Cannabinoids and Schizophrenia: A Compensation Issue?
13 August 2008. Epidemiological studies suggest cannabis use is both a risk factor for developing schizophrenia and is associated with worse symptoms and cognitive impairment in people with the disease, but the exact nature of the link between cannabis use and schizophrenia is not known (see SRF related news story). A new paper from Stephen Eggan, Takanori Hashimoto, and David Lewis at the University of Pittsburgh in Pennsylvania presents evidence for a biochemical link, showing that people with schizophrenia have lower levels of a major receptor for cannabinoids. The data, published in the July issue of the Archives of General Psychiatry, suggests that downregulation of the cannabinoid pathway could be a compensatory response to changes in GABAergic neurotransmission in the prefrontal cortex in schizophrenia. These same GABAergic aberrations may underlie the cognitive deficits seen in schizophrenia. Thus, the results could help shed light on the links between cannabis use and schizophrenia, and at the same time offer new targets for drug development aimed specifically at the cognitive aspects of the disease.
Though a cause-and-effect relationship has not been established between cannabis use and schizophrenia, it is known that long-term cannabis use in otherwise healthy people can affect working memory in a way that resembles the deficits seen in schizophrenia. In schizophrenia, Lewis and colleagues have suggested that these defects may be associated with reductions in GABA neurotransmission in the dorsolateral prefrontal cortex (for recent review, see Lewis and Gonzalez-Burgos, 2008). In that region, the cannabinoid receptor CB1R is found in a subpopulation of GABAergic, cholecystokinin-positive interneurons (distinct from the more well-known parvalbumin-containing GABA cells that Lewis's group also studies; see interview with Lewis), and functions to suppress GABA release. From this, Lewis and colleagues hypothesized that the CB1R in the prefrontal cortex might be altered in schizophrenia.
To test that idea, the investigators used in situ hybridization, and immunohistochemistry to look at CB1R mRNA and protein levels in postmortem brain tissue from 23 people with schizophrenia and 23 age-matched controls. They found that in the tissue from people with schizophrenia, both CB1R mRNA and protein showed a normal laminar distribution, but amounts were reduced. CB1R mRNA was down by 15 percent; protein was reduced by 12 percent, and both reductions were statistically significant. The CB1R protein was mainly detected in axons and synaptic terminals, and in subjects with schizophrenia, the density of CB1R-containing axons was reduced.
The reduction in CB1R correlated with reduction in markers of GABAergic neurotransmission in the same region. The subjects showed a significant within-pair correlation between differences in CB1R and the mRNA for GABA-synthesizing enzyme glutamic acid decarboxylase (GAD-67), and cholecystokinin, a neuropeptide that among its other actions appears to regulate the synthesis of endogenous cannabinoids. Because CB1R stimulation inhibits GABA release from CB1R and CCK-containing neurons, the authors suggest that the downregulation of CB1R could be a compensatory response to impaired GABA neurotransmission in the region.
Could the changes in CB1R stem from the use of antipsychotic medications, or even cannabis? Apparently not, the data suggest, as the results did not differ when adjusted for sex, diagnosis, or use of various medications. To directly test that idea that medications might affect CB1R levels, the investigators treated macaque monkeys for 17-27 months with haloperidol or olanzapine or placebo, and then looked at CB1R in the animals’ brain tissue. The distribution of CB1R in brain matched the human pattern, and the investigators found no effect of the medications on receptor mRNA levels.
The reduction of CB1R receptors did not seem to occur in response to cannabis use or dependence in the patients. In fact, the data show that mean CB1R mRNA and protein levels were higher in the subset of subjects with schizophrenia who also had a substance use disorder or a history of cannabis use, though not significantly so. This suggests that “these factors might have blunted the decreases in CB1R mRNA and protein levels in schizophrenia,” the authors write.
The results raise the possibility that decreased CB1R in the dorsolateral prefrontal cortex there could reflect the brain’s attempt to normalize cognitive function in the face of a GABA deficit. “This interpretation implies that cannabis use in vulnerable individuals would counteract these compensatory responses, providing a potential mechanism linking cannabis exposure with an increased risk for the cognitive impairments of schizophrenia,” the authors write. In addition to providing a testable hypothesis, they write, the findings suggest novel targets for treating cognitive impairment, including CB1R antagonists.—Pat McCaffrey.
Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry. 2008 Jul;65(7):772-84. Abstract
Comments on Related News
Related News: Meta-analysis Supports Case for Cannabis in Etiology of PsychosisComment by: Jim van Os
Submitted 8 August 2007
Posted 8 August 2007
This excellent review confirms the previous meta-analysis by Henquet et al. (2005) and as such does not add anything new. The importance lies in the UK context: previously the Lancet has been mostly skeptical with regard to this issue. The fact that the leading UK medical journal now also allows these findings to see daylight is a significant event and helps stimulate further funding for the effort that several groups worldwide have started working on over the last five years: the search for the mechanism explaining the link.
