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We found that the use of cannabis and other illicit substances was associated with an earlier age at onset of psychotic disorders
 
 
  --------Psychosis has a strong association with substance use.....[in this analysis] Substance users were two years younger at the onset of psychosis compared with nonusers. Age at onset was 2.7 years earlier among cannabis users compared with nonusers......Several birth cohort and population studies have suggested a potentially causal association between cannabis use and psychosis, and cannabis use has been linked to earlier onset of schizophrenia......"This finding is an important breakthrough in our understanding of the relationship between cannabis use and psychosis," they wrote in conclusion. "It raises the question of whether those substance users would still have gone on to develop psychosis a few years later." "The results of this study confirm the need for a renewed public health warning about the potential for cannabis use to bring on psychotic illness," they added...........
 
"Meta-analysis found that the age at onset of psychosis for cannabis users was 2.70 years younger (standardized mean difference = -0.414) than for nonusers; for those with broadly defined substance use, the age at onset of psychosis was 2.00 years younger (standardized mean difference = -0.315) than for nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. Differences in the proportion of cannabis users in the substance-using group made a significant contribution to the heterogeneity in the effect sizes between studies, confirming an association between cannabis use and earlier mean age at onset of psychotic illness."
 
"Conclusions The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis."
 
"The results of this study provide strong evidence that reducing cannabis use could delay or even prevent some cases of psychosis. Reducing the use of cannabis could be one of the few ways of altering the outcome of the illness because earlier onset of schizophrenia is associated with a worse prognosis and because other factors associated with age at onset, such as family history and sex, cannot be changed.47 Building on several decades of research, this finding is an important breakthrough in our understanding of the relationship between cannabis use and psychosis. It raises the question of whether those substance users would still have gone on to develop psychosis a few years later. However, even if the onset of psychosis were inevitable, an extra 2 or 3 years of psychosis-free functioning could allow many patients to achieve the important developmental milestones of late adolescence and early adulthood that could lower the long-term disability arising from psychotic disorders. The results of this study confirm the need for a renewed public health warning about the potential for cannabis use to bring on psychotic illness."

 
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Cannabis Use Linked to Earlier Psychosis
 
MedPage Today
Published: February 07, 2011
 
Action Points
 
* Point out that the results of this meta-analysis support a relationship between cannabis use and earlier onset of psychotic illness.
 
* Note that in contrast to cannabis use, alcohol use was not associated with a significantly earlier age at onset of psychosis.
 
Psychotic illness occurs significantly earlier among marijuana users, results of a meta-analysis suggest.
 
Data on more than 22,000 patients with psychosis showed an onset of symptoms almost three years earlier among users of cannabis compared with patients who had no history of substance use.
 
The age of onset also was earlier in cannabis users compared with patients in the more broadly characterized category of substance use, investigators reported online in Archives of General Psychiatry.
 
"The results of this study provide strong evidence that reducing cannabis use could delay or even prevent some cases of psychosis," Matthew Large, MD, of the University of New South Wales in Sydney, Australia, and co-authors wrote in conclusion.
 
"Reducing the use of cannabis could be one of the few ways of altering the outcome of the illness because earlier onset of schizophrenia is associated with a worse prognosis and because other factors associated with age at onset, such as family history and sex, cannot be changed."
 
Psychosis has a strong association with substance use. Patients of mental health facilities have a high prevalence of substance use, which also is more common in patients with schizophrenia compared with the general population, the authors wrote.
 
Several birth cohort and population studies have suggested a potentially causal association between cannabis use and psychosis, and cannabis use has been linked to earlier onset of schizophrenia. However, researchers in the field remain divided over the issue of a causal association, the authors continued.
 
Attempts to confirm an earlier onset of psychosis among cannabis users have been complicated by individual studies' variation in methods used to examine the association. The authors sought to resolve some of the uncertainty by means of meta-analysis.
 
A systematic search of multiple electronic databases yielded 443 potentially relevant publications. The authors whittled the list down to 83 that met their inclusion criteria: All the studies reported age at onset of psychosis among substance users and nonusers.
 
The studies comprised 8,167 substance-using patients and 14,352 patients who had no history of substance use. Although the studies had a wide range of definitions of substance use, the use was considered "clinically significant" in all 83 studies. None of the studies included tobacco in the definition of substance use.
 
