Weeding through the Hype Understanding Adolescent Cannabis Use

Weeding through the Hype: Understanding Adolescent Cannabis Use & Early Onset Psychosis Kara Bagot, M. D. Solnit Integrated Psychiatry Program Yale University Child Study Center New Haven, CT, USA Yifrah Kaminer, M. D. , MBA Professor of Psychiatry & Pediatrics University of Connecticut Health Center Farmington, CT, USA

Outline AIM: review the data on the association between adolescent onset of regular marijuana use and later psychosis Acronyms & Definitions Background and Significance Neurobiology Association with Psychosis Age of onset Manifestation: Prodrome & Psychosis Functioning & Outcome Pre-existing Vulnerability Conclusions and Limitations

When Science Doesn’t Support Beliefs Then ideology Needs to Give Way- M. Shermer 10. 2013 Motivated reasoning-when our brain finds a way to support what we want to be true. Confirmation bias that directs the mind to seek confirming facts and ignore disconfirming evidence. Cherry picking and data mining of studies to suit ideological convictions. Examples: Gun Control and Global Warming “It is better to understand the way the world is than how we would like it to be”

Facts Vs. Myths George Bernard Shaw For every complex problem, there is a simple solution…. . and it is always Wrong Beware of false knowledge (misinformation): it is more Dangerous than ignorance Scott Adams (Dilbert Cartoons) Never under-estimate the ignorance of the public

Acronyms CB 1: Cannabinoid Receptor type 1 CHR: Clinically high risk CU: Cannabis Use CUD: Cannabis Use Disorder MM: Medical Marijuana NCU: No/Never Cannabis Use FEP: First-episode Psychosis NA: Nucleus accumbens PFC: Prefrontal cortex SUD: Substance Use Disorder

Definitions: Cannabis, Cannabinoids, etc Cannabis: refers to the plant (Cannabis sativa) and its components Marijuana: comprises the dried flowering tops & leaves of the plant Hasish: consists of dried cannabis resin (THC content 2 -20%) THC: Delta 9 -Tetrahydrocannabinol is the primary psychoactive component of cannabis preparations (increasing potency trend). Cannabinoids: refers to any chemical compounds that include or are related to THC. Endocannabinoids: synthesized in the body Synthethic cannabinoids: manufactured in the lab (e. , dronabinol) Cannabidiol: a non-psychoactive cannabinoid present in cannabis products that can modulated THC effects

Concentrates BHO: Earwax, Honey oil, Shatter, Budder, Honeycomb, Sap, Dabs, Glass, Hash oil, Bubble hash Concentrated cannabis Solvent extraction of THC Butane, ethanol, isopropyl alcohol, propane ‘dabbing’ – vaporizing cannabis oil Contains 60 -90% THC One puff = one blunt SE: agitation, hallucinations, insomnia, psychosis

Quotes From Earwax Users “It literally took me down. Within a couple of minutes, the high started and you start to feel like you’re going out of your body. ” “I ended up in the mental hospital because it had been 10 days and I had gotten about 10 to 15 hours of sleep, total. ” “If I had never experienced dabs, I know I wouldn’t have experienced terrorizing psychological phenomena. The dabs can take you. ”

Does Liberalizing MJ Laws Increase Teen Use? Why is it so important? Decision to use MJ for the 1 st time is sensitive to its legal status compared to a cont’d use. The effect of lifetime harm averted is larger than inducing a quit considering MJ effect on MH problems and lowering educational attainment YES “The impact of Decriminalization is concentrated among minors, who have a higher rate of uptake in the first 5 years following its introduction”. There is a “Trickle Down” effect: 1 st time users age has been dropping. Williams & Bretteville-Jensen (J Health Economics, 2014)

Daily Use & Drug Testing in CO School Nat’l in 2011, 12 th graders daily use was 6. 6%. In CO it was 11. 7% 16% of CO students have access to MM from card holders, dispensaries , retail MJ stores. In 2007 positive tests made up to 33% compared to 2012 57% of total drug screenings. Detected THC levels increased by 76% (from 225 to 396 ng) after 2009. MJ violations (2006 -2013) increased from 23. 4% to 34% Top 9/42 states for current CU use in high-school have MM. CT ranked 2 nd (26%). Nat’l average 19. 7%. RMHIDTA, 2014

