1. IS CANNABIS A RISK FACTOR FOR SCHIZOPHRENIA? Jouko Miettunen Department of Public Health and Primary Care Institute of Public Health University of Cambridge February 3, 2003

2. CONTENTS OF THE PRESENTATION §cannabis and cannabis use §schizophrenia §association and causality §summaries and limitations of the studies §conclusions

3. SOURCE OF CANNABIS §hemp plant, Cannabis sativa §contain cannabinoids §major active component l  9 -tetrahydrocannabinol §preparations of cannabis l illicit drugs marijuana (leaves, stalks, flowers, seeds) hashish (resin) l also legal drugs §conflicting attitudes among researchers

4. CANNABIS USE §measured by questionnaires and urine/hair test §known effects l 10% become dependent and gateway to other drugs l depression and anxiety l somatic disorders (e.g. cancer) l impair cognitive and driving skills l brain effects (releases dopamine) §use as a therapeutic drug l multiple sclerosis, epilepsy, cancer, AIDS, etc. l BMA (1997): “Therapeutic Uses of Cannabis”

5. 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) 05101520 OCEANIA AFRICA India China ASIA SOUTH AMERICA United States NORTH 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%

6. 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

7. SCHIZOPHRENIA §chronic, severe, and disabling mental disease §diagnosed using structured interviews ( ICD-10: F20) §life-time prevalence approximately 1% l not increasing in general, though e.g. in south London §prevalence of some psychotic symptoms in general population (Eaton et al. 1991): l paranoid symptoms 10% l hallucinations 5-8% l bizarre delusions 2%

8. AGE AT ONSET OF SCHIZOPHRENIA 30 20 10 0 patients (%) 12-1415-1920-2425-2930-3435-3940-4445-4950-5455-59 Female Male age group years Häfner et al. 1993

9. 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 l prevalence estimates vary between samples from 5 to 50 % l 4 times more often any drugs (UK study, McCreadie 2002)

10. §younger age at onset and more males §more unemployment and alcoholism §worse course of schizophrenia l more positive symptoms l poorer compliance with treatment l more frequent hospitalisation (unclear?) l less negative symptoms in short-term (unclear?) §more patients with catatonic subtype of schizophrenia (Hambrecht and Häfner 2000) CANNABIS USERS AMONG SCHIZOPHRENIA PATIENTS

11. 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)

12. §have more psychotic symptoms than non- users at age 18-20 (Fergusson et al. 2003) l 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

13. POTENTIAL CONFOUNDERS §age and sex §urban birth, social class and marital status §alcohol use, smoking and use of other drugs §stressful life-events §migrant/minority status (e.g. Afro-Caribbeans in UK) §premorbid symptoms (e.g. social adjustment difficulties) §personality traits and IQ §familial risk of schizophrenia and/or cannabis use

14. §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

15. PROBLEMS WITH CHRONOLOGY AGE CANNABIS USE first useregular useheavy use SCHIZOPHRENIA premorbid symptomspsychotic symptomsdiagnosis What is the temporal order?

16. 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:

17. 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 l ICD-8/9 schizophrenia diagnosis §Andréasson et al. 1987 §Andréasson et al. 1989 §Zammit et al. 2002 SCHIZOPHRENIA AS AN OUTCOME

18. risk for schizophrenia: §ever used cannabis l adjusted OR 1.9 (95% CI: 1.1.-3.1) §used cannabis more than 50 times l 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)

19. 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 l 1.4% if ever used l 3.8% if used >50 times l 0.6% in controls Swedish conscript study (3)

20. SYMPTOMS AS AN OUTCOME Netherlands 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 l any symptoms: adjusted OR = 2.8 (95% CI: 1.2-6.5) l pathology level of symptoms: adj. OR = 24.2 (5.4-107.5) l 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

21. 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 l adjusted OR = 6.6 (4.8-8.3) §and schizophreniform disorder at age 26 l adjusted OR = 3.1 (0.7-13.3) (non-significant) §use of other drugs was not associated with outcome §strength: psychiatric symptoms at age 11 §limitations: no information on familial risk for schizophrenia and did not use schizophrenia as an outcome Arseneault et al. 2002

22. LIMITATIONS OF THE STUDIES §misclassification bias l lack of confirmation of the biological presence of cannabis in the organism l reliability of psychiatric diagnoses may be worse in subjects with comorbid cannabis use §not always adjusted for all potential confounders §short follow-up times §attitude of the researchers l difficult to interpret results and conclusions

23. AGE CANNABIS USE SYMPTOMS OF SCHIZOPHRENIA self-medicating patients similar risk factors for cannabis use and schizophrenia or cannabis is the trigger vulnerable patients or increased dopamine level increases positive symptoms of schizophrenia PROBLEMS WITH CHRONOLOGY Schizophrenia 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!

24. CONCLUSIONS §use of cannabis can cause psychotic symptoms and even schizophrenia especially in some vulnerable cases §BUT: l would schizophrenia have occurred in these individuals in any case (cannabis use only precipitates schizophrenia)? l does not count for many schizophrenia cases? §IN FUTURE: l large prospective studies with long follow-up time, schizophrenia diagnosis as an outcome and comprehensive information on confounding variables l case-control study starts in South London 2003