The studies included a total of 131 patient samples. Substance use included alcohol in 22 samples, cannabis in 41, and was simply defined as "substance use" in 68 samples.
 
Alcohol use was not significantly associated with earlier age at onset of psychosis.
 
On average, substance users were 1.73 years younger than nonusers were. The effect of substance use on age at onset was greater in women than in men, but not significantly so. Heavy use was associated with earlier age at onset compared with light use and former use, but also not significantly different, the authors reported.
 
Substance users were two years younger at the onset of psychosis compared with nonusers. Age at onset was 2.7 years earlier among cannabis users compared with nonusers.
 
Acknowledging limitations of the study, the authors cited the lack of information on tobacco use and its association with earlier age at onset of psychosis, and the lack of data on individual patients inherent in all meta-analyses.
 
Despite the limitations, the authors said the findings have potentially major clinical and policy implications.
 
"This finding is an important breakthrough in our understanding of the relationship between cannabis use and psychosis," they wrote in conclusion. "It raises the question of whether those substance users would still have gone on to develop psychosis a few years later."
 
"The results of this study confirm the need for a renewed public health warning about the potential for cannabis use to bring on psychotic illness," they added.
 
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Cannabis Use and Earlier Onset of Psychosis - pdf attached ONLINE FIRST
 
Download the PDF here
 
A Systematic Meta-analysis
 
Matthew Large, BSc(Med), MBBS, FRANZCP; Swapnil Sharma, MBBS, FRANZCP; Michael T. Compton, MD, MPH; Tim Slade, PhD; Olav Nielssen, MBBS, MCrim, FRANZCP
 
Arch Gen Psychiatry. Published online February 7, 2011.
 
ABSTRACT
 
Context A number of studies have found that the use of cannabis and other psychoactive substances is associated with an earlier onset of psychotic illness.
 
Objective To establish the extent to which use of cannabis, alcohol, and other psychoactive substances affects the age at onset of psychosis by meta-analysis.
 
Data Sources Peer-reviewed publications in English reporting age at onset of psychotic illness in substance-using and non-substance-using groups were located using searches of CINAHL, EMBASE, MEDLINE, PsycINFO, and ISI Web of Science. Study Selection Studies in English comparing the age at onset of psychosis in cohorts of patients who use substances with age at onset of psychosis in non-substance-using patients. The searches yielded 443 articles, from which 83 studies met the inclusion criteria.
 
Data Extraction Information on study design, study population, and effect size were extracted independently by 2 of us.
 
Data Synthesis Meta-analysis found that the age at onset of psychosis for cannabis users was 2.70 years younger (standardized mean difference = -0.414) than for nonusers; for those with broadly defined substance use, the age at onset of psychosis was 2.00 years younger (standardized mean difference = -0.315) than for nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. Differences in the proportion of cannabis users in the substance-using group made a significant contribution to the heterogeneity in the effect sizes between studies, confirming an association between cannabis use and earlier mean age at onset of psychotic illness.
 
Conclusions The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.
 
INTRODUCTION
 
Cannabis is the most widely used addictive substance after tobacco and alcohol.1 The 2009 National Survey on Drug Use and Health reported that more than 16 million Americans use cannabis on a regular basis, most of whom started using cannabis and other drugs during their teenage years.2 There is little doubt about the existence of an association between substance use and psychotic illness. National mental health surveys have repeatedly found more substance use, especially cannabis use, among people with a diagnosis of a psychotic disorder.3-5 There is a high prevalence of substance use among individuals treated in mental health settings,6 and patients with schizophrenia are more likely to use substances than members of the wider community.7-8 Prospective birth cohort and population studies suggest that the association between cannabis use and later psychosis might be causal,9-10 a conclusion supported by studies showing that cannabis use is associated with an earlier age at onset of psychotic disorders, particularly schizophrenia.11-15
 
Not all researchers agree that the association between cannabis use and earlier age at onset is causal. Sevy et al16 argue that the association between cannabis use and earlier age at onset could be explained by demographic variables, including lower socioeconomic status and the proportion of male cannabis users. Wade17 has suggested that the apparent association between earlier age at onset and cannabis use might simply be owing to older patients with first-episode psychosis being less likely to use cannabis.
 
