1. Cannabis; het endocannabinoide systeem en psychose Drs. Rebecca Kuepper, Maastricht University, Psychiatry and Neuropsychology, The Netherlands r.kuepper@sp.unimaas.nl

2. Stelling “Het gebruik van Cannabis is een RISICO FACTOR voor schizofrenie !

3. The dual images of Cannabis

4. Murray et al, Nature Reviews Neuroscience, 2007

6. Cannabis and Schizophrenia

7. Hasj Weed decreases: - negative symptoms (Compton, 2004; Peralta and Cuesta, 1992) - affective symptoms (Dixon, 1991) enhances: - positive affect - coping with negative affect - social functioning (Addington and Duchak, 1997; Spencer, 2002) In Patients…..

8. Andreasson et al. Lancet, 1987 Association between frequency of cannabis use and later psychosis 15-year follow-up cohort study in N = 45.570

9. Causaliteit ?

10. Psychosis phenotype Psychotic symptoms (5%) Psychotic experiences (15%) Schizophrenia (1%)

11. Are subclinical symptoms a marker of genetic liability? 1.Associated with risk factors for psychosis 2.Show continuity with illness 3.Cluster within families (twin studies)

12. (RR=10) 1st degree schizophrenic relative Risk factors and effect in schizophrenia RR 1 510 (Van Os et al 1998) 50% discordance prenatal exposure to influenza obstetric complications childhood trauma members of some immigrant populations urbanicity life events substance use

13. Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente ocurre a través del cerebro. Joseph le Doux, 1999 Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente ocurre a través del cerebro. Joseph le Doux, 1999 MAOA NOTCH4 SYN3 L1CAM RELN G72/G30 DAAO PRODH GRM3 Dysbindi n RGS4 NTRK1 BDNF NRG1 IL-1B DRD2 COMT SLC6A4 DRD3 DRD4 SLC6A3 HTR2A DISC1 Major gene? Rare and inconsistent

14. zelf-medicatie? symptomen of ziekte? waarom niet iedereen? waarom blijven patiënten gebruiken? DEBAT

15. EDSP EDSP EDSP (Early Developmental Stages of Psychopathology) Prospective-longitudinal study on substance use and mental disorders N = 3,021 N = 3,021 (aged 14-24, birth cohorts 1970-1981) Follow-up at t1 (+2 years, only subsample) t2 t2 (+4 years, whole sample) t3 t3 (+8 years, whole sample) CIDI (Composite International Diagnostic Interview) Substance use and clinical status were assessed using the CIDI (Composite International Diagnostic Interview) Lieb et al., 2000, Wittchen et al., 1998 CannabisPsychosis Cannabis & Psychosis

16. t0 t1 Psych Psych OR = 1.88, 95% CI: 1.11-3.17, p = 0.018 t3t2 Adjusted for age gender socio-economic status use of other drugs childhood trauma urbanicity Kuepper et al., submitted Is cannabisusetrue incidencepsychotic symptoms? Is cannabis use associated with true incidence of psychotic symptoms?

17. t0 t1 Psych OR = 0.89, 95% CI: 0.67-1.19, p = 0.45 t3t2 Adjusted for age gender socio-economic status use of other drugs childhood trauma urbanicity Kuepper et al., submitted SELFMEDICATION?

18. t0 t1 Psych t3t2 Kuepper et al., submitted Is cannabisuse persistencepsychotic symptoms? Is cannabis use associated with persistence of psychotic symptoms? Psych

19. Kuepper et al., submitted cannabis use persistence psychotic symptoms? Is continued cannabis use associated with greater risk of persistence of psychotic symptoms? Risk of persistence* of psychotic symptoms [ OR (95%CI; p-value)] Level of exposure unadjustedadjusted no use11 1.95 (1.22-3.11; 0.005)1.63 (1.01-2.64; 0.045) 2.68 (1.53-4.72; 0.001)2.21 (1.17-4.19; 0.015) use at t1 or t2 use at t1 and t2 *Persistence = psychotic symptoms at t2 AND at t3

20. cannabis use persistence psychotic symptoms? Is continued cannabis use associated with greater risk of persistence of psychotic symptoms?

21. Cannabis effects + No psychosis ???

22. Age of first use: (Arseneault et al, 2002) N=472 (12 – 23 jr)  Cann use before 14th  Cann use after 14th CAPE Community Assessment of Psychic Experiences CAPE Community Assessment of Psychic Experiences The CAPE-42 is based on the PDI-21 and PDI-40 developed by Emmanuelle Peters et al (2001)PDI-21PDI-40 (van Os, Verdoux, Hanssen) Positive dimension psychosis

23. Age of first use: Onset before age 14 yrs Onset after age 14 yrs Risik of psychotic symptoms Cannabis + Cannabis - N=472 (12 – 23 jr) Konings et al., Acta Psychiatr Scand, 2008.

