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CLINICAL FOCUS
Primary Psychiatry. 2009;16(4):35-43
The Impact of Pre-onset Cannabis
Use on Age at Onset of Prodromal
and Psychotic Symptoms
Michael T. Compton, MD, MPH, and Claire E. Ramsay, MPH
ABSTRACT
FOCUS POINTS
Schizophrenia is currently conceptualized as an illness that is caused
• Cannabis, or marijuana, is a drug that is commonly abused
by adolescents and young adults; it is the most frequently
abused illicit drug among people with schizophrenia or
other psychotic disorders.
• Among people with comorbid substance abuse and schizophrenia or other psychotic disorders, substance use and
abuse are typically initiated prior to the overt onset of the
psychotic disorder.
• Some research suggests that cannabis use prior to onset
may be associated with an earlier age at onset of psychosis, although it is difficult to establish whether this
association is causal.
• Athough additional research is needed, preliminary research
suggests that cannabis use prior to any psychiatric symptoms
may be associated with an earlier age at onset of the prodromal
symptoms that commonly precede the onset of schizophrenia.
by both genetic predispositions and exposure to stressors or environmental factors, particularly during early childhood and adolescence.
This article focuses on one such environmental factor, cannabis use,
especially use occurring prior to the onset of clinically evident psychiatric symptoms. Cannabis is commonly abused by adolescents and is
the most abused illicit drug in the context of schizophrenia. Several
first-episode studies document that the initiation of substance use
and abuse typically precedes the onset of psychosis. This article
highlights eight studies that characterize the impact of cannabis
use on the age at onset of psychosis and three studies that provide
early information on the impact of cannabis use on the age at onset
of even earlier prodromal symptoms. Future research is needed to
better characterize the impact of cannabis use on the onset of psy-
INTRODUCTION
chotic disorders and to determine if cannabis use increases the risk
Schizophrenia is currently conceptualized from the perspectives of the neurodevelopmental and diathesis-stress
models.1-3 The neurodevelopmental model integrates altered
pre- or perinatal brain development, adolescent developmental abnormalities, and potentially progressive processes that
occur after illness onset.3 The diathesis-stress model suggests
of developing a psychotic disorder, as several other studies suggest.
Based on emerging evidence, preventing or reducing cannabis use
among adolescents, particularly those at elevated risk of developing
psychosis, may delay the onset of psychosis in some.
Dr. Compton is assistant professor in the Department of Psychiatry and Behavioral Sciences and Ms. Ramsay is research coordinator of the Atlanta Cohort on the Early Course of Schizophrenia Project,
both at Emory University School of Medicine in Atlanta, Georgia.
Disclosures: Dr. Compton receives grant support from the Emory University Research Committee and the National Institute of Mental Health. Ms. Ramsay reports no affiliation with or financial interest in
any organization that may pose a conflict of interest.
Please direct all correspondence to: Michael T. Compton, MD, MPH, Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 49 Jesse Hill Jr.
Drive, S.E., Room #333, Atlanta, GA 30303; Tel: 404-778-1486; Fax: 404-616-3241; E-mail: [email protected].
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M.T. Compton, C.E. Ramsay
that symptomatic manifestations of the biologic vulnerability
for schizophrenia are influenced by exposure to stressors or
environmental factors.4 Based on these conceptualizations,
the following points are fairly well accepted among schizophrenia researchers: First, the etiology of the disorder is most
likely related to a number of genetic and early environmental
risk factors. Second, later risk factors (during adolescence
and young adulthood) and neurohormonal changes likely
impact the manifestation of underlying vulnerability. Third,
genes and environmental risk factors may interact to affect
risk. Fourth, the sequential onset of symptoms usually occurs
in a gradual fashion from the premorbid phase to the prodrome to the onset of full psychosis. Fifth, symptom onset,
phenomenology, and course are highly heterogeneous. Last,
both genetic and environmental factors contribute to this
heterogeneity.