If an association between cannabis use and an earlier age at onset of psychotic disorder were confirmed, the finding would lend support to the possible existence of a causal link between cannabis use and psychosis. This would in turn stimulate research into how cannabis can disrupt brain development and increase the vulnerability to developing psychosis. Evidence already shows that cannabis exposure is associated with a decline in cognitive performance in young people without psychosis18 and a loss of cortical thickness in early schizophrenia.19-20 Other research suggests the presence of a gene x environment interaction involving cannabis and a functional polymorphism in the enzyme catechol O -methyltransferase so that cannabis users with the Val/Val catechol O -methyltransferase genotype are at greater risk for developing psychosis21 and have a significantly younger age at onset than people with Met/Met or Val/Met alleles.22
 
However, attempts to confirm the earlier onset of psychosis among cannabis users found in individual studies have been complicated by the considerable variation in the methods used to examine the association between the age at onset of psychosis and substance use. First, there are differences in the way substances have been examined. Some studies use an omnibus measure of substance use,23-24 while others have specifically examined the associations between age at onset and use of alcohol25-26 or cannabis.27-28 Second, there are differences in the patient populations because some studies include patients with affective psychoses (psychotic depression and mania),29-30 whereas others limit samples to patients with a diagnosis of schizophrenia and related disorders.31-32 A third area of methodological variation is whether the studies examined substance use at the time of initial presentation to mental health services33-34 or later in the course of established psychotic illness.35-36 A fourth difference is in the nature of the control group, because some studies use psychotic patients with no reported substance use as controls,13 whereas the control groups of other studies include psychotic subjects who used drugs other than the drug under study.27 A fifth point of variation across studies relates to the age range of included patients, because many early-psychosis services only see individuals younger than a certain age, which is a potentially important confounding factor because cannabis use is more prevalent among younger people.17 Perhaps most importantly, few studies explicitly state whether the substance was being used prior to the onset of psychosis, which makes it difficult to draw causal inferences from a reported association.
 
We describe a meta-analysis of studies reporting age at onset and substance use to examine the consistency of the association between substance use, in particular cannabis use, and younger age at onset of psychosis.
 
We considered whether studies of the age at onset of psychosis among substance users and non-substance users would have a greater effect of earlier age at onset of psychosis in studies with a higher proportion of cannabis users compared with studies with a lower proportion of cannabis users. In the language of meta-analysis, we conducted the study with the specific a priori hypothesis that between-study heterogeneity in the age at onset of psychosis would be predicted by differences in the proportion of cannabis users in the substance-using groups.
 
We also examined demographic factors, methodological variations, and indicators of study quality to assess the possibility of a confounding effect arising from the proportion of cannabis users among substance-using groups. Hence, we considered whether between-study heterogeneity in the age at onset of psychosis was associated with the following: (1) the predominance of males in the substance-using groups, because of a potentially confounding statistical association between male sex and earlier age at onset, irrespective of substance use; (2) the proportion of patients with a diagnosis of schizophrenia in the substance-using groups, because of the possibility of a specific causal association of cannabis with schizophrenia rather than with a broader category of psychotic disorders; (3) the use of an upper age limit as a criterion for inclusion in the study, because older subjects might be less likely to use cannabis, spuriously increasing the difference in age at onset of psychotic illness in substance-using groups; (4) the use of age at onset of psychotic symptoms rather than the age at initiation of treatment as the measure of age at onset, because the initiation of treatment is not an accurate marker of the age at onset of the psychotic illness owing to well-recognized treatment delays; (5) the use of systematic methods for diagnosing psychosis and substance use, because higher-quality studies are less likely to have misclassified subjects; (6) whether the studies were conducted during first-episode psychosis or later in the illness, because subjects who commenced or stopped using cannabis after diagnosis could be misclassified; (7) whether the control group contained some subjects who used drugs other than the drug being studied, as was the case in some studies of the effects of use of particular substances such as cannabis, alcohol, and cocaine; (8) the year of publication of the study, because of the possibility that the potency of cannabis has increased over time37; and (9) the reported severity of substance use, including whether the substance use was reported to be heavy or continuous.
 