Background Prevalence CU in 12 -17 yr olds = 13. 4% >25% with CUD ~62% with FEP have h/o SUD Among new users, ~2% develop CUD during the first 1– 2 years after onset of use CUD occurs in 1/10 of adult onset cannabis users CUD occurs in 1/6 adolescent onset cannabis use (Lambert M, et al. , Acta Psychiatr Scand, 2005; Wu LT, et al. J Psych Res, 2014)

Cannabis & the Effect on the Brain

Cannabis & the Adolescent Brain Normal: neuronal maturation & rearrangement processes Endocannabanoid system involved in neuronal cell proliferation, migration and differentiation, neuronal signaling, neurotransmitter expression CB 1 expression patterns increase throughout adolescence in the frontal cortex, striatum, and hippocampus peaks in endocannabinoid levels endocannabinoid signaling determinant of maturation of the adult brain

Definitions-Psychosis Clinically high risk-those who meet one of the following criteria: a. exhibit attenuated positive symptoms in the past year b. have a brief psychotic episode of less than one week duration c. meet criteria for Schizotypal disorder d. have a first-degree relative with a diagnosis of psychotic disorder and they themselves have at least a 30% decline in functioning (as measured by Global Assessment of Functioning) in the past year Prodrome: subtle, subclinical sx that do not meet diagnostic criteria for a full-blown psychotic disorder FEP: positive sx for ≤ 6 months

Cannabis Use and Early Onset Schizophrenia Early exposure to cannabis may represent a risk for developing EOS (<18 Years). May exacerbate neurobiological alterations associated with EOS. Cannabis use is associated with a more acute mode of 1 st psychotic episode onset (N=511) (Mazzoncini R, Acta Psych Scand; 5/2010) There is a significant EOS and cannabis use disorders (CUD) interaction in the left superior parietal lobe. Both EOS and CUD had smaller gray matter volume in the parietal cortices compared with healthy controls. In the left thalamus the comorbid group had smaller gray matter volumes compared with healthy controls. Kumra et al. (AACAP; 2/2012)

Clinically High Risk …and other findings Parietal lobe dysmorphology (Henquet CL, et al. , BMJ, 2005) Pre-illness CU predicts psychosis at 4 yr follow-up Family History of Schizophrenia (Arango CC, et al. , Schizophr Bull, 2008) 1 st degree relative: 10 x risk Both parents affected: 50% risk Monozygotic twins: 80% risk

Neuro Changes seen in both CU & Psychosis Disruption of frontostriatal & limbic systems abnormal associative learning and assignment of salience Changes in hippocampus & PFC rewarding effects + inhibitory control Altered glutamatergic & dopaminergic signaling in NA Δ motivation Dopaminergic hypofrontality cognitive dysfunction + negative sx hyperdopaminergic mesolimbic positive sx Thalamic gray matter volume cognitive processing deficits

Cannabis & Link to Psychosis in Youth CB 1 on presynaptic terminals that release GABA, glutamate, serotonin, dopamine, and Ach interaction between CB 1 and its endogenous endocannabinoid ligands limit neurotransmitter release Δ GABAergic inhibitory inputs to pyramidal neurons in PFC impaired cognitive function ↑extracellular dopamine disinhibition of dopaminergic neurons aberrant reward prediction abnormal attribution of salience Ongoing CU dopamine sensitization acquired susceptibility to psychosis

Age of Onset of CU ≤ 16 yrs associated with psychosis (Mc. Grath J, et al. , Arch Gen Psych, 2010) 12 -15 yrs associated with severe psychotic sx Likelihood of acute presentation: Daily CU-42% v. Non-daily-20% (Compton MT, et al. , Schizophr Res, 2011)

Teens Initiation of MJ Use and Early-Onset Psychosis A literature review (12 eligible studies) of initiated MJ use <18 Y. O. and experience of psychotic symptoms< 25 Y. O. Early initiation increase risk of EOP (p<0. 001) In Those with pre-existing vulnerability (OR>7. 9) In those using MJ more frequently (p<0. 001) There is also a dose-response association between MJ use and EOP symptoms Those who use more tend to significantly experience greater # and severity of prodromal and diagnostic symptoms. Over treatment outcome is worse Bagot, Milin, Kaminer, (in press)

CU Initiation and Prodrome & FEP Linear association between age of CU initiation and prodrome onset & FEP NCU CU P-value Age at 26. 35± 10. 6 21. 22± 6. 0 Prodrome Onset (yrs) 0. 003 Age at FEP Onset (yrs) 0. 002 27. 12± 10. 6 21. 97± 5. 8 Leeson VC, Harrison I, Ron MA et al. The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode Schizophrenia. Schizophr Bull. 2012; 38(4): 873 -80