This article focuses on one such environmental factor,
cannabis use, especially that which occurs prior to the onset
of clinically evident psychiatric symptoms. Although adolescent-onset cannabis use has been shown by epidemiologic
research to be a risk factor (presumably a causal risk factor,
or component cause) for schizophrenia,5-10 the present article
examines this environmental factor in terms of its potential
to adversely affect two key features of disease onset—age at
onset of psychosis and age at onset of even earlier prodromal
symptoms. This qualitative summary of the literature is not
meant as a systematic review, but as a synthesis of select studies in this area.
decades,23 potentially resulting in a larger “dose” of psychoactive cannabinoids during drug use.
Unsurprisingly, given the aforementioned high population
prevalence of cannabis use, cannabis is the most abused illicit
drug in the context of schizophrenia.24 The Epidemiologic
Catchment Area study found the lifetime prevalence of a
cannabis use disorder in people with schizophrenia to be
19.7%.25 Many studies confirm high rates (20% to 70%) of
cannabis use in patients with schizophrenia.26-31 Data from 53
studies of schizophrenia revealed that 12-month prevalence
estimates of use and misuse of cannabis were 29% and 19%,
and lifetime use and misuse estimates were 42% and 23%,
respectively.32 Researchers report rates of cannabis misuse
ranging from 15% to 65% in first-episode samples.33-39
Several first-episode studies document that the initiation
of substance use and abuse typically precedes the onset of
psychosis, often by several years.31,38,40-42 When prodromal
symptoms are taken into account, one German study37 of
232 patients with a first episode of psychosis found that
29.5% of those using drugs had a drug problem >1 year
before the earliest sign of an emerging psychotic disorder.
In an additional 34.6%, drug abuse emerged at the same
time as the first symptoms. In a first-episode sample (n=133)
from the Netherlands, among those patients who had used
cannabis by the time of their first treatment contact, 64.3%
reported initiating cannabis use before the onset of social
and/or occupational dysfunction and 85.7% before the onset
of psychosis.43 In a sample of 109 hospitalized patients with
first-episode non-affective psychosis in the US, 79.8% had
used cannabis at least once in the years prior to hospitalization (Compton MT, unpublished data, March 2009). While
mean ages at the onset of prodromal symptoms and psychotic
symptoms in that sample were 19.4±5.3 and 21.8±4.7 years,
respectively, the mean age at first use of cannabis among the
87 who had used it was 15.8±4.0. These and other studies
indicate a high prevalence of cannabis use occurring prior to
the onset of psychiatric symptoms in people who develop a
psychotic disorder.
Although numerous studies show that the initiation of
substance use commonly precedes the onset of psychosis, this
does not necessarily imply a directional or causal association.
It is not surprising that substance use often precedes psychosis
given that initiation of substance use usually occurs during
adolescence. However, research establishing that early-course
patients typically begin substance use prior to onset confirms
temporality (ie, that exposure precedes outcome in a plausible
way), which is one criterion in ultimately establishing a causal
relationship. This article, which largely focuses on the possibility that pre-onset cannabis use may hasten onset of psychotic disorders, notes as important the substantial research
showing that, among patients with comorbidity, substance
use often precedes the manifestation of symptoms.
THE CROSSROADS OF SCHIZOPHRENIA
AND CANNABIS USE
Cannabis is the most commonly used illicit drug in the
United States. According to the 2006 National Survey on
Drug Use and Health, 45.4% of Americans ≥12 years of age
have tried cannabis at least once.11 Among those ≥18 years
of age with lifetime cannabis use, >50% report first using it
between 12 and 17 years of age.12,13 Earlier onset of drug use
has consistently been associated with greater risk of developing abuse and dependence.12,14-17 Cannabis use disorders
occur in approximately 4% of the general US population,
with a peak in the 18–29-year age range.15,18,19 Some 56%
of those seen in treatment for cannabis abuse/dependence
began using by 14 years of age, and 92% began by 18 years
of age.13,20 Cannabis use is now considered a substantial public health problem by many, due to several reasons, as noted
previously.21 First, US adolescents and young adults have very
high rates of cannabis use. Second, cannabis dependence in
youths predicts increased risks of using other illicit drugs and
underperforming in school.22 Third, the cannabinoid content
of smoked cannabis has increased substantially during recent
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The Impact of Pre-onset Cannabis Use on Age at Onset of Prodromal and Psychotic Symptoms
The biologic pathways linking cannabis use and psychosis
are being actively studied. Numerous research findings, six
of which are briefly described here, may demonstrate the
biologic plausibility of pre-onset cannabis use impacting not
only vulnerability for developing schizophrenia, but also the
age at onset among those who do develop the disorder. First,
exogenous cannabinoids (eg, marijuana) are extremely lipid
soluble, accumulating in fatty tissues from which they are
slowly released back into body compartments, including the
brain,23 suggesting that even occasional cannabis use leads
to long-term exposure of central receptors to cannabinoids.
