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Adolescent Initiation of Cannabis Use and Early-Onset Psychosis a
b
c
Kara Simone Bagot M.D. , Robert Milin M.D. & Yifrah Kaminer M.D., MBA a
Yale University School of Medicine, Child Study Center and Department of Psychiatry, New Haven, CT, USA b
University of Ottawa, Division of Addiction & Mental Health and Department of Psychiatry, Ottawa, Ontario, Canada c
University of Connecticut School of Medicine, Departments of Psychiatry and Pediatrics, Farmington, CT, USA Accepted author version posted online: 16 Mar 2015.
Click for updates To cite this article: Kara Simone Bagot M.D., Robert Milin M.D. & Yifrah Kaminer M.D., MBA (2015): Adolescent Initiation of Cannabis Use and Early-Onset Psychosis, Substance Abuse, DOI: 10.1080/08897077.2014.995332 To link to this article: http://dx.doi.org/10.1080/08897077.2014.995332
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ACCEPTED MANUSCRIPT Adolescent Initiation of Cannabis Use and Early-Onset Psychosis
Kara Simone Bagot, M.D.1, Robert Milin, M.D. 2, Yifrah Kaminer, M.D., MBA3
1. Yale University School of Medicine, Child Study Center and Department of Psychiatry, New Haven, CT, USA
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2. University of Ottawa, Division of Addiction & Mental Health and Department of Psychiatry, Ottawa, Ontario, Canada 3. University of Connecticut School of Medicine, Departments of Psychiatry and Pediatrics, Farmington, CT, USA
Correspondence should be addressed to Dr. Kara Bagot, Yale Child Study Center, 230 S. Frontage Road, New Haven, CT 06520-7900, USA. Email: [email protected]
ABSTRACT Background: It is important to evaluate the impact of cannabis use on onset and course of psychotic illness as the increasing number of novice cannabis users may translate into a greater public health burden. We aim to examine the relationship between adolescent onset of regular marijuana use and age of onset of prodromal symptoms, or first episode psychosis, and the manifestation of psychotic symptoms in those adolescents who use cannabis regularly. Methods: A review was conducted of the current literature for youth who initiated cannabis use prior to age 18 and experienced psychotic symptoms at, or prior to, age 25 years. Seventeen studies met
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ACCEPTED MANUSCRIPT eligibility criteria and were included in this review. Results: The current weight of evidence supports the hypothesis that early initiation of cannabis use increases the risk of early onset psychotic disorder, especially for those with a pre-existing vulnerability and who have greater severity of use. There is also a dose-response association between cannabis use and symptoms, such that those who use more tend to experience greater number and severity of prodromal and diagnostic psychotic symptoms. Those with early onset psychotic disorder and comorbid
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cannabis use show a poorer course of illness in regards to psychotic symptoms, treatment and functional outcomes, although those with early initiation of cannabis use appear to show a higher level of social functioning than non-cannabis users. Conclusions: Adolescent initiation of cannabis use is associated, in a dose-dependent fashion, with emergence and severity of psychotic symptoms and functional impairment such that those who initiate use earlier and use at higher frequencies demonstrate poorer illness and treatment outcomes. These associations appear more robust for adolescents at high-risk for developing a psychotic disorder.
Keywords cannabis, adolescent, early-onset, psychosis
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ACCEPTED MANUSCRIPT INTRODUCTION
Adolescence is a critical developmental phase for the onset and recognition of psychiatric disorders including Substance Use Disorders (SUDs). Between 70-80% of youth with a SUD have at least one co-occurring psychiatric disorder.1 Many possible relationships exist between SUDs and comorbid psychopathology; co-occurring disorders may precede, develop as a
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consequence of, moderate the severity of, or originate from a common vulnerability as SUDs.2 Substance use in the population of those with first episode psychosis (FEP; positive symptoms for six months or less) is higher than that of the general population.3 Studies have found that worldwide, up to 62% of those experiencing FEP have a lifetime history of substance abuse (SA; use of illicit substances and/or use of legal substances in amounts or ways other than intended and meeting DSM-IV criteria for such use).4 Increased rates of substance use have also been found in those with symptoms of prodromal psychotic disorders.5 Prodromal is defined as subtle, subclinical symptoms that do not meet criteria for a full-blown psychotic disorder. Adults whose SA pre-dates psychosis onset have higher recurrence of acute, severe psychotic symptoms as indicated by increased frequency of hospitalization.3, 6, 7 Cannabis is the most widely used substance in the world, especially among adolescents whose developing brains are more susceptible to substance exposure.8, 9 Given the conceivable increase in marijuana availability to youth, and decreased perception of harm, via medical marijuana and pro-legalization legislation, the association between early cannabis use (CU) and early onset psychosis is an important public health issue.10, 11
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ACCEPTED MANUSCRIPT Past-year prevalence of CU in adolescents aged 12-17 years is estimated to be 13.4%, with greater than 25% meeting criteria for Cannabis Use Disorder (CUD).12 There is evidence that CU can precipitate transient psychotic and affective experiences.13 Studies also show that CU increases the probability of later psychosis two-fold,14 with a relative risk of two-four for development of Schizophrenia for those who have used once, and relative risk of six in those who have used fifty or more times as compared to never-users.13, 15 Lifetime CUD is also
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associated, in a dose-response manner, with earlier onset of psychosis, or prodrome, approximately three years earlier,16, 17 earlier age of first psychiatric hospitalization,18 and a higher risk of relapse.15 Adolescent cannabis users report many symptoms that coincide with prodromal psychotic symptoms including hallucinations, paranoia, depression and anxiety, which may present subclinically.19-21 Continued CU can increase the risk of persistence of subclinical psychotic symptoms.22, 23 Shubart and colleagues found that compared to those who initiated use between the ages of 15-18 years, those who initiated CU prior to age 12 years were 3.1 times more likely to have the highest 10% of scores on “psychotic experiences,” and those with initiation of use between 12-15 years of age had a 1.2 times greater likelihood of experiencing severe psychotic symptoms.24 Kuepper and colleagues also demonstrated increased odds of development and persistence of incident/transient psychotic symptoms as a function of CU over time in young adults.23 Puberty is a developmental stage critical for brain maturation, with adolescence marking the stage at which dopamine sensitization likely begins.25 Exposure to high levels of tetrahydrocannabinol (THC) through CU triggers repeated activation of the endogenous
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ACCEPTED MANUSCRIPT mesolimbic dopaminergic system which may in turn lead to sensitization of this system, and progressive enhancement of acquired susceptibility to psychosis.25, 26 27 Indeed, delta-9-THC is associated with deficits in learning and recall, and positive and negative psychotic symptoms.28 Patients with Schizophrenia demonstrate greater sensitivity to the effects of delta-9-THC28 and adolescents with CU demonstrate higher rates of Schizophrenia.29 Adolescent CUD in populations that are biologically vulnerable to psychosis due to a COMT gene polymorphism
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(Valine-Methionine substitution at codon 158) may be at greater risk of development of Schizophrenia or other psychotic disorders, especially with CU before age 18.30 This is likely due to the association between the Val allele and increased levels of mesolimbic dopamine signaling and lower dopamine levels in the prefrontal cortex.31 Changes in synaptic dopamine activity in the prefrontal cortex occur until adulthood, thus increasing potential sensitivity to environmental influences during adolescence.32 Two recent neuroimaging reviews examined the effects of CU on brain morphology in psychosis,33, 34 finding some preliminary indication that subjects at risk for psychosis and those with FEP may be particularly vulnerable to structural brain changes or brain volume loss due to CU.33-35 While several studies have examined the relationship between CU and lifetime psychosis, the extant literature is limited on the relationship between adolescent-initiation CU and the onset of the psychosis prodrome and/or FEP. Additionally, given the legislative changes regarding marijuana use (i.e. adoption of medical marijuana and recreational marijuana use) coupled with increasing CU in adolescents over the past decade,12, 36 there is great concern for medical and psychiatric consequences of increased CU initiation in the context of reduced perception of