CU Initiation and Schizophrenia Outcomes Arseneault L, Cannon M, Poulton R et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002; 325(7374): 1212 -13

Manifestation: Prodrome CU onset ≤ 16 yrs associated with ↑ prodromal sx (Konings M, et al. , Acta Psychiatr Scand, 2008; Miettunen et al. , Br J Psych, 2008) Dose-response effect Age at CU initiation and odds of high level of “psychotic experiences: ” (Shubart CD, et al. , Psychol Med, 2011) ≤ 12 yrs: 3. 1 x more likely 12 -15 yrs: 1. 2 x more likely Psychosis Conversion Rate within 1 -yr of prodrome: CHR + CUD: 12. 5% v. CUD: 3. 1% (Kristensen & Cadenhead, Psych Res, 2007)

Manifestation: Psychosis CU initiation < 18 yrs associated with more sx of Schizophrenia (Arseneault L, et al. , BMJ, 2002) Age of onset of CU associated with positive sx (Mc. Grath J, et al. , Arch Gen Psych, 2010) Hallucinations Grandiosity Delusions First-rank/Thought disorder : thought echo, withdrawal, insertion, broadcasting, control, telepathy Mixed evidence on relationship between CU & negative sx

Longitudinal Study: CU Duration & Psychosis Mc. Grath J, Welham J, Scott J, et al. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. May 2010; 67(5): 440 -447.

CU Frequency & Positive Symptoms Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction. Oct 2004; 99(10): 1333 -1341.

CU v. NCU – Psychotic Symptoms at FEP Baeza I, Graell M, Moreno D, et al. Cannabis use in children and adolescents with first episode psychosis: influence on psychopathology and short-term outcome (CAFEPS study). Schizophr Res. 2009; 113(2 -3): 129 -37

Functioning Longer duration of psychosis prior to seeking treatment (Schimmelmann BG, et al. , Eur Psych, 2012) Worse functioning at treatment onset (Schimmelmann BG, et al. , Eur Psych, 2012) ↑ sx severity ↑ academic/occupational impairment h/o criminal justice system involvement Better social functioning (Auther AM, et al. , Psychol Med, 2012) Diverging evidence on cognitive functioning Associations differ by neurocognitive area examined

CU v. NCU: Cognition at FEP de la Serna E, Mayoral M, Baeza I, et al. Cognitive functioning in children and adolescents in their first episode of psychosis: differences between previous cannabis users and nonusers. J Nerv Ment Dis. 2010; 198(2): 159 -62

Outcome >50% decrease/stop CU after FEP Achieve Abstinence: mean age of CU onset = 17. 4 ± 4. 2 yrs ↓ positive and negative sx ↓ illness severity ↓ duration of hospitalization ↓ frequency of hospitalization Persistent CU: mean age of CU onset = 14. 5 ± 1. 9 yrs ↓ treatment engagement ↑ illness severity Poorer functioning at discharge ↑ positive sx ↓ medication adherence (Leeson VC et al. , Schizophr Bull, 2012; Schimmelmann BG, et al. , Eur Psych, 2012)

Adolescent Cannabis Use Effects Adult Psychosis in Individuals with Variations in the COMT Gene no adolescent cannabis use 15 disorder at age 26 % with schizophreniform 20 10 5 0 Met/Met Val/Met COMT genotype Source: Caspi et al. , Biol. Psychiatry, 57: 1117 -1127; 2005 Val/Val

Clinically High Risk Youth: COMT Gene Catechol O-methyltransferase Val Met substitution at codon 158 Valine associated with: ↑ mesolimbic dopamine signaling ↓ PFC dopamine level

Teens Initiation of MJ Use and Early-Onset Psychosis A literature review (12 eligible studies) of initiated MJ use <18 Y. O. and experience of psychotic symptoms< 25 Y. O. Early initiation increase risk of EOP (p<0. 001) In Those with pre-existing vulnerability (OR>7. 9) In those using MJ more frequently (p<0. 001) There is also a dose-response association between MJ use and EOP symptoms Those who use more tend to significantly experience greater # and severity of prodromal and diagnostic symptoms. Over treatment outcome is worse Bagot, Milin, Kaminer, (in press)