Second, exogenous and endogenous (eg, anandamide) cannabinoids exert their effects (such as modulating the release of
neurotransmitters including glutamate, norepinephrine, and
dopamine) by interactions with specific cannabinoid (CB1)
receptors44,45 that are distributed in brain regions implicated in
the pathophysiology of schizophrenia (including the cerebral
cortex, limbic areas, basal ganglia, and thalamus).23 Third,
cannabis increases mesolimbic dopaminergic transmission and
inhibits glutamatergic release.46 Fourth, several studies have
shown an increased CB1 receptor density in brain regions of
interest in schizophrenia, including the dorsolateral prefrontal
cortex and the anterior cingulate cortex,47-49 and elevated levels
of endogenous cannabinoids in the blood and cerebrospinal
fluid of patients with schizophrenia.50-52 Fifth, gene variants of
the CB1 receptor may be associated with schizophrenia and
risk of substance abuse in individuals with schizophrenia.48,53,54
However, other studies have not found an association with
risk for schizophrenia,55 and a recent meta-analysis did not
implicate these gene variants among 24 showing significant
effects.56 Sixth, acute administration of cannabis causes both
patients and controls to experience transient increases in cognitive impairments and schizophrenia-like positive and negative symptoms.57 It could be argued that these six points provide only a weak argument for a causal effect of cannabis on
hastening onset. For example, the findings of increased CB1
receptor density in regions implicated in schizophrenia are
not surprising given that CB1 receptors are relatively widely
dispersed. However, when taken together, these findings do
suggest biologic plausibility, which, like temporality, is one
criterion for eventually demonstrating causality.
Having provided some evidence supporting potential
biologic plausibility, the remainder of this article focuses on
two themes—the potential impact of early-course cannabis
use on both the age at onset of psychotic symptoms and
the age at onset of even earlier prodromal symptoms. Age at
onset of the prodrome and psychosis are critical variables to
understand because they are important prognostic factors.
An earlier age at onset is associated with a higher degree of
cognitive impairment, increased severity of psychosocial and
functional disability, more severe symptoms and behavioral
deterioration, less responsiveness to antipsychotics, decreased
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ability to tolerate discontinuation of medication, and greater
likelihood of rehospitalization.58-69 Given extensive literature
connecting earlier onset with poorer course and outcomes,
discovering potentially modifiable determinants of age at
onset is crucial. Could pre-onset cannabis use in adolescence
be one such determinant?
