January 2007 | Back to Table of Contents

Clinical and Health Affairs

Schizophrenia and Cannabis Use

By Sanjiv Kumra, M.D., M.Sc.

Abstract
Genetic predisposition and environmental risk factors are thought to play a role in the pathophysiology of schizophrenia. Exposure to cannabis is one environmental factor that’s being studied for its possible link to development of schizophrenia in adolescents. This article presents evidence that supports the hypothesis that repeated cannabis use could interfere with the development of frontal white matter in some adolescents and may exacerbate anatomic pathology in those with schizophrenia. This putative mechanism may explain the deficits in working memory and worsening in the severity of clinical symptoms in adolescents with schizophrenia who use cannabis.

Schizophrenia is a psychiatric disorder characterized by a constellation of odd behaviors and major thought disturbances. Although the onset of schizophrenia occurs most often in early adulthood, the disorder has long been identified in children and adolescents younger than 19 years. Both genetic predisposition and environmental risk factors are thought to play a role in the pathophysiology of schizophrenia. One environmental risk factor that is currently under investigation is cannabis use.

Several lines of evidence suggest an association between cannabis use and schizophrenia. Seven separate epidemiological studies have found an association between cannabis use in adolescence and subsequent development of schizophrenia, and clinical data document that cannabis use can worsen the severity of psychotic symptoms.¹ At present, cannabis use has emerged as a leading environmental risk factor contributing to the development of schizophrenia and disease morbidity.^1,2 Although use of other illicit drugs such as methamphetamine may cause psychotic symptoms, the literature overwhelmingly suggests that cannabis is more widely used by persons with schizophrenia than by the population in general. Studies also show greater cannabis use among adults who report that the onset of their psychotic symptoms occurred during adolescence.^3,4 Some data suggest that cannabis is the drug of choice (as opposed to other illicit substances that cause psychotic symptoms) for adolescents with schizophrenia and that cannabis use is associated with worsening of schizophrenic symptoms.³ Despite this evidence, there has been limited biological research on the effects of recurrent cannabis exposure on adolescent brain development.

New research, however, is beginning to offer clues as to how cannabis use might affect brain development. Animal data suggest that cannabinoid receptors and endogenous cannabinoids within the brain may play a role in the development of postnatal white matter.⁵ White-matter axons provide the physical foundation for the smooth transfer of information between corticocortical and sub-cortico cortical areas. During adolescence, ongoing white-matter development takes place in the frontal regions of the brain, which are involved in higher aspects of cognitive function and regulation of emotion.⁶ Cannabis use may interfere with the development of myelin, the insulating material around axons that allows for the efficient communication of information between areas of the brain. Abnormalities in the development of myelin sheaths may interfere with normal cognitive development and thus may contribute to cognitive difficulties that are typically seen in adolescents with schizophrenia such as problems with working memory.

Researchers at the University of Minnesota have recently begun using a magnetic resonance imaging technique called diffusion tensor imaging (DTI) to study white-matter development in the brains of both healthy and schizophrenic adolescents. It has allowed us to observe age-related increases in a measure of structural integrity in white-matter tracts in the frontal lobe of the brains of healthy volunteers but not in those of adolescents with schizophrenia, suggesting that there may be a developmental arrest in persons with schizophrenia. The frontal lobe has been implicated in the pathophysiology of core symptoms of schizophrenia such as auditory hallucinations and in working memory deficits.^7,8 In addition, we have observed that these white-matter abnormalities appear to be more severe in adolescents with schizophrenia and co-occurring cannabis use.

In this article, we present data that support the hypothesis that repeated cannabis use could interfere with frontal white-matter development in at least some adolescents and may exacerbate anatomic pathology in adolescents with schizophrenia. This, in turn, could contribute to deficits in working memory and the severity of clinical symptoms in adolescents with schizophrenia. A prospective longitudinal neuroimaging study is currently being conducted in the department of psychiatry at the University of Minnesota to test this hypothesis. If our hypothesis is confirmed, then this would provide an objective demonstration of the effect of cannabis on the clinical course of schizophrenia.