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ACCEPTED MANUSCRIPT harmfulness. Thus, reviewing the current literature on the effects of childhood/adolescent marijuana use on prodromal symptoms or FEP is of considerable importance.37 We examine the literature on youth with pre-existing vulnerability to psychosis who may be more susceptible to the effects of cannabis. We aim to study the association between adolescent onset of regular CU and age of onset of psychotic symptoms, the manifestation of psychotic symptoms in those adolescents who use cannabis regularly as compared to non-users, and whether CU is
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differentially associated with outcome and functioning as compared to non-users. It is essential to evaluate the impact of CU on onset and course of psychotic illness as the increasing number of novice cannabis users may translate into a greater public health burden, including greater incidence of early onset FEP. METHODS
This article is a narrative review of the current literature on the effects of early adolescent onset CU on FEP in late adolescence or young adulthood. We searched PubMed, Embase, Medline and PsycInfo for all relevant literature published from 1967 (limit set by OVID) to August 2014. Search terms included “cannabis,” “early onset or prodrome,” “psychosis,” and “adolescent.” Our initial search yielded 244 articles; 186 total when duplicates were removed. With limits set to human subjects, articles published in the English language, or an available English translation, and clinical trials, the yield was 165 studies. Upon review of the title and/or abstract, an additional 122 studies were deemed ineligible due to a solely adult sample, lack of CU measures and/or psychosis outcome measures. Forty-three clinical and epidemiological studies where reported associations between CU and psychosis were both primary and secondary
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ACCEPTED MANUSCRIPT outcome measures were found to be relevant to this review. Upon review of the full manuscripts for these 43 studies, 26 were found incongruous with the aims of our study due to postadolescence or unspecified age of CU initiation and/or post-young adult or unspecified age of psychosis onset. Seventeen articles met eligibility criteria and were included in this study. All three authors contributed to study selection; the first author completed the initial search with the other two authors contributing to the secondary selection process.
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Studies in this review include participants who initiated CU prior to age 18 (given developmental immaturity of the adolescent brain and it’s susceptibility to environmental factors) and experienced FEP at, or prior to, age 25 years (due to evidence of emergence of psychotic symptoms in the general population from late adolescence to mid-20’s). Studies whose participants met the aforementioned age criteria but whose mean age was greater than 30 years at time of survey were excluded due to concerns of recall bias. The stated outcome of included studies had to reflect impact of CU on at least one aspect of psychosis manifestation, prodrome, onset, symptoms, course or functioning (reported in results section as a function of study outcome measure). Initiation of CU had to precede psychosis onset; current/recent CU and/or polysubstance abuse was not exclusionary. Studies were independently and manually mined for demographic information, study design, type of substance use and psychosis. An assessment of bias was completed for each study (selection, performance, detection, attrition and reporting) based on limitations of each investigation reviewed. The majority of studies fell within a moderate risk range. Study characteristics that were evaluated included sample size, demographics, study design, and use of
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ACCEPTED MANUSCRIPT standardized, validated or widely-recognized psychiatric and functional measures, all of which may have an effect on the overall conclusions proposed in this manuscript. Summary measures recounted here consist of values reported by individual studies and include P-values, effect sizes, difference in means and risk ratios. Results were synthesized qualitatively, as individual statistical results (i.e. analyses used and manner of reporting data) varied among studies.
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REVIEW
Cannabis Use Initiation & Psychosis Onset There appears to be a stronger effect of CU on development of psychotic illness with initiation of use prior to age 16.38 While many corroborating studies have found associations between CU and younger age at psychosis onset,18, 19, 41 not all studies have found this association.37, 42 Leeson and colleagues found that age at CU initiation was linearly associated with age at both prodrome and psychosis onset, with younger age of initiation predicting early FEP.41 The significance of the relationship between CU onset and psychosis onset was maintained when cannabis users were dichotomized into low frequency (≤2x/week) and high frequency CU. 41 Age at initiation of CU has been also found to be associated with age at first hospitalization.18 Further, baseline CU has been shown to predict emergence of psychotic disorders in adolescents at high risk for psychosis at four-year follow-up.43 Adolescents with daily CU have been shown to have a greater likelihood of acute onset psychosis as compared to those with non-daily use (42.1% v. 20%).45 Non-daily users are more likely to have a sub-acute presentation (43.35% v. 23.7%).45 This has been corroborated in other
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ACCEPTED MANUSCRIPT adolescent studies which have found increasing risk of psychosis with increased frequency of pre-psychosis CU in both the clinically high-risk (CHR)44 and the general population, with the largest risk in those who have used 50 or more times.46 Those who are at high-risk for psychosis and meet criteria for CUD demonstrate a greater rate of conversion to psychosis within one-year of prodrome as compared to their non-cannabis abusing counterparts.47
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Cannabis Use & Prodrome In determining the predictive value of adolescent CU between the ages of 12-18 on prodromal symptoms prior to the age of 19 years, Compton and colleagues did not find any significant differences between those who reported CU prior to psychosis onset versus those who did not report CU (CU-69.9% v. NCU-80.8%). These relationships remained statistically insignificant when frequency of use (daily CU-39.4% v. non-daily CU-60.6%), and number of prodromal symptoms were taken into account.45 In contrast, Konings and colleagues found that those with CU onset prior to age 14 demonstrated higher levels of prodromal psychotic symptoms.48 Additionally, Miettunen et al. found that in a sample of nearly 6300 adolescents, 15-16 year olds with a lifetime history of CU had a higher mean number of prodromal symptoms and were more likely to report 3 or more symptoms (OR=2.79).49 They also demonstrated a dose-response effect such that number of prodromal symptoms increased with CU frequency.49 Similarly, Leeson et al. found that daily/near daily CU during adolescence was associated with more negative symptoms.41 Finally, youth who were prior cannabis users, but were abstinent prior to prodrome onset, demonstrated fewer positive symptoms and had fewer indicators of disorganized thought process as compared to those who were still using.41
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Psychotic Symptoms Those who initiate CU by age 15 and age 18 demonstrate more symptoms of Schizophrenia by age 26 as compared to never-users.19 A noteworthy study has shown that as the duration of CU increases from first use (≥6 yrs), the odds of development of a non-affective psychosis increase (aOR=2.2), as well as number/severity of delusions (aOR=4.3) and
