Cannabis and schizophrenia: A calculated risk?

1. Cannabis and schizophrenia:A calculated risk? Martin Frisher School of Pharmacy, Keele University Scottish Drugs Forum Soapbar, Skunk, Annihilation… what’s happening with cannabinoids? Glasgow, 16th March 2016

2. Part 1: background 2 Background: Why the controversy? Issues: What does the evidence tell us? Conclusion: Science and politics

3. Cannabis and Mental Health in context (2008) Does cannabis use lead to mental health problems, and if so, which ones? If someone smokes cannabis are they at risk of developing mental health problems that would not otherwise have occurred? What is the contribution of cannabis to mental health problems compared to other drugs and alcohol? How does cannabis compare to other mental health risk factors? What is the population impact of cannabis with respect to mental health? What are the policy implications of the relationship between cannabis and mental health? https://ncpic.org.au/static/pdfs/young-people-training-package/cannabis-and-mental-health-put-into-context.pdf

4. Part 1: background 4 Daily Mail headline 29th October 2011:  “Just ONE cannabis joint can bring on schizophrenia”. (Winner of the 2011 Orwellian Prize for Journalistic Misrepresentation) http://www.dailymail.co.uk/health/article-2053486/cannabis-joint-cause-psychiatric-episodes-similar-schizophrenia-damaging-memory.html During decision-making phases of a spatial working memory task, CP5540-induced deficits in hippocampal theta and prefrontal gamma oscillations were observed. Kucewicz, M., Tricklebank, M., Bogacz, R., & Jones, M. (2011). Dysfunctional Prefrontal Cortical Network Activity and Interactions following Cannabinoid Receptor Activation. Journal of Neuroscience, 31 (43), 15560-15568http://deevybee.blogspot.co.uk/2012/01/2011-orwellian-prize-for-journalistic.html

5. Alternatively…. Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats. Cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state. Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats. Psychopharmacology (Berl). 2013 Feb;225(3):531-42.

6. Perceptions of risk (and Benefit) People tend underestimate dangers of common events like driving a car. People are more worried by dramatic but infrequent events than by "boring" risks like slipping on a wet floor. People are less likely to fear the risk of an unhealthy lifestyle than (for example) levels of pesticides in foods. People tend to be less likely to fear natural disasters than man-made disasters. Risks perceived to be have benefits (e.g. medicines) are more accepted than risks perceived to have little benefit. http://www.eufic.org/article/en/food-safety-quality/risk-communication/artid/risk-activities-into-perspective/ and Fischhoff et al. Acceptable Risk. Cambridge University Press

7. Statin Drugs Given for 5 Years for Heart Disease Prevention (Without Known Heart Disease) Without Statins With Statins (treatment) http://www.knowabouthealth.com/ Statin prescriptions treble in ten years to hit almost 60million: NHS spends £100m handing out pills to seven million Britons (Daily May, July 2014) Example-10% risk of heart attack over 5 years (risk reduction of 10% over 5 years, i.e. 10% to 9%) Number-Needed-to-Treat (NNT) over 5 years: 1 in 104 were helped (preventing heart attack); Number-Needed-to-harm (NNH) over 5 years: 1 in 100 were harmed (develop diabetes) http://www.thennt.com/nnt/statins-for-heart-disease-prevention-without-prior-heart-disease/[2015]

8. Claims About Cannabis use ‘We often come across claims about cannabis’ impact on the brain…..claims that cannabis use lowers IQ by up to 8 points, that use of the drug causes schizophrenia, and that it impairs cognitive function in the long term. What’s fascinating about these claims is that they’re almost always “based on the scientific evidence.” But is that really the case?’ (Professor David Nutt) http://www.drugscience.org.uk/blog/2015/09/08/heres-why-we-hear-so-many-false-claims-about-cannabis/

9. The Wootton Report (1968) • There is no evidence that smoking of cannabis is producing - in otherwise normal people - conditions of dependence or psychosis, requiring medical treatment. • Advisory Committee on Drug Dependence, Cannabis, (The Wootton Report), 1968.