Cannabis Use and Adolescent Brain Development
During adolescence, the brain is still developing, in particular, the regions involving the frontal cortex, as well as the white matter. Electrophysiological, cerebral glucose-metabolism, postmortem, and structural magnetic resonance imaging studies provide empirical evidence for the ongoing maturation of the fiber projections to the frontal lobe during adolescence.^6,9-11 These studies suggest that adolescence may be a critical period in the development of neural pathways and especially in the development of the prefrontal cortical regions. It also may be a period when these pathways might be most susceptible to environmental insult (eg, the toxic effects of cannabis).

White-Matter Pathology in Schizophrenia
There is increasing evidence that schizophrenia may be a neuro-developmental disorder associated with a disruption in oligodendrocyte function, and thus, a disruption in white-matter development.¹² Indeed, a postmortem study reported fewer oligodendrocytes in the brains of patients with schizophrenia compared with those of healthy volunteers.¹³ Other genetic studies have confirmed a link between oligodendrocyte development and schizophrenia.¹⁴ Data from patients with metachromatic leukodystrophy, a genetic disorder that impairs growth of the myelin sheath, also suggest that a disruption of frontal white-matter integrity during adolescence may be important in the pathophysiologic mechanism of schizophrenia.¹⁵

Longitudinal studies of young adults with schizophrenia have found a progressive decline in frontal lobe white-matter volume during a 2-year follow-up period, as opposed to the enlargement of white-matter volume seen in healthy individuals. Morphologic changes in white-matter volume in the early course of schizophrenia were most evident in the frontal lobes. These changes have been interpreted to represent a dysmaturation process in schizophrenia, in which white matter in the frontal lobe fails to undergo the usual process of myelination or increased interconnection. Decreasing frontal lobe white-matter volume was associated with greater severity of negative symptoms and poorer executive functioning.¹⁶

Using Diffusion Tensor Imaging to Study White Matter
If the pathophysiology of schizophrenia reflects a disturbance in white matter, then such abnormalities might be observed using DTI. Diffusion tensor imaging allows measurement of the microstructural features of white matter and, thus, permits the study of fiber connections among anatomically and functionally defined regions of the brain.^17,18 It is based on sensitizing the magnetic resonance signal to the movement (on the order of micrometers) of water within tissue and determining the extent of water diffusion between axons or myelin sheaths, thus measuring the structural organization of white-matter fiber tracts.

In white matter, water diffusion is greater along fiber tracts than along the axons, where it is restricted by the surrounding myelin sheath and cell membrane.¹⁹ This, termed anisotropic diffusion, is in contrast to the movement of free water, which has an isotropic distribution. Most studies using DTI have focused on fractional anisotropy, which provides a measure of the structural organization of white-matter fiber tracts and is seen as the “intensity” or “brightness” of activation in DTI images.²⁰ Fractional anisotropy yields values between 0 (ie, isotropic or unrestricted diffusion) and 1 (ie, anisotropic or restricted diffusion caused by barriers, as in organized white-matter fibers).

Diffusion tensor imaging has been used to characterize maturation of the frontal white matter during childhood.²¹ These microstructural changes likely reflect corresponding increases in axonal and myelin thickness. Using such imaging techniques, several prior studies have reported lower fractional anisotropic diffusion and a lack of healthy asymmetry in this diffusion in adolescent and adult patients with schizophrenia as compared with normal controls.^22,23 Overall, such data support a hypothesis that patients with schizophrenia may represent a population that is more susceptible to the neurotoxic effects of cannabis because of pre-existing white-matter pathology.

The Effects of Cannabis
How might exposure to cannabis adversely affect white-matter development in adolescents with schizophrenia? The mechanisms by which cannabis use might potentially affect oligodendrocyte function during adolescence include direct (receptor-mediated) and toxic (high-dose nonspecific) effects.

