and evidence that schizophrenia is a neurodevelopmental disorder, the most scientifically conservative stance is that the association between cannabis and psychotic disorders is not causal. As described by Dumas et al (2002), there are three possible models explaining the cannabis–schizotypal link: (1) cannabis use increases risk for schizotypal traits; (2) schizotypal traits increase risk for cannabis use; (3) a third causal variable underlies both cannabis use and schizotypal traits. The data do not demonstrate causality but may reflect self-medication or a shared risk factor.

Haney and Evins: Moving the Field Forward

Despite differing on their interpretation of the evidence-supporting causality, the authors agree on the biological plausibility of a causal relationship between adolescent cannabis use and negative psychiatric outcome. CB1 cannabinoid receptors are the most common G-coupled protein receptors in the brain, at concentrations 10-fold higher than opioid receptors, for example, and endocannabinoids are an abundant CNS neuromodulatory system (Passie et al, 2012). Further, adolescence is a critical time of synaptic and circuit development, and CB1 receptors are ubiquitous in the prefrontal cortex, a brain site heavily impacted by schizophrenia (Malone et al, 2010; Hill, 2014). Exogenous cannabinoid use could disrupt endocannabinoid-directed brain organization during this period of rapid development, impacting neurobiological and therefore psychiatric outcome. The authors therefore agree with those (eg, Moore et al, 2007) who argue that even without data to demonstrate causation, the potential for long-term brain changes by regular cannabis exposure during adolescence is sufficient to warn the public against the risk of adverse psychiatric outcomes with adolescent cannabis use.

The authors also share concern about the impact of extraordinarily high THC concentrations in new routes of THC administration, such as marijuana e-cigarettes and dabbing (>60%THC), which may heighten the likelihood of adverse psychiatric consequences, particularly if regular use begins in adolescence. Cannabis smokers typically adjust their inhalation patterns and smoking topography as a function of cannabis strength (eg, inhaling more forcefully on low potency than high potency cannabis cigarettes; Heishman et al, 1989; Cooper and Haney, 2009), but this titration would be difficult with new routes of very potent THC administration.

In terms of moving the field forward: further study of the gene–environment interaction could improve our understanding of the association between cannabis use and schizophrenia. Polygenic effects (Pan et al, 2015) from large genome-wide association studies (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) could be calculated for those who do or do not use cannabis to potentially clarify some of the shared genetic risks that may underlie the association. Prospective, longitudinal studies, with assessments commencing in youth prior to initiation of drug use that include family history, prospective and ongoing psychiatric evaluation, genetics and neuroimaging such as the upcoming ABCD study would contribute understanding of how cannabis use influences the onset of schizophrenia (albeit not definitively demonstrating causality). Given that intellectual and neuromotor abnormalities in childhood are evident long before a diagnosis of schizophrenia (Larson et al, 2010), it would be useful to capture these symptoms early in development to observe whether those who later smoke cannabis have a worse prognosis than a group with comparable childhood symptoms who do not smoke cannabis.