RESULTS
 
SEARCHES

 
We found 83 studies containing a total of 131 samples of the mean age at onset of psychosis in substance-using and non-substance-using individuals with psychotic disorders (Figure, eTable, eFigure, and eReferences). The 131 included samples comprised 8167 substance-using patients (mean [SD], 62.4 [69.0] substance-using patients per sample) and 14 352 non-substance-using patients (mean [SD], 109.6 [137.3] non-substance-using patients per sample).
 
PUBLICATION BIAS
 
There was no statistical evidence of publication bias. The funnel plot was symmetrical, indicating that there was no statistical evidence of missing studies. No study was identified by the trim and fill method; therefore, no adjustment of the point estimate was made. The classic fail-safe N test found that 1098 studies of a similar size with an effect size of 0 would be needed to return the study to P > .05.
 
META-ANALYSIS
 
Meta-analysis of age at onset of psychosis revealed that the age at onset was 2.70 years earlier among samples of cannabis users (z = -7.18; P < .001) and was 2.00 years earlier in samples with unspecified substance use compared with non-substance-using controls (z = -6.87; P < .001) (Table 1). Alcohol-using samples were nonsignificantly younger than the control groups (-0.28 years; z = -0.47; P = .64). Overall, the mean age of the substance-using groups in the 131 samples was 1.73 years younger than in the control groups (z = -2.74; P = .006). Subgroup analyses demonstrated that the pooled estimate of the effect size indicating earlier age at onset among substance users was greater among women (-3.40 years) than among men (-1.87 years), but this difference was not statistically significance (Table 1). The pooled estimate of the effect size indicating earlier age at onset was greater in heavy or continuous substance users (-2.72 years) than in subjects who were rated as having lighter substance use or who had stopped use (-2.07 years), but this difference between groups was not statistically significant (Table 1).
 
META-REGRESSION AND MULTIPLE META-REGRESSION
 
First, a higher proportion of cannabis users among the substance-using groups was associated with a greater negative effect size, indicating an earlier mean age at onset of psychosis. This could be seen in the group of studies that specifically examined cannabis use and was also demonstrated by meta-regression (Table 2) and multiple meta-regression (Table 2). Second, meta-regression suggested that an overrepresentation of males in the substance-using groups was associated with a greater negative effect size, indicating an earlier mean age at onset of psychosis. Third, meta-regression indicated that samples that included subjects older than 45 years also had an earlier age at onset of psychosis associated with substance use when compared with the group of studies that included younger patients only. Multiple meta-regression found that cannabis use and the sample age range made independent contributions to the observed heterogeneity in effect sizes, while a trend toward a higher ratio of males contributing to a larger negative effect size was not significant.
 
Other variables that did not contribute to the heterogeneity of effect size of substance use on age at onset included the following: the proportion of patients with schizophrenia and related nonaffective psychotic disorders; whether the study used systematic measures for diagnosis; whether the study was conducted in patients with first-episode psychosis; whether the control groups might have included some users of other substances; whether the onset of psychosis was defined by the onset of symptoms or the date of initial treatment; and the year of publication of the study.
 
COMMENT
 
We found that the use of cannabis and other illicit substances was associated with an earlier age at onset of psychotic disorders. In contrast, alcohol use alone did not appear to be significantly associated with a younger age at onset of psychosis. With regard to our a priori hypothesis, we found that a higher proportion of cannabis users in the substance-using groups significantly contributed to the heterogeneity in the effect size, indicating an earlier mean age at onset of psychosis in samples with more cannabis users.
 
With respect to the demographic and clinical factors, we found that an increased proportion of males in the substance-using groups relative to control groups significantly contributed to the heterogeneity in the effect size, but this was not independent of the association between cannabis use and age at onset when examined with multiple meta-regression. Hence, there was no evidence that the association between male sex and earlier age at onset of psychosis was the reason for the association between cannabis use and an earlier age at onset. Furthermore, the proportion of patients with schizophrenia did not significantly contribute to the heterogeneity in the effect size, suggesting that a possible association between young age, cannabis use, and a diagnosis of schizophrenia rather than affective psychosis could not explain the association between cannabis use and an earlier age at onset of psychosis.
 