♦ Direct Effects
Two types of cannabinoid receptors, CB1 and CB2, have been identified. The CB1 receptors are concentrated in the central nervous system, whereas the CB2 receptors are expressed in the immune system. Cannabinoid receptors are usually located in nerve terminals; thus proteins must travel down axons after synthesis in the cell body; some fiber tracts consequently show elevated ligand binding. In the rat brain during late gestation and the early postnatal period, CB1 receptors have been localized in subcortical white matter. This information supports the role of the endogenous cannabinoid system in the molecular functions associated with these cells during neural development, including guidance of neuronal migration and axonal elongation, and formation of myelin.²⁴ Data from in vitro studies suggest that cells of oligodendroglial lineage express CB1 receptors.²⁵ During postnatal rat brain development, functional CB1 receptors have been located in neuronal fiber-enriched areas.²⁶ In humans, it is plausible that CB1 receptors may also modulate oligodendroglial development.²⁷ Based on the in vitro studies of Molina-Holgado and colleagues that have shown cannabinoid-induced prevention of oligodendrocyte death, it is possible that long-term exposure might cause down-regulation of the CB1 receptors and suppress oligodendrocyte function over time.²⁵ As summarized by Davis et al., abnormalities in or death of oligodendroglia could readily lead to abnormalities in myelin integrity, including myelin initiation, deposition, compaction, and maintenance.¹²

♦ Toxic Effects
Pre-existing neuropathological features of schizophrenia render white matter especially vulnerable to the toxic effects of repeated cannabis exposure during adolescence.¹² Animal studies suggest that long-term cannabinoid exposure may have deleterious effects on oligodendroglial function resulting in the underexpression of myelin-related genes (eg, myelin basic protein).²⁸ Lower myelin basic protein immunoreactivity has also been reported in the frontal cortex of persons with schizophrenia.²⁹

Despite a biological rationale for anticipating that cannabis exposure might have an adverse effect on brain development, to date, there have been only 2 published structural magnetic resonance imaging studies of adult cannabis users, which have yielded conflicting results. Bloch et al. reported no evidence of cerebral atrophy or global or regional changes in white-matter tissue volume in 18 young adults who were frequent marijuana users (mean age, 22.3 ± 0.5 years) compared with 13 age-matched controls, nor did they find any meaningful correlations of white-matter volume with the subjects’ reported age upon their first use of marijuana.³⁰ However, another study that examined cannabis use found that adult subjects who started using marijuana before age 17 showed smaller whole-brain volumes than those who started using it later.³¹

Summary
Epidemiological studies suggest that cannabis use during adolescence is associated with greater risk for later development of schizophrenia. Although these studies support an association between cannabis use and schizophrenia, little data support a hypothesis that cannabis use is associated with abnormalities of brain morphology in patients with schizophrenia.³²

In this article, we have presented the hypothesis that because of pre-existing white-matter pathology in persons with schizophrenia, these individuals may be genetically susceptible to environmental agents such as cannabis that could exacerbate abnormal development of frontal white matter.¹² We believe that these neurotoxic effects would be most pronounced in the frontal lobe because this is a region of the brain where there is marked development of white matter during adolescence and young adulthood. Also, the frontal lobe is part of a neural network that supports both working memory processes and enables recognition of one’s own actions.³³ Thus, it is possible that recurrent exposure to cannabis may exacerbate abnormal development of frontal white matter that would lead to a disruption in the mechanisms that allow for the correct self-attribution of actions. A breakdown in these mechanisms could lead to auditory hallucinations and/or paranoid ideation, which are considered to be primary or diagnostic symptoms of schizophrenia.

If recurrent exposure to cannabis were found to contribute to the progression of white-matter abnormalities in patients with schizophrenia, then new and more effective efforts to limit cannabis use will need to be developed. MM

Sanjiv Kumra is chief of the division of child psychiatry at the University of Minnesota.

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