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Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis
Comment by: John McGrath, SRF Advisor
Submitted 9 August 2007
Posted 10 August 2007
I recommend the Primary Papers
It is reassuring to see that the results of the latest meta-analysis (Moore et al., 2007) are consistent with previous meta-analyses, and that the various meta-analyses are broadly consistent with the now much-tortured primary data. Despite the meta-analysis fatigue, the results are too important to ignore.
When thinking about the impact of cannabis on schizophrenia frequency measures, it is important to remember that cannabis use may translate to an increase in the prevalence of active psychosis via two mechanisms. The data suggest that as the prevalence of cannabis use increases in a population, the incidence of schizophrenia should also increase (Hickman et al., 2007). Furthermore, in those with established schizophrenia, cannabis use is associated with poorer outcomes (i.e., reduced remission rates). Thus, from a modeling perspective, increased cannabis use could lead to an increase in the prevalence of active psychosis via two mechanisms (i.e., increased “inflow” and decreased “outflow”) (McGrath and Saha, 2007).
The prevalence of active psychosis in the community may be “under the influence” of cannabis from more than one perspective.
Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review. Lancet. 2007 July 28; 370:319-328. Abstract
McGrath J, Saha S. Thought experiments on the incidence and prevalence of schizophrenia “under the influence” of cannabis. Addictions 2007 Apr;102(4):514-5. Abstract
Hickman M, Vickerman P, Macleod J, Kirkbride J, Jones PB. Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and
Wales. Addiction. 2007 Apr;102(4):597-606. Abstract
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Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis
Comment by: Dana March, Ezra Susser (SRF Advisor)
Submitted 20 August 2007
Posted 20 August 2007
The recent meta-analysis in the Lancet (Moore et al., 2007) regarding cannabis use and psychotic or affective mental health outcomes is, indeed, a necessary contribution. It is the first systematic review restricted to longitudinal studies of cannabis use and mental health outcomes. For this addition to the contours of the literature, Zammit and colleagues are to be commended.
We may be more optimistic than the authors, however, about the potential for future longitudinal studies to shed further light on the question of causality, and perhaps more cautious about the present state of the evidence. Given the public health and policy implications, we propose a concerted effort to complete observational studies that are designed to rule out the main alternative explanations for the association (e.g., genetic or social factors that independently influence both cannabis use and psychosis). The Swedish conscript study (Zammit et al., 2002) is a fine example of one such study. We should also be considering natural experiments and designs based on instrumental variables enabled by in order to complement this work. For instance, we might capitalize on situations created by policy changes that affect the availability—and therefore use—of cannabis in order to examine the impact on the development of psychosis. Whether at the individual or the population level, both creativity and rigor are required.
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007 Jul 28;370(9584):
Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002 Nov 23;325 (7374):1199. Abstract
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Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis
Comment by: Amresh Shrivastava
Submitted 20 October 2007
Posted 24 October 2007
Current interest in cannabis and the onset of psychosis is laudable. The Lancet paper no doubt establishes a causal link based upon what has been known in the literature (Raphael et al., 2005; Roberts et al., 2007; Rey et al., 2004; Wittchen et al., 2007). The authors need to be congratulated for taking extreme care to incorporate most of the studies and also for making conclusions with a sense of skepticism. That is where further questions arise.
1. Cannabis is used only in certain cultures and known to be involved in a maximum 50 percent of cases of psychosis, schizophrenia, and schizophreniform psychosis (Gregg et al., 2007). In that sense, are there two different phenotypes of schizophrenia, a) where exposure to cannabis is necessarily a factor and b) where a different set of potentiating or precipitating factors work, not cannabis?
2. Even if we focus only on the first possibility, there are few unanswered questions such as, what are the concurrent clinical conditions along with cannabis abuse? Do these patients have cognitive dysfunction? Is that reflective of broader brain mechanism changes?
3. There seems to be no reliable biological explanation as to why exposure to cannabis should precipitate psychosis. Cannabis is one of the most commonly used illicit drugs. Its active compound “cannabidols” has 64 active isomers, each having differing effects on health and behavior. There is strong support for a link between cannabis and development—exacerbation of psychosis as well as other mental health conditions (e.g., anxiety, depression). Further research is needed to determine the underlying neurochemical processes and their possible contributions to etiology, as well as the social factors that contribute to the increasing use of cannabis by young people.
