Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.1 DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.2 Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.3 As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population3). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.
A look at substance-induced psychosis
Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box4). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.5 Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.4 Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.6 The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.7 In 1998, Hall7 proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.7 The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.7 Hall7 concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.
Box
Schizophrenia, cannabis, and brain changes
Schizophrenia is associated with several structural changes in the brain, including lateral ventriculomegaly, reduced prefrontal cortex volume, and generalized atrophy. These changes may precede illness and act as a risk marker.4 A multivariate regression analysis that compared patients with schizophrenia who were cannabis users vs patients with schizophrenia who were nonusers found that those with high-level cannabis use had relatively higher left and right lateral ventricle volume (r = 0.208, P = .13, and r = 0.226, P = .007, respectively) as well as increased third ventricle volume (r = 0.271, P = .001).4 These changes were dose-dependent and may lead to worse disease outcomes.4
Cannabis, COMT, and homocysteine
Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetrahydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.3
In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.3 Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.3 This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.
A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.8 Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-d-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.8
The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.8 Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.8 There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.8 Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.
Research paints a mixed picture
A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.6 Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.
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