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