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hallucinations (aOR=2.8).38 These associations held true for sibling pairs, decreasing the likelihood that unmeasured confounding factors affected outcomes.38 Stefanis and colleagues found that age of onset of CU, controlling for lifetime frequency/amount of use, was more robustly associated with positive symptoms such that those with onset of use prior to, or at, age 15 years had greater occurrence of hallucinations, grandiosity, and first-rank symptoms.20 Cannabis use in those with initiation of use between 1619 years of age was only associated with first-rank symptoms.20 With negative symptoms, they also found a large difference in effect size between the two CU groups dichotomized by age, such that adolescents who initiated CU at a younger age, independent of frequency, demonstrated greater effect sizes.20 Indeed, Schubart et al. found that those with CU prior to age 12 (OR=1.7) or with first use between 12-15 years of age (OR=1.1) had greater likelihood of experiencing negative symptoms. The authors also found evidence of a dose-response effect such that who used a greater quantity, or at a greater frequency, were more likely to experience negative or overall psychotic symptoms.24 Stefanis and colleagues also evaluated the effect of frequency of CU in adolescents, dichotomized as initiation of use at, or before, age 15 and after age 15, on emergence of
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ACCEPTED MANUSCRIPT psychotic symptoms.20 The authors found that CU on 5 or more occasions and systematic (daily) use was associated with all four dimensions of positive psychotic symptoms; hallucinations, paranoia, grandiosity and first-rank symptoms (thought disorders including thought echo, withdrawal, insertion, broadcasting, control and telepathy).20 Less frequent lifetime use was associated with fewer dimensions of positive symptoms; two-four occasions was associated with paranoia, grandiosity and first-rank symptoms and single use was associated with paranoia and
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grandiosity.20 Significant differences were found between CU groups (≤15 versus 16-19 years at CU initiation) on all four positive dimensions. Cannabis use across all levels, single-systematic, was associated with negative symptoms, with more robust findings as use increased.20 Baeza and colleagues found that Spanish adolescents with premorbid CU had worse functioning, more positive symptoms and greater manic symptoms at time of FEP.37 However, cannabis-using adolescents also demonstrated less negative symptoms and fewer psychotic symptoms overall. In contrast, Leeson found that although cannabis users were younger at prodrome onset than nonusers, there were no differences in psychotic symptoms, mode of onset or duration of untreated psychosis.41 Social & Cognitive Functioning Schimmelmann and colleagues found that adolescents whose CU predated onset of psychotic symptoms, as compared to non-users, demonstrated longer duration of psychotic symptoms and had worse functioning, including greater symptom severity, greater academic/occupational impairment and history of criminal justice system involvement prior to treatment.42 Auther and colleagues evaluated a cohort of 160 adolescents to determine if CU in a CHR population was associated with prodromal symptoms.50 They defined high-risk as a score
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ACCEPTED MANUSCRIPT of 3-5 on the following positive symptoms: unusual ideas, suspiciousness, grandiosity, perceptual abnormalities, and disorganized communication. Of the thirty-five adolescents who were CHR and used cannabis, 49% used ≤19 times and were more likely to be Caucasian (88.6%) and older (16.74±1.96 years v. 15.65±2.12 years) than high-risk adolescents without a lifetime history of CU. This sub-sample also demonstrated significantly lower prodromal social anhedonia and negative symptoms, and higher social functioning.50 A small subset of adolescents
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who met criteria for cannabis abuse (N=10) had higher IQs than non-abusers. As with the cannabis users, the abusers were less socially anhedonic and had better baseline social functioning than non-abusers.50 Finally, CHR adolescents who also used cannabis demonstrated significantly higher social functioning than non-users and that those who met DSM-IV criteria for cannabis abuse also demonstrated significantly higher social functioning than non-abusers at approximately 2-year follow-up.50 In a study evaluating premorbid functioning as a function of early (12-15 years) and late (15-18 years) CU, adolescents with non-affective psychotic disorders who had early CU initiation demonstrated better social functioning than those who did not use before age 15.45 However, those with early initiation CU tended to perform more poorly academically. Additionally, adolescents who used cannabis at, or before, age 18 did significantly worse academically as compared to those who did not use prior to onset of psychosis.45 Although it appears that, in general, initiation of CU is associated with better cognitive functioning in those with psychotic illnesses, there is diverging evidence on specific neurocognitive areas for which this association holds true. It has been shown that those who use less frequently (≤2x/week) demonstrate higher IQ than their high-frequency CU counterparts.41
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ACCEPTED MANUSCRIPT In a study evaluating the effect of prior CU on cognitive functioning at time of FEP in adolescents, cannabis users and non-users demonstrated similar outcomes on all tests of working memory and learning, and select measures of attention and executive functioning as compared to controls.43 In another study, cannabis users showed no differences in working memory or verbal learning, and greater ability to plan compared to non-users when premorbid IQ was taken into account.41 Pencer et al. found that CU in adolescents on admission to a specialized early
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intervention program for FEP was predictive of better functional/social outcome (i.e. being either gainfully employed or in school) at one and two-year follow-up over the course of treatment. These adolescents also showed significant reduction of CU over the duration of treatment follow-up.52 Course of Cannabis Use & Psychosis Up to 54.7% of adolescents with baseline CU decrease or stop use after FEP.42 Baeza et al. found an 11.5% decrease in CU six months after FEP.37 At 15-month follow-up, age at CU onset has been shown to predict persistent CU (OR=1.43), with mean age of initiation of 14.53±1.94 years for persistent users and 17.39±4.19 years in those who achieved abstinence.41 Adolescents who abuse cannabis also demonstrate a higher rate of medication non-adherence.42 However, only those adolescents who continue CU after psychotic diagnosis demonstrate higher rates of non-engagement in treatment and greater severity of psychotic illness. This translates into higher rates of positive symptoms, and poorer functioning at discharge from the hospital, even after controlling for medication non-adherence.42 Previous cannabis users who have since achieved cessation demonstrate significantly fewer positive and negative symptoms and better general and total PANSS scores than persistent
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ACCEPTED MANUSCRIPT cannabis users, new cannabis users (whose outcome was in between continued and never users) and never users (NCU). Persistent CU at six-months was associated with significantly fewer positive symptoms as compared to NCU. Continued CU at both four-week and six-month follow-up was associated with fewer negative symptoms and lower general and total PANSS scores than NCU. However, there was no difference between groups in hospital readmission rates at six-month follow-up.37 Finally, Leeson et al. also found that indicators of disease
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outcome, including duration of hospital admission and length of time between admissions, up to two years following initial presentation, were better in those who achieved abstinence as compared to persistent users.41 DISCUSSION
Although adolescents are more likely to engage in CU,53 and the onset of psychotic disorders may occur in adolescents aged 15-17,54 the data presented here appear to validate the independent association between early CU and early onset FEP. The earlier the age of initiation of regular CU and the greater the frequency and/or duration of use, the more robust the association with earlier onset of prodrome and FEP, and the severity and number of symptoms experienced. Earlier studies that attribute FEP onset to the age at which adolescents access treatment (as opposed to the true onset of prodromal psychotic symptoms) and sample an older population (recall bias) may suffer from limitations in methodology. Certain positive symptoms demonstrate greater susceptibility to sensitization by cannabis such as grandiosity and paranoia. Additionally, a dose response effect appears to govern the emergence, and type of positive symptoms.20 Contrary to adult studies where CU is associated with fewer, or no difference, in