The methods used in this study allowed us to examine whether the observed association between substance use and earlier age at onset might be a result of substance use being more common among younger people, including those with schizophrenia, which has been a criticism of individual studies.17 We found that the use of an upper age limit as an inclusion criterion significantly contributed to the heterogeneity in the effect size, suggesting that the presence of a greater number of older non-cannabis users in a sample might spuriously contribute to the difference in mean age between the substance-using and non-substance-using groups. However, the finding of an association between the proportion of cannabis users and earlier age at onset was statistically independent of age inclusion criteria. This suggests that some of the observed difference in the age at onset of psychosis in substance-using and non-substance-using groups might well be because of the association between young age and substance abuse but that the observed effect cannot be wholly explained by an association between young age and cannabis use.
 
No other methodological or study quality issues that we examined were associated with between-study heterogeneity in effect size for age at onset of psychosis. These included measures of the severity of substance use, how the onset of psychosis was measured, whether structured instruments were used to make the diagnoses of psychosis and substance abuse, whether the study only included patients with first-episode psychosis, the possibility that users of other substances were included in the control groups, and the year the study was conducted. Hence, it was unlikely that variations in the methods or the quality of studies greatly affected the main finding of a significantly younger age at onset of psychosis among substance users, especially users of cannabis.
 
One limitation of this study was the absence of data to enable us to examine the extent to which tobacco use is associated with an earlier age at onset, because insufficient tobacco use data were available for meta-analysis. It is conceivable that the apparent association between cannabis and psychosis is in fact related to a neurotoxin in tobacco, which is almost always mixed with cannabis. However, this is a weakness of all naturalistic studies of cannabis and psychosis, and tobacco use by itself has not been considered to be a factor contributing to exacerbations of psychosis in people with established illness.
 
A further limitation of this form of study is the possibility of ecological fallacy in meta-analyses that do not examine data from individual subjects.42 An example might be if the non-cannabis-using patients in the substance-using groups had the youngest age at onset. A future study using individual patient data could clarify the influence of tobacco use and confirm that the finding was not due to an ecological fallacy.42
 
A number of hypotheses have been proposed to explain the association between cannabis use and schizophrenia, including the following: (1) that cannabis use is a causal factor for schizophrenia; (2) that cannabis use precipitates psychosis in vulnerable people; (3) that cannabis use exacerbates symptoms of schizophrenia; and (4) that people with schizophrenia are more likely to use cannabis.43 This study lends weight to the view that cannabis use precipitates schizophrenia and other psychotic disorders, perhaps by an interaction between genetic and environmental factors as has been suggested for cannabis and catechol O -methyltransferase21-22 or by disrupting brain development, especially during the important neurological maturation that takes place during adolescence.44 Our findings do not support the view that people with a propensity to develop psychosis at a young age are simply more likely to use all substances, because alcohol use was not associated with a younger age at onset. However, the possibility that those who are destined to develop psychosis at an early age are more prone to use substances such as tobacco could be examined in future studies.
 
The results of this systematic review and meta-analysis represent strong scientific evidence for an association between substance use, particularly the use of cannabis, and an earlier age at onset of psychotic illnesses. The association between the extent of cannabis use in the substance-using group and the effect size as well as the weaker association between earlier age at onset and alcohol use support the hypothesis that cannabis use is a causal factor in psychotic disorders. The finding raises the important questions of whether cannabis and other substances can trigger psychosis by direct neurotoxic effects, by alterations in dopamine activity, or by other changes in neurotransmission and the extent to which any adverse effects on the brain are reversible.45-46 These results confirm the need for further neurobiological research to find the mechanisms by which cannabis use triggers or brings forward psychotic illness.
 
The results of this study provide strong evidence that reducing cannabis use could delay or even prevent some cases of psychosis. Reducing the use of cannabis could be one of the few ways of altering the outcome of the illness because earlier onset of schizophrenia is associated with a worse prognosis and because other factors associated with age at onset, such as family history and sex, cannot be changed.47 Building on several decades of research, this finding is an important breakthrough in our understanding of the relationship between cannabis use and psychosis. It raises the question of whether those substance users would still have gone on to develop psychosis a few years later. However, even if the onset of psychosis were inevitable, an extra 2 or 3 years of psychosis-free functioning could allow many patients to achieve the important developmental milestones of late adolescence and early adulthood that could lower the long-term disability arising from psychotic disorders. The results of this study confirm the need for a renewed public health warning about the potential for cannabis use to bring on psychotic illness.
 
 
 
 
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