10. Understanding Psychosis andSchizophrenia There appears to be a continuum between good and poor mental health that we all move up and down along at different points in our lives. For example, at different times we may be more or less anxious, suspicious or depressed….. This ‘continuum model’ raises questions about traditional psychiatric diagnosis. http://www.bps.org.uk/networks-and-communities/member-microsite/division-clinical-psychology/understanding-psychosis-and-schizophrenia

11. What is psychosis? http://schizophreniabulletin.oxfordjournals.org/content/35/3/482/F2.expansion The term "psychosis" is very broad and can mean anything from relatively normal aberrant experiences through to the complex and catatonic expressions of schizophrenia and bipolar type 1 disorder. In properly diagnosed psychiatric disorders (where other causes have been excluded by extensive medical and biological laboratory tests), psychosis is a descriptive term for the hallucinations, delusions and impaired insight that may occur. Gage, SH; Hickman, M; Zammit, S (12 August 2015). Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biological Psychiatry.

12. What is Schizophrenia? Schizophrenia is characterised by three symptom categories: positive symptoms, including delusions, thought and speech disorders, and hallucinations; negative symptoms, such as blunted affect, avolition, anhedonia and asociality; and cognitive dysfunction related to executive function, attention and working memory. McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K. Cannabis and schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD004837. DOI: 10.1002/14651858.CD004837.pub3. There is no objective test for schizophrenia. http://www.webmd.com/schizophrenia/guide/schizophrenia-tests

13. Understanding Psychosis andSchizophrenia As psychiatrist Jim Van Os puts it: ‘The complicated….term suggests that schizophrenia really is a “thing”, i.e. a “brain disease”. This is a false suggestion.’ Most people would agree on how to identify a unicorn even though they are mythical rather than real creatures. The problem is that the existence of the label can give the misleading impression of the existence of the ‘thing’. So to be clear: the experiences and distress are very real, but the explanation – that there is an illness called ‘schizophrenia’ causing them – may not be true. http://www.bps.org.uk/networks-and-communities/member-microsite/division-clinical-psychology/understanding-psychosis-and-schizophrenia

14. The Problem of Psychiatry-Schizophreniaby Thomas Szasz Mental illness is a metaphor for human problems in living-the nonexistence of mental illnesses does not impede the flourishing of schizophrenia psychiatry. The history of schizophrenia, from Eugen Bleuler’s invention of the “diagnosis” in 1911 to the present “treatments” of it, is an example of the futility of trying to solve a problem defined in essentialist terms by empirical means. Szasz, T. (2007). Essence or existence: The problem of psychiatry-schizophrenia. www.szasz.com/schizophrenia1.pdf, May 17

15. PROBLEMS WITH POOLING STUDIES Various exposure and outcome combinations in the studies: SCHIZOPHRENIA CANNABIS USE • 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. From: IS CANNABIS A RISK FACTOR FOR SCHIZOPHRENIA? Jouko Miettunen, 2003 www.joukomiettunen.net/uploads/thesis%20presentation%20170603.ppt

16. Claims About Cannabis use http://cannabisclinicians.org/effects-of-cbd-and-thc/ Whilst someone is actually ‘stoned’, the principal psychoactive component of cannabis, THC, can sometimes have unwanted psychosis-like effects, such as anxiety and paranoid delusions. This is a reason that many people try the drug and don’t like it; but transient paranoia isn’t the same as schizophrenia. Persistent drug use of any kind may seriously complicate and worsen pre-existing mental health problems, and the use of cannabis seems able to exacerbate symptoms in a person with an illness like schizophrenia, or latent vulnerabilities. http://www.drugscience.org.uk/blog/2015/09/08/heres-why-we-hear-so-many-false-claims-about-cannabis/

17. Lifetime prevalence of schizophrenia in the general population ABSOLUTE RISK 1% (1 per 100 people) Source: American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders: DSM-IV, 4th ed. Washington (DC): American Psychiatric Association.

18. Lifetime prevalence of schizophrenia in the general population ABSOLUTE RISK 0.4% (4 per 1,000)/ 0.8% with cannabis? Bhugra D (2005) The global prevalence of schizophrenia. PLoS Med 2(5): e151.