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ACCEPTED MANUSCRIPT negative symptoms,55, 56 there appears to be greater uncertainty as to the association between the two in adolescents. Studies have demonstrated both a positive association between CU and negative symptoms, with a large dose response effect,20 as well as a negative association between CU and negative symptoms.50 This discrepancy may be due in part to the type of population being studied. Cannabis-using adolescents who did not demonstrate more negative symptoms than their NCU peers may have already been labeled as high-risk for development of psychosis
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based on pre-existing psychotic symptoms. Some studies have demonstrated that CU in CHR adolescents and early CU in FEP is associated with better premorbid social functioning than NCU adolescents,45, 50 which may be due to development of fewer negative symptoms. Better social functioning may lead to greater exposure, and access to illicit substances through increased social contacts. Also, a degree of social sophistication is required to obtain illicit substances when the user is underage and may contribute to the finding of better socialization. The finding that CU is associated with poorer academic functioning is consistent with research in students without psychosis that also demonstrate poor academic performance in the context of CU.57 The literature in adolescents appears to be consistent with the adult literature that demonstrates better cognitive functioning in those with comorbid CU and psychotic disorders.58, 59
However, there is also evidence that those with lifetime CU have poorer clinical and functional
outcomes. Although these two statements appear contradictory, as better cognitive functioning is usually associated with less severe illness, this may reflect the effect of cannabis on psychotic illness. The postulated neuroprotective effect of high premorbid cognitive functioning may be negated by CU (high frequency>low frequency), contributing to the earlier age of onset. This
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ACCEPTED MANUSCRIPT also provides evidence for the hypothesis that CU increases the vulnerability to psychosis in susceptible populations. Persistent cannabis users demonstrate poor outcomes even after treatment for FEP. There is evidence that early initiation and regular use contribute to substance dependence,12 which likely explains the association between regular/high-frequency CU at psychosis presentation and continued use after treatment follow-up. Those with SA and comorbid psychotic illness have
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poorer health outcomes, including earlier age of first hospitalization, than mental illness alone likely because SA interferes with ability to comply with a treatment regimen. The following paradigms have been used to explain the association between CUD and psychiatric comorbidity: 1) psychiatric disorders developing as a consequence of SA, 2) psychiatric disorders altering the course of SA, 3) SA developing as a consequence of psychiatric disorders (self-medication hypothesis), 4) SA altering the course of psychiatric disorders, 5) SA and psychiatric disorders originating from a common vulnerability, and 6) SA and psychiatric disorders being mutually exclusive but coincidentally manifested.60 Although the exact mechanism of action and biological underpinnings of the association between CU and FEP remain unclear, given the data reported here, it appears that cannabis alters the course of psychosis by triggering early onset of disease in a vulnerable youth population. Limitations There are several limitations to this review. Many of the included studies have crosssectional study designs making it difficult to ascertain with certainty the direction of effect. It also introduces recall bias via reliance on retrospective self-report of SA and psychosis. This is of additional concern as CU itself may cause memory impairment. Additionally, two studies had
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ACCEPTED MANUSCRIPT small sample sizes, thus limiting the power and ability to detect small-medium effects. Sampling of subjects may be biased as individuals with more than one disorder are more likely to seek clinical services, resulting in an erroneously higher estimate of the prevalence of the association between these disorders. Also, several studies did not control for confounding factors such as polysubstance abuse and did not differentiate between CU alone and polysubstance abuse. Further, CU was not quantified by frequency, duration and/or amount in some studies, and in
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those that did, CU categories were either imprecise or were not standard across studies, making comparisons difficult. Also, no studies quantified concentration of THC used. In regards to psychosis, the criteria for determining prodromal versus subclinical symptomatology and factors that classified one as CHR were not always transparent. Additionally, findings were not classified by type of psychotic illness, nor were psychotic disorders differentiated from affective disorders with psychotic features in some studies. Finally, for many of the studies, effect sizes and precision of results (confidence intervals) were not reported. However, studies included in this review span different regions of the world, increasing generalizability. Additionally, participants had clearly identified cannabis initiation in adolescence prior to psychosis onset allowing for associations to be made between the two events. CONCLUSION
Adolescent initiation of CU is associated with emergence and severity of psychotic symptoms and functional impairments in a dose-dependent manner such that those who initiate use earlier and consume at higher frequencies demonstrate poorer illness and treatment
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ACCEPTED MANUSCRIPT outcomes. The association between early CU and later psychosis appears to be more robust for CHR adolescents. Despite demonstrating better social and cognitive functioning and likely fewer negative symptoms at baseline, persistent cannabis users with comorbid FEP have poorer clinical, functional and treatment outcomes with a greater burden of illness. 61 Future research should longitudinally examine the trajectory from initiation of cannabis use in childhood/adolescence to psychosis onset in those who solely abuse cannabis. Additionally,
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measurement and standardization of quantity, frequency and type of cannabis use would also help clarify the association between CU and psychosis.
FUNDING Dr. Bagot reports no financial support or conflicts of interest. Dr. Kaminer receives financial support from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism and royalties for books from Hazelden, Routledge and APPI. Dr. Milin receives financial support from the Institute of Mental Health Research, University of Ottawa and has received speaker honorarium from Bristol-Myers Squibb Canada, American Academy of Child and Adolescent Psychiatry, and American Academy of Addiction Psychiatry. There were no funding sources for conducting this research or manuscript preparation.
AUTHOR CONTRIBUTIONS
Dr. Bagot completed the initial literature search for data collection, drafted the initial and subsequent versions of this manuscript, including designing and formatting and revised and
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ACCEPTED MANUSCRIPT approved the final manuscript as submitted. Dr. Milin provided additional articles to include in the review (beyond the initial literature search) in regards to data collection as well as provided analyses of those and the original articles, edited each draft of the manuscript, and approved the final manuscript. Dr. Kaminer conceptualized the review, aided in the selection and analysis of included articles, edited each draft of the manuscript, and approved the final manuscript with
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revisions as submitted.
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ACCEPTED MANUSCRIPT TABLE 1
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Source (Referenc e No.) Arseneault et al., 2002 (19)
Sample (N; age) 759
Canna bis Use (N) CU≤15 yrs=2916≤CU ≥18 yrs= 236 -CHR+ CU=35 -CHR+ CA=10
Assessmen t Tools
Outcome
Structured psych interview (DSM-IV)
CU by age 15 assoc. w sx of: S (p=0.001) & SP (p=0.009) CU by age 18 assoc. w sx of: S (p=0.008)
SOPS, WISC-III, WAIS-R, KSADS, GF: Social & Role
CHR+CU v. CHR+NCU: baseline-↓ social anhedonia (p
Substance Abuse Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/wsub20
Adolescent Initiation of Cannabis Use and Early-Onset Psychosis a
b
c
Kara Simone Bagot M.D. , Robert Milin M.D. & Yifrah Kaminer M.D., MBA a
Yale University School of Medicine, Child Study Center and Department of Psychiatry, New Haven, CT, USA b
University of Ottawa, Division of Addiction & Mental Health and Department of Psychiatry, Ottawa, Ontario, Canada c
University of Connecticut School of Medicine, Departments of Psychiatry and Pediatrics, Farmington, CT, USA Accepted author version posted online: 16 Mar 2015.