THE IMPACT OF PRE-PSYCHOTIC
CANNABIS USE ON THE AGE AT
ONSET OF PSYCHOSIS
At least eight studies, generally collecting cross-sectional or
retrospective information from individuals with a recent onset
of psychosis, have examined the potential impact of cannabis
use on the age at onset of psychosis. These studies, discussed
briefly here, are also summarized in the Table (Compton
MT, unpublished data, March 2009).28,34,38,42,43,70,71 Although
numerous older studies explored the relationship between
substance abuse and psychosis, Hambrecht and Häfner28 were
perhaps the first to study the exact timing of the onset of
substance use and symptoms in first-episode psychosis. In the
Age, Beginning, and Course (ABC) schizophrenia study,28 they
found that the mean age at onset of the first negative symptom,
first positive symptom, and first admission were lower in the
32% who had abused drugs prior to admission than in those
who had not. The mean ages at first positive and negative
symptoms were each 5.7 years younger for those with a history
of drug abuse than for those with no substance abuse history
(21.1 compared to 26.8, and 24.3 compared to 30.0, respectively). Among those who reported a history of drug abuse, the
mean age at onset of drug abuse was 18.6 years, or 1.5 and 5.7
years before the mean age at onset of the first negative and first
positive symptoms. However, the analysis of age at onset was
not restricted to those who had initiated drug abuse specifically
before, rather than during or after, the onset of illness. In addition, the independent effects of particular substances of abuse
were not considered (although 90% of those abusing drugs in
the sample had abused cannabis, 63% had used other drugs as
well). Finally, the study did not examine the impact of drug use
before it reached the threshold of drug abuse.
Among a sample of patients in New York State with a first
episode of either affective or non-affective psychosis (n=541),
symptom onset among men and women was examined by
Rabinowitz and colleagues38 in three groups: those with no
lifetime substance use disorder diagnosis, those in remission
or with mild substance use, and those with current moderateto-severe substance abuse at the time of admission. Females
with current moderate-to-severe substance abuse were 6 years
younger at the onset of first psychotic symptoms than their
counterparts with no lifetime substance use. No significant
impact on the age at onset was observed for males. However,
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M.T. Compton, C.E. Ramsay
the inclusion of patients with affective as well as non-affective psychoses introduces heterogeneity in the expected age at
onset, disease mechanisms, gender distribution, and rates of
comorbid substance abuse. Nonetheless, this study is notable
for accounting for the severity of substance use.
In the Calgary Early Psychosis Program, which assesses and
treats patients with a recent onset of psychosis, 44% of 357
consecutively admitted patients had substance abuse or dependence in the previous year.70 In this sample, Van Mastrigt and
colleagues70 found that patients who had misused cannabis (or
cannabis and alcohol) were younger and had an earlier age at
onset of positive psychotic symptoms than non-users or those
who misused alcohol only or alcohol and other drugs. These
findings suggest that a link may exist between cannabis use and
age at onset of psychosis, and that this effect may be related to
the cannabis, per se, as opposed to personality traits or other
vulnerabilities that lead to a substance use disorder, given that
misuse of other substances did not carry the same association.
However, without data on the age at first cannabis use or
abuse, or on the onset of prodromal or negative symptoms, it
is not possible to establish the directionality of the association
between cannabis use and the age at onset of symptoms.
Veen and colleagues43 used an incidence cohort of patients
in the Netherlands to examine the independent influences of
gender and cannabis use on early course features. The sample
(n=133) included natives of the Netherlands, first- and second-generation immigrants from Surinam and Morocco, and
individuals from other racial/ethnic groups. Patients who used
cannabis (n=70) had an earlier median age at onset compared
to the 63 patients not using cannabis. In a multiple regression
analysis, male cannabis users (n=55) were found to have had
their first psychotic episode a mean of 6.9 years earlier than
37 male nonusers. Cannabis use was a stronger predictor of
age at first psychotic episode than gender. However, the study
did not control for the effects of family history or the use
of other substances (eg, alcohol, cocaine). Furthermore, the
study treated cannabis use as categoric/dichotomous variable
(which is true of most studies conducted to date) and therefore could not examine potential dose-effect relationships.
Mauri and colleagues42 retrospectively studied 285 firstepisode patients in Italy and found that patients abusing cannabis had an earlier age at onset compared with those who
did not abuse cannabis, though it is unclear how onset was
operationalized. Further, this comparison failed to control for
TABLE
A SUMMARY OF EIGHT STUDIES EXAMINING THE POTENTIAL IMPACT OF PRE-ONSET CANNABIS USE ON AGE AT ONSET OF
PSYCHOSIS28,34,38,42,43,70,71
Sample Size and
Diagnoses
Diagnoses
Year
Study
Location
Main Findings Regarding Substance Use and Age at Onset of Psychosis
1996
Hambrecht and
Häfner28
Mannheim,
Germany
232; schizophrenia or a Drug abuse was associated with a lower age at first sign, first positive symptom, and first
paranoid disorder
negative symptom of schizophrenia. The onset of drug abuse typically preceded the first
positive and negative symptoms, but preceded the first sign in only 27.6% of cases.
