Cannabis and Psychosis

1. Cannabis and Psychosis Erik Messamore, MD, PhD Medical Director, Best Practices in Schizophrenia Treatment (BeST) Center Associate Professor of Psychiatry, Northeast Ohio Medical University Presentation to the first episode schizophrenia treatment group January 25, 2017

2. Association between cannabis and psychosis is well-established • “excessive” cannabis use was responsible for psychotic reactions in 9.5% (222/2344) of cases in asylums in India. • according to an 1890 study by the Indian Hemp Drugs Commission • Frequently disbelieved since >92% of users never experience psychosis

3. Outline • Mechanisms for cannabis-associated psychosis • Clinical/epidemiological evidence of relevance to schizophrenia-like psychosis • N-acetylcysteine as possible treatment tool in cannabis dependence; negative symptoms of schizophrenia

4. Cannabis as a dopamine-releasing drug Research subject secretly smoked marijuana during a break in PET scan study of D2 receptors. ‘After’ use image shows displacement of PET-label from D2 receptors, indicating marijuana-stimulation of endogenous dopamine release (Voruganti, 2001)

5. Cannabis as a dopamine-releasing drug Increasing blood THC levels reduce D2 PET-labeling, indicating that marijuana stimulates endogenous dopamine release (Stokes, 2009)

6. COMTCatechol-O-Methyltransferase • Might mediate cannabis – psychosis association • Inactivates catecholamine neurotransmitters (dopamine, norepinephrine, epinephrine) • By adding a methyl group (donated by S-adenosylmethionine SAM-e) • Particularly important for DA inactivation in the prefrontal cortex (due to low DA transporter activity)

7. COMT Val158Met Mutation • Functional polymorphism (aka mutation) in COMT gene  valine or methionine at position #158 •  3 possible configurations • Val/Val - most rapid DA metabolism • Val/Met • Met/Met - slowest enzyme activity

8. COMT variant mediates cannabis-psychosis association • Dunedin Multidisciplinary Health and Development Study • N=803 • 26% of study members were classified as adolescent-onset cannabis users if they had used cannabis before age 15 or if they were at least monthly cannabis users by age 18 • Strongly increased prevalence of schizophreniform diagnoses by age 26 among cannabis users with Val/Val genotype • Caspi, A., et al. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol. Psychiatry 57, 1117–1127.

9. COMT-cannabis replication studies • COMT val/val genotype is more susceptible to acute psychosis from THC • COMT val/val association with cannabis-associated persistent psychosis is less evident in replication studies • But association is stronger when early life adversity is considered in data analysis.

10. Earlier age of onset of schizophrenia among early, frequent cannabis users • Age at onset was 1.8 years earlier in cannabis users compared to non-users Dekker, 2012 • 3.2 year earlier age of onset for cannabis users vs non-users DiForti, 2014 • 3 year earlier onset of schizophrenia-spectrum disorder among cannabis users Helle, 2016 • 6.2 year earlier age of onset for daily users of high-potency cannabis DiForti, 2014

11. Cannabis association with increased risk of schizophrenia-like psychosis • Sibling pair analysis • N = 3,081 • 21 year follow up McGrath, 2010

12. Dose-response relationship:higher cannabis load  greater schizophrenia risk • Swedish military conscripts (i.e., 97% of 18 to 20 year old males) n = 45,570 • At 27 year followup: Zammit, 2002

13. Dose-response relationship:higher cannabis load  greater schizophrenia risk • National Epidemiologic Survey on Alcohol and Related Conditions. US nationally representative sample • n = 34653 Davis, 2013

14. Cannabis use is associated with worse outcomes in first episode psychosis • 2,026 individuals with FEP • Cannabis users (46% of sample) had: • Higher rates of hospitalization • Higher rates of involuntary treatment • Higher rates of med switching and polypharmacy • (indicators of treatment resistance) Patel, 2016

15. N-acetylcysteine (NAC) • Acetylated derivative of the amino acid cysteine • Precursor to glutathione, the body’s primary antioxidant • Reduces inflammatory cytokines (IL-1b; TNF-a; IL-6) • Normalizes elevated glutamate levels Dean, 2011

16. Glu levels in dorsal anterior cingulate cortex were elevated in cocaine dependent pts • Glu levels correlated with impulsivity • Glu levels normalized after single 2400 mg dose of NAC

17. NAC may increase success at cannabis cessation • N=116 cannabis-dependent adolescents • All received contingency management and brief weekly counseling • Cannabis-positive test was assumed for any missed visits Gray et al., 2012

18. NAC may improve tobacco quitting success • Froeliger, B., McConnell, P.A., Stankeviciute, N., McClure, E.A., Kalivas, P.W., and Gray, K.M. (2015). The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend 156, 234–242. • Prado, E., Maes, M., Piccoli, L.G., Baracat, M., Barbosa, D.S., Franco, O., Dodd, S., Berk, M., and Vargas Nunes, S.O. (2015). N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep. 20, 215–222. • Schmaal, L., Berk, L., Hulstijn, K.P., Cousijn, J., Wiers, R.W., and van den Brink, W. (2011). Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 17, 211–216.

19. Berk et al., 2008 • 1000 mg NAC vs PBO • N=140 • Chronically ill patients, including 45% of sample on clozapine • Effect on negative and general symptoms (not on positive symptoms)

20. Farokhnia et al., 1013 • NAC 1000 mg BID vs PBO • Adjunctive to risperidone • N=42 • NAC reduced severity of negative symptoms