Click for updates To cite this article: Kara Simone Bagot M.D., Robert Milin M.D. & Yifrah Kaminer M.D., MBA (2015): Adolescent Initiation of Cannabis Use and Early-Onset Psychosis, Substance Abuse, DOI: 10.1080/08897077.2014.995332 To link to this article: http://dx.doi.org/10.1080/08897077.2014.995332
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ACCEPTED MANUSCRIPT Adolescent Initiation of Cannabis Use and Early-Onset Psychosis
Kara Simone Bagot, M.D.1, Robert Milin, M.D. 2, Yifrah Kaminer, M.D., MBA3
1. Yale University School of Medicine, Child Study Center and Department of Psychiatry, New Haven, CT, USA
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2. University of Ottawa, Division of Addiction & Mental Health and Department of Psychiatry, Ottawa, Ontario, Canada 3. University of Connecticut School of Medicine, Departments of Psychiatry and Pediatrics, Farmington, CT, USA
Correspondence should be addressed to Dr. Kara Bagot, Yale Child Study Center, 230 S. Frontage Road, New Haven, CT 06520-7900, USA. Email: [email protected]
ABSTRACT Background: It is important to evaluate the impact of cannabis use on onset and course of psychotic illness as the increasing number of novice cannabis users may translate into a greater public health burden. We aim to examine the relationship between adolescent onset of regular marijuana use and age of onset of prodromal symptoms, or first episode psychosis, and the manifestation of psychotic symptoms in those adolescents who use cannabis regularly. Methods: A review was conducted of the current literature for youth who initiated cannabis use prior to age 18 and experienced psychotic symptoms at, or prior to, age 25 years. Seventeen studies met
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ACCEPTED MANUSCRIPT eligibility criteria and were included in this review. Results: The current weight of evidence supports the hypothesis that early initiation of cannabis use increases the risk of early onset psychotic disorder, especially for those with a pre-existing vulnerability and who have greater severity of use. There is also a dose-response association between cannabis use and symptoms, such that those who use more tend to experience greater number and severity of prodromal and diagnostic psychotic symptoms. Those with early onset psychotic disorder and comorbid
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cannabis use show a poorer course of illness in regards to psychotic symptoms, treatment and functional outcomes, although those with early initiation of cannabis use appear to show a higher level of social functioning than non-cannabis users. Conclusions: Adolescent initiation of cannabis use is associated, in a dose-dependent fashion, with emergence and severity of psychotic symptoms and functional impairment such that those who initiate use earlier and use at higher frequencies demonstrate poorer illness and treatment outcomes. These associations appear more robust for adolescents at high-risk for developing a psychotic disorder.
Keywords cannabis, adolescent, early-onset, psychosis
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ACCEPTED MANUSCRIPT INTRODUCTION
Adolescence is a critical developmental phase for the onset and recognition of psychiatric disorders including Substance Use Disorders (SUDs). Between 70-80% of youth with a SUD have at least one co-occurring psychiatric disorder.1 Many possible relationships exist between SUDs and comorbid psychopathology; co-occurring disorders may precede, develop as a
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consequence of, moderate the severity of, or originate from a common vulnerability as SUDs.2 Substance use in the population of those with first episode psychosis (FEP; positive symptoms for six months or less) is higher than that of the general population.3 Studies have found that worldwide, up to 62% of those experiencing FEP have a lifetime history of substance abuse (SA; use of illicit substances and/or use of legal substances in amounts or ways other than intended and meeting DSM-IV criteria for such use).4 Increased rates of substance use have also been found in those with symptoms of prodromal psychotic disorders.5 Prodromal is defined as subtle, subclinical symptoms that do not meet criteria for a full-blown psychotic disorder. Adults whose SA pre-dates psychosis onset have higher recurrence of acute, severe psychotic symptoms as indicated by increased frequency of hospitalization.3, 6, 7 Cannabis is the most widely used substance in the world, especially among adolescents whose developing brains are more susceptible to substance exposure.8, 9 Given the conceivable increase in marijuana availability to youth, and decreased perception of harm, via medical marijuana and pro-legalization legislation, the association between early cannabis use (CU) and early onset psychosis is an important public health issue.10, 11
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ACCEPTED MANUSCRIPT Past-year prevalence of CU in adolescents aged 12-17 years is estimated to be 13.4%, with greater than 25% meeting criteria for Cannabis Use Disorder (CUD).12 There is evidence that CU can precipitate transient psychotic and affective experiences.13 Studies also show that CU increases the probability of later psychosis two-fold,14 with a relative risk of two-four for development of Schizophrenia for those who have used once, and relative risk of six in those who have used fifty or more times as compared to never-users.13, 15 Lifetime CUD is also
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associated, in a dose-response manner, with earlier onset of psychosis, or prodrome, approximately three years earlier,16, 17 earlier age of first psychiatric hospitalization,18 and a higher risk of relapse.15 Adolescent cannabis users report many symptoms that coincide with prodromal psychotic symptoms including hallucinations, paranoia, depression and anxiety, which may present subclinically.19-21 Continued CU can increase the risk of persistence of subclinical psychotic symptoms.22, 23 Shubart and colleagues found that compared to those who initiated use between the ages of 15-18 years, those who initiated CU prior to age 12 years were 3.1 times more likely to have the highest 10% of scores on “psychotic experiences,” and those with initiation of use between 12-15 years of age had a 1.2 times greater likelihood of experiencing severe psychotic symptoms.24 Kuepper and colleagues also demonstrated increased odds of development and persistence of incident/transient psychotic symptoms as a function of CU over time in young adults.23 Puberty is a developmental stage critical for brain maturation, with adolescence marking the stage at which dopamine sensitization likely begins.25 Exposure to high levels of tetrahydrocannabinol (THC) through CU triggers repeated activation of the endogenous
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ACCEPTED MANUSCRIPT mesolimbic dopaminergic system which may in turn lead to sensitization of this system, and progressive enhancement of acquired susceptibility to psychosis.25, 26 27 Indeed, delta-9-THC is associated with deficits in learning and recall, and positive and negative psychotic symptoms.28 Patients with Schizophrenia demonstrate greater sensitivity to the effects of delta-9-THC28 and adolescents with CU demonstrate higher rates of Schizophrenia.29 Adolescent CUD in populations that are biologically vulnerable to psychosis due to a COMT gene polymorphism
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(Valine-Methionine substitution at codon 158) may be at greater risk of development of Schizophrenia or other psychotic disorders, especially with CU before age 18.30 This is likely due to the association between the Val allele and increased levels of mesolimbic dopamine signaling and lower dopamine levels in the prefrontal cortex.31 Changes in synaptic dopamine activity in the prefrontal cortex occur until adulthood, thus increasing potential sensitivity to environmental influences during adolescence.32 Two recent neuroimaging reviews examined the effects of CU on brain morphology in psychosis,33, 34 finding some preliminary indication that subjects at risk for psychosis and those with FEP may be particularly vulnerable to structural brain changes or brain volume loss due to CU.33-35 While several studies have examined the relationship between CU and lifetime psychosis, the extant literature is limited on the relationship between adolescent-initiation CU and the onset of the psychosis prodrome and/or FEP. Additionally, given the legislative changes regarding marijuana use (i.e. adoption of medical marijuana and recreational marijuana use) coupled with increasing CU in adolescents over the past decade,12, 36 there is great concern for medical and psychiatric consequences of increased CU initiation in the context of reduced perception of