24. Cannabis No sign of psychosis liability Subclinical symptoms (SCL- 90) Psychotic symptoms Start: 4 years later: EDSP; n=2436 THC * vulnerability interaction

25. % psychotic symptoms risk difference No predisposition Baseline predisposition 15% 21% 6% 25% 26% 51% Henquet et al., BMJ 2006 - + + - THC * vulnerability interaction Adjusted RD: 5.6% and 23.8% (for age, sex, SES, urbanicity, trauma, predisposition at follow-up)

26. Genetische kwetsbaarheid ? Dopamine: COMT-gene Dopamine breakdown psychosiscognition COMT Endophenotype D’Souza et al, 2005 Val Met Val158Met:

27. Het dagelijks leven van patiënten Cannabis Stemming Hallucinaties 60 observaties: PATRONEN VAN GEBRUIK EN SYMPTOMEN

28. COMT x Cannabis: ESM Hallucinations ‘hearing voices’ ‘seeing things’ Henquet et al., Neuropsychopharm, 2006. Henquet et al., Acta Psych Scan, 2009. 40 controls, 40 psychotic patients

29. Gene-environment interplay Psychosis Henquet et al., Schizophrenia Bull, 2009.

30. Beyond GEI… Cannabis No Childhood trauma Childhood trauma Psychotic symptoms (CAPE) Assessed at age 7: Assessed at age 19: The Greek Birth Cohort study; N= 3500 Bakoula, Stefanis et al

31. Beyond GEI… B= 0.20 (0.02-0.38), p= 0.027 Effect Size cannabis on CAPE score Konings et al., in preparation B= 1.36 (0.67-1.59), p= 0.000

32. Growing up in rural environment Growing up in urban environment Psychotic symptoms T2: T3: EDSP study EDSP study (age 14-24) EDSP; (Wittchen, LIeb, 1998) n=2436 Cannabis

33. Cannabis X urbanicity % psychotic symptoms risk difference* - 8% -1.0% 95%CI: -0.7-0.05, p = 0.758 + 6% - 7% 7.0% 95%CI: 0.01-0.12, p =0.019 + 15% *Adjusted for age, gender, socio-economic status, use of other drugs, childhood trauma rural urban Kuepper et al., submitted

34. Cross-sensitization stress X THC Kuepper et al., Schiz Res 2010

35. Hasj Weed  9-tetrahydrocannabinol (THC)  8-THC Cannabidiol (CBD) Cannabinol (CBN) Cannabigerol Cannabichromene How THC might cause psychosis (Mechoulam, 1960’s)

36. Endocannabinoids act to modulate e.g. GABA and glutamate

37. Neurobiology: THC and dopamine In rodents –THC facilitates DA transmission in several brain regions including PFC and striatum (Chen et al., 1990; Jentsch et al., 1997, 1998; Tanda et al., 1997) In humans –THC might increase DA release in striatum (Voruganti et al., 2001, Bossong et al., 2008) biological pathway to psychosis?

38. DA in schizophrenia hypo Mesocortical DA hypo- activity hyper Mesolimbic DA hyper- activity DA D1 receptors DA D2 receptors Negative and cognitive symptoms Positive and disorganized symptoms Cognitive tasks Imaging

39. Dopamine release can be inferred from displacement of IBZM or [18F]Fallypride

41. Rebecca Kuepper; Prof. Koen van Laere

42. L R Striatum Baseline Following THC PET study [ 18 F]Fallypride Baseline

43. Burst firing of DA neurones in the ventral tegmental area (VTA) signifies the appearance of novel or salient stimuli. Abnormal or dysregulated bursting in dopaminergic neurones may lead to the attachment of aberrant salience to otherwise mundane percepts and concepts and a delusional- style of thinking. “…In this way, an unexpected sound, the comments of a TV news reader or eye contact with a stranger are transformed from trivial everyday occurrences into highly salient events of great personal meaning to the psychotic individual”. Hyland, B. I.,(2002) Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114, 475-492 Kapur, S et al (2005) Schizophr Res 79, 59-68 Murray RM et al (2007) Nat. Rev Neurosci (2007). Dopamine and Aberrant Salience

44. Why do patients with schizophrenia use cannabis?? Why do patients with schizophrenia use cannabis??

45. Acute effecten geen THC Hallucinaties na THC Stemming geen THC na THC “Ik voel me opgewekt...” “Ik hoor stemmen...” Henquet et al., BJP 2010.

46. Sub-acuut Acuut Effecten van Cannabis “Ik voel me ontspannen...” “Ik hoor stemmen...” Henquet et al., BJP 2010.

47. Patienten zijn verhoogd gevoelig voor cannabis Patienten zijn verhoogd gevoelig voor cannabis

48. TREATMENT???

49. Minder angst / stress Meer stemmen Stress Geautomatiseerde overtuigingen Als ik drink  Ben ik meer relaxed  word ik leuk gevonden Als ik cannabis gebruik  Ben ik minder angstig  Heb ik minder last van stemmen

50. Behandeling: Cognitieve gedrags therapie Motiverende gespreksvoering Terugvalpreventie Gedurende 1 jaar Voor- en Nameting van symptomen en middelengebruik X Verwachtingen van gebruik

51. Maastricht: Leuven: Dr. Cecile HenquetProf.dr. Koen van Laere Monique Konings (GGzEindhoven) Maurice Smits (Mondriaan) Dr. Inez Germeys Dr. Marinus van Kroonenburgh (azM) Prof.dr. Jim van Os Grants:Zon-MW NWO (Veni-grant)

52. Questions? r.kuepper@sp.unimaas.nl