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At least 13 longitudinal cohort studies have tested whether there is a relationship between early marijuana smoking and a later onset of psychosis (Murray et al., 2017). These studies were conducted in a number of different locations worldwide, including Germany, the Netherlands, the United Kingdom, Sweden, New Zealand, and the United States. Of the 13 studies published thus far, 10 found a significantly increased risk of developing a psychotic illness (e.g., schizophrenia) or severe psychotic symptoms, while a trend in the same direction was reported in the other three (Murray et al., 2017). Several factors appear to influence this relationship: (1) amount of cannabis use, (2) cannabis potency, (3) age of initiation of use, and (4) preexisting vulnerability (van der Steur et al., 2020). These factors are taken up in order.
First, greater usage of cannabis has consistently been associated with increased risk for psychosis, with the highest amounts of use yielding an odds ratio (OR) of almost 4 (Marconi et al., 2016). OR is a standard measure of risk of developing a disease or disorder, and an OR of 4 means that the those who use very high amounts of cannabis have four times the likelihood of developing a psychotic disorder compared to non-users.
Second, use of marijuana with higher THC content but lower CBD content also increases the risk for psychosis. This was shown dramatically in a London study comparing patients suffering from their first psychotic episode with matched controls (Di Forti et al., 2015). Regular use of “skunk” cannabis, a preparation that has high levels of THC but very low CBD, was associated with a much greater risk of experiencing a psychotic episode than using low-potency cannabis or no cannabis at all. The apparent ameliorating effect of CBD is consistent with other evidence that this cannabinoid may have antipsychotic properties.
Third, initiation of cannabis use in early adolescence also increases the risk for developing a psychotic disorder (Rabin and George, 2017). Researchers theorize that the still-developing adolescent brain is more vulnerable to the disruptive effects of repeated phytocannabinoid exposure than the adult brain.
Lastly, clinical researchers have identified people termed “ultra-high risk” (UHR) who are already in a pre-psychotic state and have a significant likelihood of transitioning to a psychotic episode within the next few years (see Fusar-Poli et al., 2013). A study of UHR cannabis users found that the greatest likelihood of transition to psychosis over a 2-year period occurred in those who used the substance frequently, had started using before the age of 15 years, and continued to use even after initial symptoms occurred (Valmaggia et al., 2014). Research on cannabis users overall (not confined to UHR individuals) additionally found that continued use after the onset of psychosis increased the rate of relapse compared to those who discontinued their use as well as non-users (Schoeler et al., 2016).
Most researchers who are studying the relationship between cannabis use and psychosis argue for a type of causal connection between these phenomena. However, if true, the direction of causation is still in dispute based on genetic analyses. There is growing evidence that genetic risk factors for cannabis use and for schizophrenia are positively correlated, meaning that many of the same genes confer risk for both outcomes. However, analyses directed toward determining possible causation have reached opposing conclusions. For instance, the genetic study by Vaucher and coworkers (2018) concluded that the direction of causation is likely cannabis use increasing the likelihood of developing schizophrenia. In contrast, two other genetic studies using different populations of participants concluded that the data more strongly supported the hypothesis that risk for schizophrenia increased the likelihood of cannabis use (Gage et al., 2017; Pasman et al., 2018). In that case, early symptoms of the emerging psychotic disorder may predispose individuals to self-medicate with drugs such as cannabis. It should be kept in mind that researchers do not exclude the possibility of bidirectional causation in which each factor may positively affect the other.
Mechanistic studies have largely focused on pathways by which adolescent cannabis use (especially early and heavy use of high-potency cannabis) could interact with preexisting genetic vulnerability to increase the risk for developing a psychotic disorder. A model summarizing such a pathway is shown in Figure 1. Research implicating the endocannabinoid system in the pathophysiology of schizophrenia supports the hypothesis that disruption of this system during adolescence could cause downstream neurochemical changes that contribute to the onset of schizophrenia or a related psychotic disorder (Fakhoury, 2017; Minichino et al., 2019). Zamberletti and Rubino (2021) recently reviewed animal studies demonstrating some of the key effects of adolescent treatment with THC or synthetic cannabinoids, which include alterations in the cortical glutamatergic and GABAergic systems, premature synaptic pruning of PFC pyramidal neurons, and epigenetic changes involved in synaptic plasticity. All of these changes are related to the neurobehavioral systems that are dysfunctional in schizophrenia. Continued research will be important for clarifying the relationship between adolescent cannabis use and later psychosis, including the mechanisms involved in this relationship.
Figure 1 Factors that influence the risk of developing a psychotic disorder in chronic cannabis users eCB, endocannabinoid. (Modified from Rabin and George, 2017.)
References
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