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ACCEPTED MANUSCRIPT harmfulness. Thus, reviewing the current literature on the effects of childhood/adolescent marijuana use on prodromal symptoms or FEP is of considerable importance.37 We examine the literature on youth with pre-existing vulnerability to psychosis who may be more susceptible to the effects of cannabis. We aim to study the association between adolescent onset of regular CU and age of onset of psychotic symptoms, the manifestation of psychotic symptoms in those adolescents who use cannabis regularly as compared to non-users, and whether CU is
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differentially associated with outcome and functioning as compared to non-users. It is essential to evaluate the impact of CU on onset and course of psychotic illness as the increasing number of novice cannabis users may translate into a greater public health burden, including greater incidence of early onset FEP. METHODS
This article is a narrative review of the current literature on the effects of early adolescent onset CU on FEP in late adolescence or young adulthood. We searched PubMed, Embase, Medline and PsycInfo for all relevant literature published from 1967 (limit set by OVID) to August 2014. Search terms included “cannabis,” “early onset or prodrome,” “psychosis,” and “adolescent.” Our initial search yielded 244 articles; 186 total when duplicates were removed. With limits set to human subjects, articles published in the English language, or an available English translation, and clinical trials, the yield was 165 studies. Upon review of the title and/or abstract, an additional 122 studies were deemed ineligible due to a solely adult sample, lack of CU measures and/or psychosis outcome measures. Forty-three clinical and epidemiological studies where reported associations between CU and psychosis were both primary and secondary
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ACCEPTED MANUSCRIPT outcome measures were found to be relevant to this review. Upon review of the full manuscripts for these 43 studies, 26 were found incongruous with the aims of our study due to postadolescence or unspecified age of CU initiation and/or post-young adult or unspecified age of psychosis onset. Seventeen articles met eligibility criteria and were included in this study. All three authors contributed to study selection; the first author completed the initial search with the other two authors contributing to the secondary selection process.
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Studies in this review include participants who initiated CU prior to age 18 (given developmental immaturity of the adolescent brain and it’s susceptibility to environmental factors) and experienced FEP at, or prior to, age 25 years (due to evidence of emergence of psychotic symptoms in the general population from late adolescence to mid-20’s). Studies whose participants met the aforementioned age criteria but whose mean age was greater than 30 years at time of survey were excluded due to concerns of recall bias. The stated outcome of included studies had to reflect impact of CU on at least one aspect of psychosis manifestation, prodrome, onset, symptoms, course or functioning (reported in results section as a function of study outcome measure). Initiation of CU had to precede psychosis onset; current/recent CU and/or polysubstance abuse was not exclusionary. Studies were independently and manually mined for demographic information, study design, type of substance use and psychosis. An assessment of bias was completed for each study (selection, performance, detection, attrition and reporting) based on limitations of each investigation reviewed. The majority of studies fell within a moderate risk range. Study characteristics that were evaluated included sample size, demographics, study design, and use of
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ACCEPTED MANUSCRIPT standardized, validated or widely-recognized psychiatric and functional measures, all of which may have an effect on the overall conclusions proposed in this manuscript. Summary measures recounted here consist of values reported by individual studies and include P-values, effect sizes, difference in means and risk ratios. Results were synthesized qualitatively, as individual statistical results (i.e. analyses used and manner of reporting data) varied among studies.
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REVIEW
Cannabis Use Initiation & Psychosis Onset There appears to be a stronger effect of CU on development of psychotic illness with initiation of use prior to age 16.38 While many corroborating studies have found associations between CU and younger age at psychosis onset,18, 19, 41 not all studies have found this association.37, 42 Leeson and colleagues found that age at CU initiation was linearly associated with age at both prodrome and psychosis onset, with younger age of initiation predicting early FEP.41 The significance of the relationship between CU onset and psychosis onset was maintained when cannabis users were dichotomized into low frequency (≤2x/week) and high frequency CU. 41 Age at initiation of CU has been also found to be associated with age at first hospitalization.18 Further, baseline CU has been shown to predict emergence of psychotic disorders in adolescents at high risk for psychosis at four-year follow-up.43 Adolescents with daily CU have been shown to have a greater likelihood of acute onset psychosis as compared to those with non-daily use (42.1% v. 20%).45 Non-daily users are more likely to have a sub-acute presentation (43.35% v. 23.7%).45 This has been corroborated in other
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ACCEPTED MANUSCRIPT adolescent studies which have found increasing risk of psychosis with increased frequency of pre-psychosis CU in both the clinically high-risk (CHR)44 and the general population, with the largest risk in those who have used 50 or more times.46 Those who are at high-risk for psychosis and meet criteria for CUD demonstrate a greater rate of conversion to psychosis within one-year of prodrome as compared to their non-cannabis abusing counterparts.47
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Cannabis Use & Prodrome In determining the predictive value of adolescent CU between the ages of 12-18 on prodromal symptoms prior to the age of 19 years, Compton and colleagues did not find any significant differences between those who reported CU prior to psychosis onset versus those who did not report CU (CU-69.9% v. NCU-80.8%). These relationships remained statistically insignificant when frequency of use (daily CU-39.4% v. non-daily CU-60.6%), and number of prodromal symptoms were taken into account.45 In contrast, Konings and colleagues found that those with CU onset prior to age 14 demonstrated higher levels of prodromal psychotic symptoms.48 Additionally, Miettunen et al. found that in a sample of nearly 6300 adolescents, 15-16 year olds with a lifetime history of CU had a higher mean number of prodromal symptoms and were more likely to report 3 or more symptoms (OR=2.79).49 They also demonstrated a dose-response effect such that number of prodromal symptoms increased with CU frequency.49 Similarly, Leeson et al. found that daily/near daily CU during adolescence was associated with more negative symptoms.41 Finally, youth who were prior cannabis users, but were abstinent prior to prodrome onset, demonstrated fewer positive symptoms and had fewer indicators of disorganized thought process as compared to those who were still using.41
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Psychotic Symptoms Those who initiate CU by age 15 and age 18 demonstrate more symptoms of Schizophrenia by age 26 as compared to never-users.19 A noteworthy study has shown that as the duration of CU increases from first use (≥6 yrs), the odds of development of a non-affective psychosis increase (aOR=2.2), as well as number/severity of delusions (aOR=4.3) and