1998
Rabinowitz et al38
New York,
United States
541; first-episode
affective or non-affective psychoses
Females with current moderate-to-severe substance use had an earlier age at onset of
psychotic symptoms than those with no history of substance abuse. This association
was not found among males in the sample.
2004
Van Mastrigt
et al70
Calgary,
Canada
357; consecutive
admissions to an early
psychosis program
Cannabis use at entry was associated with a younger age at onset of psychosis. Those who
used cannabis (or cannabis and alcohol) had a younger age at onset of psychosis (when the
first positive symptom emerged) than non-users, alcohol-only users, and multi-drug users.
2004
Veen et al43
The Hague,
Netherlands
133; first-episode nonaffective psychosis
Prior cannabis abuse was associated with an earlier age at onset of both social and
occupational dysfunction and psychosis. However, when controlling for gender, this
association only remained significant for the onset of psychosis.
2006
Mauri et al42
Milan, Italy
285; first-episode
schizophrenia
Among those with cannabis abuse, the mean age at onset of psychosis was significantly
lower (24.0±6.3) than that of patients not using cannabis (26.8±6.5).
2006
Barnes et al34
London, United 152; first-episode
Kingdom
psychosis
Cannabis use and gender had independent effects on age at onset, after adjusting for
the use of alcohol and other drugs. Cannabis use was significantly associated with an
earlier age at onset, with an average decrease of 5 years.
2008
González-Pinto
et al71
Vitoria, Spain
131; first-episode
affective or non-affective psychoses
Higher levels of cannabis use were associated with a younger age at onset (7, 8.5, and 12
years, respectively) for those with cannabis use, abuse, and dependence. By comparison,
gender and other substance use had little effect on age at onset.
2009
Compton et al,
unpublished data
Atlanta,
Georgia,
United States
109; first-episode nonaffective psychosis
Progression to daily cannabis and daily tobacco use were associated with an earlier age at
onset of psychosis (the level of frequency of use was treated as a time-dependent covariate).
Compton MT, Ramsay CE. Primary Psychiatry
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The Impact of Pre-onset Cannabis Use on Age at Onset of Prodromal and Psychotic Symptoms
the influence of gender, and only 18% of females had used
substances compared to 44% of males. Additionally, much of
the data were obtained by retrospectively reviewing medical
records (which are presumably less thorough and accurate
than formal research assessments), 56% of patients having
used drugs were multi-drug abusers (and this apparently was
not controlled for), and the amount and duration of substance use was not considered.
In London, Barnes and colleagues34 assessed 152 first-episode patients and found that those reporting past substance
use were significantly younger at the onset of psychotic symptoms compared with those who had not used substances. In
a linear regression, use of any substances other than cannabis
was not significantly related to age at onset, though gender
and cannabis use were. The age at onset of psychosis was on
average 4.2 years older for women and 5.0 years younger for
participants using cannabis, adjusting for the other variables.
In this study, like most others, cannabis was the most prevalently used illicit substance, and, therefore, detecting an effect
of cannabis may be easier than finding effects of other drugs,
given issues of statistical power. Unfortunately, inquiries
about past substance use did not include detailed assessment
of the frequency and quantity of drugs taken, and it is unclear
whether the initiation of cannabis use in fact preceded the
onset of symptoms in the patients included in the analysis.
González-Pinto and colleagues71 found, among 131 first-episode patients in Spain, a significant, gradual reduction in age
at onset as the level of use of cannabis increased—a decrement
of 7, 8.5, and 12 years for patients with cannabis use, abuse,
and dependence, respectively. The effect was not explained by
the use of other drugs or gender. However, the study included
patients with affective psychosis, who would be expected
to have a later age at onset, and likely a lower prevalence of
comorbid cannabis use. In addition, the study did not take into
account the duration of cannabis use and it is not clear exactly
how age at onset was operationalized.
