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IS CANNABIS A RISK FACTOR
FOR SCHIZOPHRENIA?
Jouko MiettunenDepartment of Public Health and Primary CareInstitute of Public HealthUniversity of Cambridge February 3, 2003
CONTENTS OF THE PRESENTATION
cannabis and cannabis use
schizophrenia
association and causality
summaries and limitations
of the studies
conclusions
SOURCE OF CANNABIS
hemp plant, Cannabis sativacontain cannabinoidsmajor active component
9-tetrahydrocannabinol
preparations of cannabis illicit drugs
• marijuana (leaves, stalks, flowers, seeds)
• hashish (resin)
also legal drugs
conflicting attitudes among researchers
CANNABIS USE
measured by questionnaires and urine/hair testknown effects
10% become dependent and gateway to other drugs depression and anxiety somatic disorders (e.g. cancer) impair cognitive and driving skills brain effects (releases dopamine)
use as a therapeutic drug multiple sclerosis, epilepsy, cancer, AIDS, etc. BMA (1997): “Therapeutic Uses of Cannabis”
PREVALENCE OF CANNABIS USE
United Nations Office on Drugs and Crime
Annual prevalence estimates of cannabis use in the late 1990s
(“official statistics” i.e. various questionnaires, surveys and estimates)
0 5 10 15 20
OCEANIAAFRICA
India
China
ASIA
SOUTH AMERICA
United StatesNORTH AMERICA
Netherlands
United Kingdom
EUROPE
TOTAL
% of population age 15 and above
3.5%4.9%9.4%4.1%
18.8%8.1%3.2%
6.6%8.3%4.7%
1.6%0.5%
CANNABIS USE BY AGE
current monthly use (survey in New York, N=1,160)
Chen et al. 1995
use among UK students (Webb et al. 1996)• any use 60% and regular use 20%
use is increasing in most countries• especially among people under age 16• in some parts of the world more common than alcohol use
SCHIZOPHRENIA
chronic, severe, and disabling mental disease
diagnosed using structured interviews (ICD-10: F20)
life-time prevalence approximately 1% not increasing in general, though e.g. in south London
prevalence of some psychotic symptoms in general population (Eaton et al. 1991):
paranoid symptoms 10% hallucinations 5-8% bizarre delusions 2%
AGE AT ONSET OF SCHIZOPHRENIA
30
20
10
0
pati
ents
(%
)
12-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
FemaleMale
age group
years
Häfner et al. 1993
PREVALENCE OF CANNABIS USE AMONG PSYCHOTIC PATIENTS
difficult to compare due to the selection of cases
(inpatients/outpatients) and controls
most case-control studies report that cannabis use is
about 2 times more common among psychotic patients
than among general population based controls
among schizophrenia patients prevalence estimates vary between samples from 5 to 50 %
4 times more often any drugs (UK study, McCreadie 2002)
younger age at onset and more malesmore unemployment and alcoholismworse course of schizophrenia
more positive symptoms poorer compliance with treatment more frequent hospitalisation (unclear?) less negative symptoms in short-term (unclear?)
more patients with catatonic subtype of schizophrenia (Hambrecht and Häfner 2000)
CANNABIS USERS AMONG SCHIZOPHRENIA PATIENTS
EFFECTS OF CANNABIS USE ON VULNERABLE CASES
cannabis use is a risk for psychotic diagnosis in
subjects who have already have symptoms
(van Os et al. 2002)
patients with cannabis associated psychosis have
increased familial risk for schizophrenia
(McGuire et al. 1995)
some recent high-risk studies
(Phillips et al. 2002, Miller et al. 2001)
have more psychotic symptoms than non-users at age 18-20 (Fergusson et al. 2003) adjusted OR 1.8 (95% CI: 1.2-2.6)
have more often schizotypal personality traits (Williams et al. 1996, Dumas et al. 2002)
CANNABIS USERS IN GENERAL POPULATION
POTENTIAL CONFOUNDERS
age and sexurban birth, social class and marital statusalcohol use, smoking and use of other drugsstressful life-eventsmigrant/minority status (e.g. Afro-Caribbeans in UK)
premorbid symptoms (e.g. social adjustment difficulties)
personality traits and IQfamilial risk of schizophrenia and/or cannabis use
generally accepted that cannabis intoxication can cause brief psychotic episodes
can cannabis use cause schizophrenia?
or can the direction of causality be reversed?