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hallucinations (aOR=2.8).38 These associations held true for sibling pairs, decreasing the likelihood that unmeasured confounding factors affected outcomes.38 Stefanis and colleagues found that age of onset of CU, controlling for lifetime frequency/amount of use, was more robustly associated with positive symptoms such that those with onset of use prior to, or at, age 15 years had greater occurrence of hallucinations, grandiosity, and first-rank symptoms.20 Cannabis use in those with initiation of use between 1619 years of age was only associated with first-rank symptoms.20 With negative symptoms, they also found a large difference in effect size between the two CU groups dichotomized by age, such that adolescents who initiated CU at a younger age, independent of frequency, demonstrated greater effect sizes.20 Indeed, Schubart et al. found that those with CU prior to age 12 (OR=1.7) or with first use between 12-15 years of age (OR=1.1) had greater likelihood of experiencing negative symptoms. The authors also found evidence of a dose-response effect such that who used a greater quantity, or at a greater frequency, were more likely to experience negative or overall psychotic symptoms.24 Stefanis and colleagues also evaluated the effect of frequency of CU in adolescents, dichotomized as initiation of use at, or before, age 15 and after age 15, on emergence of
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ACCEPTED MANUSCRIPT psychotic symptoms.20 The authors found that CU on 5 or more occasions and systematic (daily) use was associated with all four dimensions of positive psychotic symptoms; hallucinations, paranoia, grandiosity and first-rank symptoms (thought disorders including thought echo, withdrawal, insertion, broadcasting, control and telepathy).20 Less frequent lifetime use was associated with fewer dimensions of positive symptoms; two-four occasions was associated with paranoia, grandiosity and first-rank symptoms and single use was associated with paranoia and
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grandiosity.20 Significant differences were found between CU groups (≤15 versus 16-19 years at CU initiation) on all four positive dimensions. Cannabis use across all levels, single-systematic, was associated with negative symptoms, with more robust findings as use increased.20 Baeza and colleagues found that Spanish adolescents with premorbid CU had worse functioning, more positive symptoms and greater manic symptoms at time of FEP.37 However, cannabis-using adolescents also demonstrated less negative symptoms and fewer psychotic symptoms overall. In contrast, Leeson found that although cannabis users were younger at prodrome onset than nonusers, there were no differences in psychotic symptoms, mode of onset or duration of untreated psychosis.41 Social & Cognitive Functioning Schimmelmann and colleagues found that adolescents whose CU predated onset of psychotic symptoms, as compared to non-users, demonstrated longer duration of psychotic symptoms and had worse functioning, including greater symptom severity, greater academic/occupational impairment and history of criminal justice system involvement prior to treatment.42 Auther and colleagues evaluated a cohort of 160 adolescents to determine if CU in a CHR population was associated with prodromal symptoms.50 They defined high-risk as a score
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ACCEPTED MANUSCRIPT of 3-5 on the following positive symptoms: unusual ideas, suspiciousness, grandiosity, perceptual abnormalities, and disorganized communication. Of the thirty-five adolescents who were CHR and used cannabis, 49% used ≤19 times and were more likely to be Caucasian (88.6%) and older (16.74±1.96 years v. 15.65±2.12 years) than high-risk adolescents without a lifetime history of CU. This sub-sample also demonstrated significantly lower prodromal social anhedonia and negative symptoms, and higher social functioning.50 A small subset of adolescents
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who met criteria for cannabis abuse (N=10) had higher IQs than non-abusers. As with the cannabis users, the abusers were less socially anhedonic and had better baseline social functioning than non-abusers.50 Finally, CHR adolescents who also used cannabis demonstrated significantly higher social functioning than non-users and that those who met DSM-IV criteria for cannabis abuse also demonstrated significantly higher social functioning than non-abusers at approximately 2-year follow-up.50 In a study evaluating premorbid functioning as a function of early (12-15 years) and late (15-18 years) CU, adolescents with non-affective psychotic disorders who had early CU initiation demonstrated better social functioning than those who did not use before age 15.45 However, those with early initiation CU tended to perform more poorly academically. Additionally, adolescents who used cannabis at, or before, age 18 did significantly worse academically as compared to those who did not use prior to onset of psychosis.45 Although it appears that, in general, initiation of CU is associated with better cognitive functioning in those with psychotic illnesses, there is diverging evidence on specific neurocognitive areas for which this association holds true. It has been shown that those who use less frequently (≤2x/week) demonstrate higher IQ than their high-frequency CU counterparts.41
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ACCEPTED MANUSCRIPT In a study evaluating the effect of prior CU on cognitive functioning at time of FEP in adolescents, cannabis users and non-users demonstrated similar outcomes on all tests of working memory and learning, and select measures of attention and executive functioning as compared to controls.43 In another study, cannabis users showed no differences in working memory or verbal learning, and greater ability to plan compared to non-users when premorbid IQ was taken into account.41 Pencer et al. found that CU in adolescents on admission to a specialized early
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intervention program for FEP was predictive of better functional/social outcome (i.e. being either gainfully employed or in school) at one and two-year follow-up over the course of treatment. These adolescents also showed significant reduction of CU over the duration of treatment follow-up.52 Course of Cannabis Use & Psychosis Up to 54.7% of adolescents with baseline CU decrease or stop use after FEP.42 Baeza et al. found an 11.5% decrease in CU six months after FEP.37 At 15-month follow-up, age at CU onset has been shown to predict persistent CU (OR=1.43), with mean age of initiation of 14.53±1.94 years for persistent users and 17.39±4.19 years in those who achieved abstinence.41 Adolescents who abuse cannabis also demonstrate a higher rate of medication non-adherence.42 However, only those adolescents who continue CU after psychotic diagnosis demonstrate higher rates of non-engagement in treatment and greater severity of psychotic illness. This translates into higher rates of positive symptoms, and poorer functioning at discharge from the hospital, even after controlling for medication non-adherence.42 Previous cannabis users who have since achieved cessation demonstrate significantly fewer positive and negative symptoms and better general and total PANSS scores than persistent
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ACCEPTED MANUSCRIPT cannabis users, new cannabis users (whose outcome was in between continued and never users) and never users (NCU). Persistent CU at six-months was associated with significantly fewer positive symptoms as compared to NCU. Continued CU at both four-week and six-month follow-up was associated with fewer negative symptoms and lower general and total PANSS scores than NCU. However, there was no difference between groups in hospital readmission rates at six-month follow-up.37 Finally, Leeson et al. also found that indicators of disease
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outcome, including duration of hospital admission and length of time between admissions, up to two years following initial presentation, were better in those who achieved abstinence as compared to persistent users.41 DISCUSSION
Although adolescents are more likely to engage in CU,53 and the onset of psychotic disorders may occur in adolescents aged 15-17,54 the data presented here appear to validate the independent association between early CU and early onset FEP. The earlier the age of initiation of regular CU and the greater the frequency and/or duration of use, the more robust the association with earlier onset of prodrome and FEP, and the severity and number of symptoms experienced. Earlier studies that attribute FEP onset to the age at which adolescents access treatment (as opposed to the true onset of prodromal psychotic symptoms) and sample an older population (recall bias) may suffer from limitations in methodology. Certain positive symptoms demonstrate greater susceptibility to sensitization by cannabis such as grandiosity and paranoia. Additionally, a dose response effect appears to govern the emergence, and type of positive symptoms.20 Contrary to adult studies where CU is associated with fewer, or no difference, in