Recently, Compton and colleagues (Compton MT, unpublished data, March 2009) examined the impact of prior cannabis use on the age at onset of psychosis in 109 patients
hospitalized for a first episode of psychosis. This group found
that both daily cannabis and daily tobacco use occurring before
onset of psychosis had a significant effect on the risk of onset
of psychosis (hazard ratios of 2.0 and 1.8, respectively, P<.05),
P
when the level of frequency of use was treated as a time-dependent covariate in Cox regressions (ie, progression to daily use
was associated with a higher risk of onset). Of note, cannabis
and tobacco use were highly correlated (eg, having ever used
nicotine was highly associated with having ever used cannabis,
χ2=25.5, P
P<.001 [Compton MT, unpublished data, March
2009]) and therefore may not represent two independent risk
factors. A gender by progression to daily cannabis use interaction was observed—progression to daily use was related to a
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much larger increased relative risk for onset of psychosis in
females (hazard ratio=5.1) than in males (hazard ratio=3.4).
Although this study took into account the frequency of cannabis use (ie, never, ever but not weekly use, weekly but not daily
use, or daily use), it did not assess quantity of use and did not
gather detailed information on patterns of use.
IMPACT OF PRE-PRODROMAL CANNABIS
USE ON THE AGE AT ONSET OF THE
PRODROME
While the previously reviewed studies suggest, through various analytic designs, that cannabis use may be associated with a
younger age at onset of psychotic symptoms, only a few groups
have attempted to determine if cannabis use is associated with
a younger age at onset of prodromal symptoms. The prodrome
is the syndromal period commonly comprised of non-specific
psychiatric symptoms, emerging attenuated positive symptoms, negative symptoms, and psychosocial decline—commonly lasting several months to a few years—that precedes the
emergence of frank psychosis in most patients. One critique
of the literature is that the possible influence of cannabis use
on prodromal symptoms has not been adequately explored.34
Doing so could shed light on the competing hypotheses that
substance use precipitates or hastens onset of the illness versus
that very early, subtle symptoms of the illness make patients
vulnerable to substance use.
Hambrecht and Häfner28 conducted one of very few studies that included an analysis of prodromal symptoms in relation to substance use. In 232 first-episode patients from the
ABC schizophrenia study, they found that the mean age at
onset of the first sign was lower in the 32% who had abused
drugs prior to admission than in those who had not. First
signs included the first negative, positive, or non-specific psychiatric symptom if it occurred continuously until the onset
of psychosis. In this way, the “first sign” represented the onset
of the prodrome, if a prodrome had occurred, or psychosis, if
there had been no prodrome. The age at first-sign onset was
7.2 years younger among those who had abused drugs than
among those who had no history of drug or alcohol abuse
(18.5 compared to 25.7 years).
In the report by Veen and colleagues,43 the relationship
between prior cannabis use and the age at onset of the first
sign of social or occupational dysfunction, which could be
considered a proxy for the age at onset of the prodrome, was
examined. In this cohort, the median age at onset was 18.1
years among patients using cannabis, as compared to 27.7 years
in those not using cannabis. However, in a linear regression,
gender was a more important predictor of age at onset, and
after controlling for this variable, cannabis use was not a significant predictor. This study did not use a precise indicator of the
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M.T. Compton, C.E. Ramsay
DISCUSSION AND UNANSWERED
QUESTIONS
onset of the prodrome, but it is noteworthy for its analysis of
the effect of prior cannabis use on onset. Like their analysis of
age at onset of psychosis, Veen and colleagues43 did not control
for family history or other substance abuse, and they treated
cannabis use as a categorical variable.
