Hello. Thanks for inviting me to speak at this table.
I'm Romina Mizrahi. I am an associate professor of psychiatry at the University of Toronto and I work as a clinician-scientist at the Research Imaging Centre in CAMH, the Centre for Addiction and Mental Health, and in the new Focus on Youth Psychosis Prevention Clinic at CAMH.
Today I'm going to focus on the effects of cannabis on the brain, in particular on its relation to increased risk for psychosis. I will not talk about any cannabis-related harms related to addiction, including dependence or abuse, as my colleagues here today have more expertise in this area.
First I'm going to describe the brain system within which cannabis acts in the brain. It is called the endocannabinoid system or eCB. Then I will briefly discuss the data linking the eCB to schizophrenia. Finally I will integrate this into the critical timeframe of adolescence, given the maturational times for the eCB system in the brain and the concurrent time for psychosis emergence.
Cannabinoids—the active components of cannabis—exert their effects on the brain by acting on the eCB system, the endogenous or internal cannabis system. Among other functions, the eCB system is involved in neuro-protection, modulation of pain, control of certain phases of memory processing, modulation of immune and inflammatory responses, and stress and appetite regulation.
One important characteristic of the eCB is that it acts on demand; that is, it works when and where it's needed to modulate neurotransmitter release, including of dopamine, which is a key neurotransmitter in schizophrenia and its treatment.
Over the years, a number of separate lines of research have converged on cannabinoids, including eCB, as potential contributors to schizophrenia. Before I briefly summarize the data, I would like to draw your attention to my wording. I have said, “contributors”, and this is important, as none of the studies I will soon mention have shown cannabis to be sufficient or necessary to cause schizophrenia. A short summary follows.
First, very well-replicated epidemiological studies show a twofold increase in the incidence of schizophrenia with early cannabis use, with the maximum reported effects to be around a sixfold increase in risk, and increased reported risk with early use—before 15 years of age—and in a dose-dependent fashion. That is, the younger the youth, the more the risk.
Second, altered levels of peripheral eCB markers in both CSF—cerebrospinal fluid—and blood are found in patients with schizophrenia, including dramatic elevations of anandamide, which is an endogenous cannabinoid.
Third, epidemiological studies suggest an interaction between cannabis use and the number of genetic polymorphisms, conferring an elevated risk of developing schizophrenia upon a genetically vulnerable population.
Fourth, there is an association between eCB and genetic polymorphism in schizophrenia.
Fifth, there is increased CB1 receptor binding in the frontal cortex and anterior cingulate cortex, as shown in post-mortem studies.
Sixth, there is elevated CB1 binding in vivo in patients with schizophrenia, as measured by two positron emission tomography studies worldwide. While that technology is still in its infancy, these studies, while sometimes inconsistent, point to a prominent role for eCB in schizophrenia.
Patients with schizophrenia and those at risk for the disease exhibit alarmingly high levels of drug use, most commonly of cannabis, despite increased risk of psychotic experiences. In accounting for this apparent paradox, evidence derived from animal studies implicates the eCB in regulation of the stress response. Cannabinoids elicit behavioural as well as neurochemical changes that are dependent on the environmental conditions under which they are administered.
For example, cannabinoids administered to rats housed in stressful conditions alter dopamine uptake and metabolism, whereas such an effect is absent is rats housed in normal conditions.
Further to this point, cross-sensitization between THC and stress has been reported, suggesting that the physiological and psychological effects of cannabis may be altered in individuals experiencing environmental adversity. It is conceivable that social stress in individuals vulnerable to psychosis leads to a dampened or blunted eCB system, further increasing cannabis use and in turn stimulating CB1 receptors by exogenous cannabis use, which may disregulate the stress response.
This would suggest that cannabis use in psychosis and in those at risk for the disease could represent an attempt to regulate an abnormal stress response. While this hypothesis may be a reasonable explanation for the observed elevated cannabis use in those at risk and in schizophrenia patients, it does not explain why cannabis use itself may lead to psychosis in risk populations. There is no data as yet that would answer these questions.
In fact, our understanding of the eCB in psychosis and in cannabis users is very limited. Notably, the human cortical eCB system undergoes dramatic changes in early life and adolescence, with both synthesis and hydrolysis increasing until early adulthood.
These early changes in the eCB system could potentially explain the sensitivity of this age group to cannabis use and the effect of social stress on those vulnerable to schizophrenia. In line with this, it has been shown that cannabis use before the age of 15 years leads to increased risk of psychosis, while later use may not. In this regard, understanding the role of the eCB system, particularly during adolescence, may provide a better understanding of the effects of cannabis on the developing brain.
Advances in our understanding of schizophrenia underscore both its complexity and its heterogeneous nature. That it is now conceptualized as a neurodevelopmental disorder speaks to this, given that the illness does not routinely declare itself until late adolescence or early adulthood. Numerous influences may play a contributing role during the interval, which in turn could contribute to its marked heterogeneity, reflected across presentation, symptomatology, and illness trajectory. The marked variability in response to current treatment underscores these points.
In summary, cannabis use, genetic vulnerability, social stress, and other social and environmental risk factors interact in a complex, age-dependent manner, leading to the observed epidemiological link between cannabis and schizophrenia.
Research of this sort faces considerable challenges. Imaging approaches appropriate for investigating the eCB system in the living brain are in very early stages of development, with a specific PET radioligand to target the system only becoming available in the last three to five years. Over the coming years, research using those novel agents and PET are likely to provide insights and greatly advance our understanding of the molecular-level changes in the brain elicited by cannabis use.
Furthermore, the eCB is very sensitive to multiple environmental perturbations, including social stress, making measurement in clinical populations challenging. The complex of the temporal aspects of the progression towards disease and the resulting challenge in capturing this critical window may also hinder relevant investigations.
Additionally, the number of components of smoked cannabis makes understanding complex. For example, while THC has been shown to produce psychotic-like experiences even in normal individuals, cannabidiol, another major component of cannabis, has been reported to have an anti-psychotic effect.
Focusing on adolescents with multiple risk factors as a starting point, social programs addressing the potential risks associated with cannabis use could impact the way schizophrenia is perceived and managed within society.
Investigating how these potential factors affect molecular targets in the brain may provide ways to treat schizophrenia, perhaps even prevent it.