19. The worst effect of cannabis in one chart (based on a monograph at doi:10.1111/add.12703) RELATIVE RISK http://www.mirror.co.uk/news/ampp3d/worst-effect-cannabis-one-chart-4395081 (October, 2014)

20. Absolute vs relative risk of cannabis psychosis The risk of "cannabis psychosis" is very small. Which means that even when the numbers are doubled or multiplied sevenfold for people who have the genetic marker they still remain small. This is why you will never find absolute numbers in so-called scare articles. "A sevenfold increase" sounds much scarier than a 0.007 chance for heavy users with the genetic marker and a 0.002 for moderate users with the genetic marker compared to a 0.001 chance without. These numbers are rough estimates to show the dynamics of presenting numbers. I did a long Google search on the risks of cannabis psychosis in absolute numbers but couldn't find any. http://disinfo.com/2012/11/why-cannabis-doesnt-make-most-people-psychotic/

21. Part 2: The evidence • “Evidence establishes clear link between use of cannabis and mental health”. • Rey Joseph M, Tennant Christopher C. Cannabis and mental health: More evidence establishes clear link between use of cannabis and psychiatric illness. BMJ 2002; 325 :1183

22. Bradford-Hill’s Checklist (1965) For Judging Causality Austin Bradford Hill (1897-1991) • Temporality • Strength • Specificity • Consistency • Biological Plausibility www.drabruzzi.com/hills_criteria_of_causation.htm

23. Cannabis use in adolescence and risk for adult psychosis • Arseneault Louise, Cannon Mary, Poulton Richie, Murray Robin, CaspiAvshalom, Moffitt Terrie E et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study BMJ 2002; 325 :1212 Cannabis use at 15, Odds Ratio [yes/no] (OR) = 3.71, 95% CI 1.04 to 13.19, i.e. 271% higher for those taking cannabis; but not significant after controlling for psychotic symptoms age 11, OR=3.12, 95% CI 0.73 to 13.29

24. first-episode psychosis attributable to use of high potency cannabis: a case-control study The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis. Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted Odds Ratio=5·4). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24%. De Forti M et.al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. The Lancet Psychiatry Volume 2, Issue 3, March 2015, Pages 233–238

25. THE DEVELOPMENT OF PSYCHOSIS • “Cannabis use was not associated with the development of psychosis in an 'ultra' high-risk group”. • Phillips et al. Australian & New Zealand Journal of Psychiatry. 36(6):800-806, December 2002 • doi: 10.1046/j.1440-1614.2002.01089.x http://psych.colorado.edu/~clinical/mittal/research-interests.html

26. Association between Cannabis and Psychosis • How can we explain that…the incidence of schizophrenia has remained stable? • The causal influence of cannabis…is “probably not easily visible”. • Arseneault et al. Causal association between cannabis and psychosis: examination of the evidence. Br. J. Psychiatry, Feb 2004

27. Government vs science over drug and alcohol policy • Keele researchers found no increase in the number of cases of schizophrenia…..thus there is not even any increase in the incidence of schizophrenia to explain. • Professor David Nutt, Lancet November 9, 2009

28. Schizophrenia Prevalence per 100,000 PYE by ageband Number of cannabis users in england and wales, 1970-2002 Frisher M, Crome I, Martino O, Croft P. Assessing the impact of cannabis use on trends in diagnosed schizophrenia in the United Kingdom from 1996 to 2005. Schizophrenia Research 2009 Sep;113(2-3):123-8 Hickman M., Vickerman P., Macleod J., Kirkbride J., Jones P. B. Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and Wales. Addiction 2007; 102: 597–606

29. Hospital Episode Statistics. Schizophrenia Diagnoses 1998-2006 http://www.hscic.gov.uk/hes

30. Preventing schizophrenia by stopping cannabis use ABSOLUTE RISK 30 Based on assumption that there is a 2.1 increased risk for “heavy” cannabis use and 1.3 increased risk for “light “cannabis use. It would be necessary to stop 2,800 heavy cannabis users in young men and over 5,000 heavy cannabis users in young women to prevent a single case of schizophrenia. Among light cannabis users, those numbers rise to over 10,000 young men and nearly 30,000 young women to prevent one case of schizophrenia. Hickman M et al. If cannabis caused schizophrenia-how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction, 2009; 104 (11): 1856