Similar to their findings pertaining to age at onset of psychosis, Compton and colleagues (Compton MT, unpublished
data, March 2009) examined the impact of prior cannabis
use on the age at onset of illness/prodromal symptoms in
109 hospitalized first-episode patients. When considering
the level of frequency of use as a time-dependent covariate in
Cox regressions, both daily cannabis and tobacco use had a
significant effect on the risk of onset of the symptoms (which
represented the onset of the prodrome in 70% of the sample),
hastening onset (hazard ratios=2.1 and 1.8, respectively). As
noted above, although this analysis accounted for the frequency of cannabis use, other methodologic limitations make
the results preliminary, requiring further research.
In summary, several studies suggest that cannabis use among
first-episode patients prior to onset may be associated with an
earlier age at onset of positive psychotic symptoms. Much less
is known about potential associations between pre-prodromal
cannabis use and the onset of prodromal symptoms. The
Figure depicts hypothesized symptom development and the
accumulation of functional impairment in the early course
of schizophrenia in patients with a history of cannabis use
compared to those without a history of cannabis use. Further
research is needed to show whether pre-onset cannabis use is
in fact an independent risk factor for developing a psychotic
disorder or for an earlier emergence of symptoms among those
who do develop a disorder. Support for the psychotogenic
properties of cannabis during a prodromal period comes from
FIGURE
SYMPTOM DEVELOPMENT AND THE ACCUMULATION OF FUNCTIONAL IMPAIRMENT IN THE EARLY COURSE OF SCHIZOPHRENIA
IN THOSE WITH A HISTORY OF CANNABIS USE (LEFT), COMPARED TO THOSE WITHOUT A HISTORY OF CANNABIS USE (RIGHT)
Normal, non-psychotic premorbid level of functioning
Threshold for a prodromal syndrome
Threshold for psychosis
Accumulation of functional impairment from schizophrenia
with prior and concurrent cannabis abuse.
Accumulation of functional impairment from schizophrenia
without cannabis abuse.
Emergence of Symptoms and Accummulation of Functional Impairment Over Time
The curves represent the development of symptoms over time, from premorbid social and academic impairments, to the development of prodromal symptoms, to the onset (and resolution, with treatment) of frank psychotic symptoms. The width of the curve represents the accumulation of functional impairment at each stage. Based on the early evidence available,
it is postulated that first-episode patients with a history of cannabis use are likely to have an earlier age at illness onset, as represented by the left-shift of the curve. Some evidence
also suggests those using cannabis will accumulate more functional impairment even during the premorbid phase and then throughout the early course of the illness, with a higher
likelihood of school drop-out and incarceration, a greater severity of positive symptoms, and poorer response to therapy.
Compton MT, Ramsay CE. Primary Psychiatry
Psychiatry. Vol 16, No 4. 2009.
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The Impact of Pre-onset Cannabis Use on Age at Onset of Prodromal and Psychotic Symptoms
the finding that perceptual disturbances fluctuate over time
with cannabis use in a clinical high-risk cohort.72
As stated above, an earlier age at onset of psychosis is a
poor prognostic indicator. If further research proves a link
between adolescent, pre-onset cannabis use and age at onset,
then decreasing cannabis use among adolescents may delay
the onset of psychosis among those destined to develop a psychotic disorder. Some have argued that there now exists sufficient evidence to inform the public that using cannabis could
increase the risk of developing a psychotic illness73; this may
be especially relevant for at-risk groups. Programs to decrease
cannabis use may be particularly beneficial in adolescents
identified as being at very high risk for psychosis, by virtue
of a positive family history or by being identified as potentially prodromal or at “ultra-high risk” based on emerging
psychiatric symptoms and functional decline. Just as decreasing cannabis use has been suggested as a potential preventive
intervention to reduce the incidence of schizophrenia,74,75
reducing cannabis use also could delay onset among those
who do, nonetheless, develop the disorder.76
Numerous unanswered questions should be the focus of
ongoing research. First, given the high comorbidity between
cannabis abuse and the abuse of other addictive substances,
especially nicotine and alcohol,77,78 the independent effects
of pre-onset cannabis use, as well as pre-onset nicotine,
alcohol, and other drug use, should be examined. Although
the neurobiologic feasibility of the cannabis/psychosis link
was pointed out above, it must be recognized that alcohol
and other drugs impact upon dopaminergic, glutamatergic,
and other neurotransmitter systems affected by schizophrenia. Regarding potential effects of alcohol and cannabis, for