CAUSALITY BETWEEN CANNABIS USE AND SCHIZOPHRENIA
PROBLEMS WITH CHRONOLOGY
AGE
CANNABIS USE
first use regular use heavy use
SCHIZOPHRENIA
premorbid symptoms psychotic symptoms diagnosis
What is the temporal order?
PROBLEMS WITH POOLING THE STUDIES
CANNABIS USE SCHIZOPHRENIA
•any use
•regular use
•heavy use
•times in a life-time
•times in a year/month/…
•current use
•cannabis abuse/dependence
•etc.
•any psychotic symptoms
•symptoms in a year/month
•pathological level of symptoms
•need for care due to symptoms
•any psychotic diagnosis
•schizophreniform disorder
•schizophrenia
•etc.
Various exposure and outcome combinations in the studies:
Swedish conscript study (1)
cohort of 18-20 year old males (N=50,045)questionnaires at conscription 1969/70 hospital register follow-up until 1995
ICD-8/9 schizophrenia diagnosis
Andréasson et al. 1987
Andréasson et al. 1989
Zammit et al. 2002
SCHIZOPHRENIA AS AN OUTCOME
risk for schizophrenia:
ever used cannabis
adjusted OR 1.9 (95% CI: 1.1.-3.1)
used cannabis more than 50 times
adjusted OR 6.7 (95% CI: 2.1.-21.7)
significant linear trend for frequency of use
cannabis use was not associated with other
psychoses than schizophrenia
Swedish conscript study (2)
limitations:no information on possible confounding factors in
the follow-up period
no information on familial risk for schizophrenia
validity of the exposure (underreporting?)
validity of the outcome (underreporting?)
not many cannabis users got schizophrenia 1.4% if ever used 3.8% if used >50 times 0.6% in controls
Swedish conscript study (3)
SYMPTOMS AS AN OUTCOMENetherlands 1996-99
population based survey (N=4,045; 18-64 years)any cannabis use predicted the presence of
psychotic symptoms at 3-year follow-up any symptoms: adjusted OR = 2.8 (95% CI: 1.2-6.5) pathology level of symptoms: adj. OR = 24.2 (5.4-107.5) statistically significant trend for dose-response
cannabis use was a risk for psychotic diagnosis in subjects who already have psychotic symptoms
limitations: no information on familial risk for schizophrenia, short follow-up and 43% drop-outs
van Os et al. 2002
New Zealand 1983-99
general population birth cohort 1972-73 (N=759)cannabis use ≥3 times prior to age 15 predicted schizophrenia symptoms at 26
adjusted OR = 6.6 (4.8-8.3) and schizophreniform disorder at age 26
adjusted OR = 3.1 (0.7-13.3) (non-significant) use of other drugs was not associated with outcomestrength: psychiatric symptoms at age 11limitations: no information on familial risk for
schizophrenia and did not use schizophrenia as an outcome
Arseneault et al. 2002
LIMITATIONS OF THE STUDIES
misclassification bias lack of confirmation of the biological presence of
cannabis in the organism
reliability of psychiatric diagnoses may be worse in
subjects with comorbid cannabis use
not always adjusted for all potential confoundersshort follow-up timesattitude of the researchers
difficult to interpret results and conclusions
AGE
CANNABIS USE
SYMPTOMS OF SCHIZOPHRENIA
self-medicating patients
similar risk factors for cannabis use and
schizophreniaor
cannabis is the trigger
vulnerable patientsor
increased dopamine levelincreases positive symptoms
of schizophrenia
PROBLEMS WITH CHRONOLOGYSchizophrenia patients using cannabis can be defined into groups chronologically
all the groups include also people who have schizophrenia independently on cannabis use, and vice versa!
CONCLUSIONSuse of cannabis can cause psychotic symptoms and even
schizophrenia especially in some vulnerable casesBUT:
would schizophrenia have occurred in these individuals in any case (cannabis use only precipitates schizophrenia)?
does not count for many schizophrenia cases?
IN FUTURE: large prospective studies with long follow-up time, schizophrenia
diagnosis as an outcome and comprehensive information on confounding variables
case-control study starts in South London 2003