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ACCEPTED MANUSCRIPT negative symptoms,55, 56 there appears to be greater uncertainty as to the association between the two in adolescents. Studies have demonstrated both a positive association between CU and negative symptoms, with a large dose response effect,20 as well as a negative association between CU and negative symptoms.50 This discrepancy may be due in part to the type of population being studied. Cannabis-using adolescents who did not demonstrate more negative symptoms than their NCU peers may have already been labeled as high-risk for development of psychosis
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based on pre-existing psychotic symptoms. Some studies have demonstrated that CU in CHR adolescents and early CU in FEP is associated with better premorbid social functioning than NCU adolescents,45, 50 which may be due to development of fewer negative symptoms. Better social functioning may lead to greater exposure, and access to illicit substances through increased social contacts. Also, a degree of social sophistication is required to obtain illicit substances when the user is underage and may contribute to the finding of better socialization. The finding that CU is associated with poorer academic functioning is consistent with research in students without psychosis that also demonstrate poor academic performance in the context of CU.57 The literature in adolescents appears to be consistent with the adult literature that demonstrates better cognitive functioning in those with comorbid CU and psychotic disorders.58, 59
However, there is also evidence that those with lifetime CU have poorer clinical and functional
outcomes. Although these two statements appear contradictory, as better cognitive functioning is usually associated with less severe illness, this may reflect the effect of cannabis on psychotic illness. The postulated neuroprotective effect of high premorbid cognitive functioning may be negated by CU (high frequency>low frequency), contributing to the earlier age of onset. This
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ACCEPTED MANUSCRIPT also provides evidence for the hypothesis that CU increases the vulnerability to psychosis in susceptible populations. Persistent cannabis users demonstrate poor outcomes even after treatment for FEP. There is evidence that early initiation and regular use contribute to substance dependence,12 which likely explains the association between regular/high-frequency CU at psychosis presentation and continued use after treatment follow-up. Those with SA and comorbid psychotic illness have
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poorer health outcomes, including earlier age of first hospitalization, than mental illness alone likely because SA interferes with ability to comply with a treatment regimen. The following paradigms have been used to explain the association between CUD and psychiatric comorbidity: 1) psychiatric disorders developing as a consequence of SA, 2) psychiatric disorders altering the course of SA, 3) SA developing as a consequence of psychiatric disorders (self-medication hypothesis), 4) SA altering the course of psychiatric disorders, 5) SA and psychiatric disorders originating from a common vulnerability, and 6) SA and psychiatric disorders being mutually exclusive but coincidentally manifested.60 Although the exact mechanism of action and biological underpinnings of the association between CU and FEP remain unclear, given the data reported here, it appears that cannabis alters the course of psychosis by triggering early onset of disease in a vulnerable youth population. Limitations There are several limitations to this review. Many of the included studies have crosssectional study designs making it difficult to ascertain with certainty the direction of effect. It also introduces recall bias via reliance on retrospective self-report of SA and psychosis. This is of additional concern as CU itself may cause memory impairment. Additionally, two studies had
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ACCEPTED MANUSCRIPT small sample sizes, thus limiting the power and ability to detect small-medium effects. Sampling of subjects may be biased as individuals with more than one disorder are more likely to seek clinical services, resulting in an erroneously higher estimate of the prevalence of the association between these disorders. Also, several studies did not control for confounding factors such as polysubstance abuse and did not differentiate between CU alone and polysubstance abuse. Further, CU was not quantified by frequency, duration and/or amount in some studies, and in
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those that did, CU categories were either imprecise or were not standard across studies, making comparisons difficult. Also, no studies quantified concentration of THC used. In regards to psychosis, the criteria for determining prodromal versus subclinical symptomatology and factors that classified one as CHR were not always transparent. Additionally, findings were not classified by type of psychotic illness, nor were psychotic disorders differentiated from affective disorders with psychotic features in some studies. Finally, for many of the studies, effect sizes and precision of results (confidence intervals) were not reported. However, studies included in this review span different regions of the world, increasing generalizability. Additionally, participants had clearly identified cannabis initiation in adolescence prior to psychosis onset allowing for associations to be made between the two events. CONCLUSION
Adolescent initiation of CU is associated with emergence and severity of psychotic symptoms and functional impairments in a dose-dependent manner such that those who initiate use earlier and consume at higher frequencies demonstrate poorer illness and treatment
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ACCEPTED MANUSCRIPT outcomes. The association between early CU and later psychosis appears to be more robust for CHR adolescents. Despite demonstrating better social and cognitive functioning and likely fewer negative symptoms at baseline, persistent cannabis users with comorbid FEP have poorer clinical, functional and treatment outcomes with a greater burden of illness. 61 Future research should longitudinally examine the trajectory from initiation of cannabis use in childhood/adolescence to psychosis onset in those who solely abuse cannabis. Additionally,
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measurement and standardization of quantity, frequency and type of cannabis use would also help clarify the association between CU and psychosis.
FUNDING Dr. Bagot reports no financial support or conflicts of interest. Dr. Kaminer receives financial support from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism and royalties for books from Hazelden, Routledge and APPI. Dr. Milin receives financial support from the Institute of Mental Health Research, University of Ottawa and has received speaker honorarium from Bristol-Myers Squibb Canada, American Academy of Child and Adolescent Psychiatry, and American Academy of Addiction Psychiatry. There were no funding sources for conducting this research or manuscript preparation.
AUTHOR CONTRIBUTIONS
Dr. Bagot completed the initial literature search for data collection, drafted the initial and subsequent versions of this manuscript, including designing and formatting and revised and
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ACCEPTED MANUSCRIPT approved the final manuscript as submitted. Dr. Milin provided additional articles to include in the review (beyond the initial literature search) in regards to data collection as well as provided analyses of those and the original articles, edited each draft of the manuscript, and approved the final manuscript. Dr. Kaminer conceptualized the review, aided in the selection and analysis of included articles, edited each draft of the manuscript, and approved the final manuscript with
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revisions as submitted.
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ACCEPTED MANUSCRIPT TABLE 1
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Source (Referenc e No.) Arseneault et al., 2002 (19)
Sample (N; age) 759
Canna bis Use (N) CU≤15 yrs=2916≤CU ≥18 yrs= 236 -CHR+ CU=35 -CHR+ CA=10
Assessmen t Tools
Outcome
Structured psych interview (DSM-IV)
CU by age 15 assoc. w sx of: S (p=0.001) & SP (p=0.009) CU by age 18 assoc. w sx of: S (p=0.008)
SOPS, WISC-III, WAIS-R, KSADS, GF: Social & Role
CHR+CU v. CHR+NCU: baseline-↓ social anhedonia (p