example, on psychosis risk, the same neural structures are
indeed affected by both substances, at least at a global level
(mesolimbic dopamine pathways and the central reward
system in general), though alcohol and cannabis exert their
effects partly through different receptors (ie, γ-aminobutyric acid-ergic/glutamatergic and cannabinoid receptors,
respectively). Some evidence suggests that alcohol may
exert modulatory actions in the endogenous cannabinoid
system.79 In addition to cannabis and alcohol, nicotine
use is also a critical variable to examine for a couple of
reasons: Cigarette smoking is highly prevalent in individuals with schizophrenia80,81 (even in those with first-episode
psychosis),82 and there is increasing interest in the literature
in biologic links between the central nicotinic system and
schizophrenia.83-85 However, though such elucidation of
single-drug effects would be beneficial, it must be emphasized, as noted above, that the independent effects of each
substance will be difficult to parse given the high degree of
comorbidity across substances, especially cannabis, alcohol,
and nicotine. Relatively large sample sizes likely will be necessary to examine independent effects.
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A second direction for future research pertains to the issue
of causality versus association. Like any observational study,
the studies described here cannot rule out the possibility of
reverse causality, in which the disease processes associated
with the later development of psychosis render an individual
more susceptible to the initiation of substance use and abuse
earlier in life. Even if further research indicates that pre-onset
cannabis use is associated with an earlier age at onset, sorting
out whether the cannabis use causes an earlier onset or is a
marker of a disease process or subtype associated with earlier
onset will be challenging. Similar questions pertain to the link
between cannabis use and risk of developing schizophrenia—
causality remains difficult to prove, and a shared diathesis for
both psychotic illnesses and substance abuse may be at play.
Third, regarding a potential impact of cannabis use on prodromal symptomatology, it is possible that cannabis use causes
prodrome-like (but not definitively prodromal) symptoms in
patients who later develop a psychotic disorder. That is, cannabis use in adolescence among patients who later develop a
psychotic disorder may lead to apathy, academic problems, and
other prodromal-appearing difficulties, though such problems
may not necessarily be inherent to the schizophrenia process or
they may not alter the course of the developing psychotic disorder in a way that conveys long-term course implications. A
number of studies suggest that cannabis use is associated with
schizotypal features in people who may or may not develop
schizophrenia.21 Furthermore, in a recent study86 involving
6,330 adolescents (15–16 years of age) in a Finnish prospective
birth cohort, the 356 (5.6%) participants who had used cannabis endorsed a higher mean number of “prodromal” symptoms,
and a dose-response relationship was evident. However, actual
prodromal symptoms can only be confirmed retrospectively;
it remains to be determined through further longitudinal
research whether or not the symptoms assessed in that study
actually represented a prodrome.
A fourth important issue requiring further, more methodologically rigorous research, relates to the measurement of
substance use in relation to ages at onset of prodromal and
psychotic symptoms. As noted above, not all prior studies commented on (in fact, most did not) or restricted the analyses to
those whose drug use/abuse preceded the onset of psychotic
and/or prodromal symptoms,28,34,70,71 which is critical to the
research question. To advance the field in this area, future
research should carefully examine the timing of the initiation
of cannabis use and the development of psychotic symptoms
as well as earlier prodromal symptoms using well-defined
operationalizations of onset. Such retrospective measurement
is admittedly a difficult task. Comprehensive assessments of
cannabis and other substance use with reliable and valid retrospective measures that incorporate calendars, timelines, and
significant life events should be used to gather data on amount,
duration, frequency, and patterns of use, thus allowing for
41
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M.T. Compton, C.E. Ramsay
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effects. Additionally, because the limited research in this area
to date has generally consisted of cross-sectional and retrospective studies, other research designs, including case-control and
longitudinal studies, would be beneficial.
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consistent findings in schizophrenia research.87,88 For example,
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