31. Part 3: conclusion Cannabis and schizophrenia:A calculated risk?

32. Cannabis and mental health (June 2014) 32 There is growing evidence that people with serious mental illness, including depression and psychosis, are more likely to use cannabis or have used it for long periods of time in the past.  Regular use of the drug has appeared to double the risk of developing a psychotic episode or long-term schizophrenia. However, does cannabis cause depression and schizophrenia or do people with these disorders use it as a medication? Research has strongly suggested that there is a clear link between early cannabis use and later mental health problems in those with a genetic vulnerability - and that there is a particular issue with the use of cannabis by adolescents. http://www.rcpsych.ac.uk/healthadvice/problemsdisorders/cannabis.aspx

33. Stronger evidence is needed before accepting that cannabis plays an important role in the aetiology of schizophrenia in the population 33 From a scientific perspective….the extent to which use of cannabis leads to an increased incidence of schizophrenia, independently of confounding characteristics and separate from effects of chronic intoxication, remains uncertain. Whether preventing cannabis use will have any substantial impact on preventing psychotic disorders in the population, or within specific subgroups at risk, is yet to be adequately determined. Hickman et al. If cannabis caused schizophrenia-how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction, 2009; 104 (11): 1856 DOI: 10.1111/j.1360-0443.2009.02736.x

34. Cannabis and Psychosis (2010) • Home Office Website (2010): “the regular use of cannabis is known to be associated with an increase in the risk of later developing psychotic illnesses including schizophrenia”. • “The contentious issue of whether cannabis use can cause serious psychotic disorders….cannot be answered from the existing data” (McLaren et al, 2010). • See also “Complaining to Frank” http://ukcia.org/wordpress/?p=66

35. Talk to FRANK 2016: CANNABISclear risk information? Using cannabis has also been linked, in some people, to serious, long-term mental health problems. Regular cannabis use, especially when young, can lead to an increased risk of later developing a psychotic illness like schizophrenia. http://www.talktofrank.com/drug/cannabis

36. addiction-related hypothesis As an alternative to the “psychotogenic hypothesis” we would like to propose the “addiction-related hypothesis” according to which it would rather be addiction-related than acute psychotogenic effects which would render subjects vulnerable for schizophrenia. According to this hypothesis one would thus expect correlations for schizophrenia not only with acutely psychotogenic drugs (e.g. cannabis, amphetamines) but also, and in similar strength, with drugs that do not have “psychotogenic” properties (e.g. heroin or nicotine). Thus, the specificity criterion (Hill, 1965) would apply to all addictive drugs instead of only to cannabis. In other words, cannabis should not notably be different compared to nicotine or heroin, but all these addictive substances should differ from non-addictive substances with regard to their association to schizophrenia Zullino DF, et al. Cannabis causes schizophrenia? So does nicotine Addiction Research & Theory Volume 18, Issue 6. 2010.

37. Comparing cannabis to other (addictive?) substances 37 “The increase of psychosis risk related to cannabis use is smaller than the increase related to the use of alcohol (eightfold increase in men) and various prescription drugs”. “If society is really so concerned with increased psychosis (as opposed to merely using it as a stick to beat on cannabis use) then it ought to address the harms of these substances, rather than repeating the risk of cannabis use over and over again”. http://disinfo.com/2012/11/why-cannabis-doesnt-make-most-people-psychotic/ (comment)

38. Cannabis mental health risks 'must be taught‘ (2004) http://www.mentorfoundation.org/uploads/UK_Hayzy_Dayz_Leaflet.pdf The Home Office has commissioned Mentor Foundation UK, a drug use prevention charity, to produce a million leaflets on the health risks of cannabis to be distributed across the country from January 29, 2004. http://www.guardian.co.uk/society/2004/jan/07/drugsandalcohol.politics

39. Netherlandish Proverbs (also called The Topsy Turvy World) by Pieter Bruegel the Elder, 1559 Does cannabis use lead to mental health problems, and if so, which ones? If someone smokes cannabis are they at risk of developing mental health problems that would not otherwise have occurred? What is the contribution of cannabis to mental health problems compared to other drugs and alcohol? How does cannabis compare to other mental health risk factors? What is the population impact of cannabis with respect to mental health? What are the policy implications of the relationship between cannabis and mental health? 39