4. There is a theory that preexisting cognitive dysfunction is a core feature of schizophrenia. Accepting this, there are no studies to show “causal relationship” between cannabis and cognitive dysfunction.
The current levels of information and understanding, though collected over last 25-30 years of research, are far from adequate to establish any direct relationship except “mere association.” It is hoped that more precise biological, imaging, and neuropsychological studies would be able to throw fresh light on this important area of research.
Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuroimaging, mainly done in non-psychotic populations, shows little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Δ9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Δ9-tetrahydrocannabinol induces psychotic-like states and memory impairments in healthy volunteers (Linszen et al., 2007).
On the basis of six studies, it is concluded that there was insufficient evidence to prove conclusively that long-term cannabis use causes or does not cause residual abnormalities. The results of several reviews were also inconclusive as to whether cannabis use during adolescence may have a lasting effect on cognitive functioning and brain structure. However, it could not rule out that a) certain cognitive and cerebral abnormalities existed in patients before cannabis use began and b) that patients were suffering from subacute effects of cannabis (Weeda et al., 2006).
Continued cannabis use by persons with schizophrenia predicts a small increase in psychotic symptom severity but not vice versa (Degenhardt et al., 2007). Currently, there is a lot of interest in cannabis use as a risk factor for the development of schizophrenia. Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. In this situation, we need to examine the similarities between these in the context of the neurobiology underlying cognitive dysfunction, particularly implicating the endogenous cannabinoid system, which plays a significant role in attention, learning, and memory, and in general, inhibitory regulatory mechanisms in the brain. Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. The theoretical and clinical significance of further research in this field is enhancing our understanding of underlying pathophysiology and improving the provision of treatments for substance use and mental illness (Solowij et al., 2007). Many studies now show a robust and consistent association between cannabis consumption and the ulterior development of psychosis. Furthermore, our better understanding of cannabis biology allows the proposal of a plausible hypothetical model, based notably on possible interactions between cannabis and dopaminergic neurotransmission (Jockers-Scherubl, 2006). Do they suffer from other disorders, which are underlying or may be causal or comorbid, and do these comorbid conditions also have neurocognitive changes, e.g., psychosis, ADHD, LD, Tourette disorder, and other movement disorders, or depression? Is there an interrelationship among these factors to cause abuse and degree of cannabis consumption?
Raphael B, Wooding S, Stevens G, Connor J. Comorbidity: cannabis and complexity. J Psychiatr Pract. 2005 May; 11(3): 161-7.
Roberts RE, Roberts CR, Xing Y. Comorbidity of substance use disorders and other psychiatric disorders among adolescents: Evidence from an epidemiologic survey. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S4-13. Epub 2007 Feb 1.
Rey JM, Martin A, Krabman P. Is the party over? Cannabis and juvenile psychiatric disorder: the past 10 years. J Am Acad Child Adolesc Psychiatry. 2004 Oct; 43(10): 1194-205. Abstract
Wittchen HU, Frohlich C, Behrendt S. Cannabis use and cannabis use disorders and their relationship to mental disorders: A 10-year prospective-longitudinal community study in adolescents. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S60-70. Epub 2007 Jan 25.
Gregg L, Barrowclough C, Haddock G. Reasons for increased substance use in psychosis. Clin Psychol Rev. 2007 May;27(4):494-510. Epub 2007 Jan 19. Abstract
Linszen D, van Amelsvoort T. Cannabis and psychosis: an update on course and biological plausible mechanisms. Curr Opin Psychiatry. 2007 Mar; 20(2): 116-20. Abstract
Weeda MR, Peters BD, De Haan L, Linszen DH. Residual neuropsychological, structural and functional brain abnormalities after long-term cannabis use] Tijdschr Psychiatr. 2006; 48(3): 185-93. Abstract
Degenhardt L, Tennant C, Gilmour S, Schofield D, Nash L, Hall W,McKay D. The temporal dynamics of relationships between cannabis, psychosis and depression among young adults with psychotic disorders: findings from a 10-month prospective study. Psychol Med. 2007 Feb 9; 1-8.
Solowij N, Michie PT. Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci. 2007 Jan; 32(1): 30-52. Abstract
Jockers-Scherubl MC. [Schizophrenia and cannabis consumption: epidemiology and clinical symptoms] Prax Kinderpsychol Kinderpsychiatr. 2006; 55(7): 533-43. Abstract
Curtis L, Rey-Bellet P, Merlo MC. [Cannabis and psychosis] Rev Med Suisse. 2006 Sep 20; 2(79): 2099-100, 2102-3.
Costentin J. [Neurobiology of cannabis--recent data enlightening driving disturbances] Ann Pharm Fr. 2006 May; 64(3): 148-59. Abstract
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