Limitations of the Current Literature Poly-substance use Concentration of THC (high potency CU) CU not quantified Recall bias Small sample sizes Prodrome v. Substance-Induced Psychosis

Conclusions Independent association between early CU and early onset FEP ↓ age &↑ frequency and/or duration of CU associated more robustly with earlier onset prodrome & FEP and severity of sx Greater sensitivity of select positive sx to CU Dose-response effect Uncertainty of association between CU and negative sx Explained by better premorbid social functioning? Better cognitive functioning Poorer academic functioning Poorer disease outcomes

Past 20 Years Cannabis Research Summary Driving under the influence (DUI) of MJ doubles car crash risk; One in 10 regular user develop dependence (1 in 6 if early initiation) and increases the use of other illicit drugs Regular use doubles the risks of: psychosis, school leaving and cognitive impairment These associations persist after controlling for confounding variables in longitudinal studies Some claim for: 1) shared causes of risk factors, 2) that educational deficits in regular users are impaired as a combination of: a higher preexisting risk pre use, the adverse effects of regular use, increased affiliation with other users who reject school leading to premature school termination Hall W, Addiction (2015)

Parents and Sibs MJ Use: The Future is Now Over 40% of variance associated with the risk for CUD has been reported to be transmissible, that is, conveyed to children via conjointly genetic and parenting influences. Hopfer C, et al. (2013) We are made wise NOT by the recollection of our past, but by the responsibility of the future. George Bernard Shaw

References Arango CC. Moreno S. Martinez S, et al. Longitudinal brain changes in early-onset psychosis. Schizophr Bull. 2008; 34(2): 341 -353. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. Nov 23 2002; 325(7374): 1212 -1213. Auther AM, Mc. Laughlin D, Carrion RE, Nagachandran P, Correll CU, Cornblatt BA. Prospective study of cannabis use in adolescents at clinical high risk for psychosis: impact on conversion to psychosis and functional outcome. Psychol Med. Dec 2012; 42(12): 2485 -2497. Compton MT, Broussard B, Ramsay CE, Stewart T. Pre-illness cannabis use and the early course of nonaffective psychotic disorders: associations with premorbid functioning, the prodrome, and mode of onset of psychosis. Schizophr Res. Mar 2011; 126(1 -3): 71 -76. Henquet, C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005; 330(7481): 11. Kristensen K, Cadenhead KS. Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res. May 30 2007; 151(1 -2): 151 -154. Konings M, Henquet C, Maharajh HD, Hutchinson G, Van Os J. Early exposure to cannabis and risk for psychosis in young adolescents in Trinidad. Acta Psychiatr Scand. Sep 2008; 118(3): 209 -213. Lambert M, Conus P, Lubman DI, et al. The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis. Acta Psychiatr Scand. Aug 2005; 112(2): 141 -148. Leeson VC, Harrison I, Ron MA, Barnes TR, Joyce EM. The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia. Schizophr Bull. Jun 2012; 38(4): 873 -880. Mc. Grath J, Welham J, Scott J, et al. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. May 2010; 67(5): 440 -447. Miettunen J, Tormanen S, Murray GK, et al. Association of cannabis use with prodromal symptoms of psychosis in adolescence. Br J Psychiatry. Jun 2008; 192(6): 470 -471. Schimmelmann BG, Conus P, Cotton S, Kupferschmid S, Mc. Gorry PD, Lambert M. Prevalence and impact of cannabis use disorders in adolescents with early onset first episode psychosis. Eur Psychiatry. Aug 2012; 27(6): 463 -469. Schubart CD, van Gastel WA, Breetvelt EJ, et al. Cannabis use at a young age is associated with psychotic experiences. Psychol Med. Jun 2011; 41(6): 1301 -1310. Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction. Oct 2004; 99(10): 1333 -1341. Wu LT, Brady KT, Mannelli P, Killeen TK. Cannabis use disorders are comparatively prevalent among nonwhite racial/ethnic groups and adolescents: A national study. J Psychiatr Res. Mar 2014; 50: 26 -35.

END OF PRESENTATION Contact Info: Kaminer@uchc. edu

Synthetic Cannabanoids: Spice • K 2, Fake weed, Yucatan fire, Skunk, Moon rocks… • Herbal mixture • Effects similar to cannabis • “safer” • 2 nd in abuse to marijuana • 5 most frequently used chemicals – Schedule 1 controlled substances • Act on same receptors as THC • Bind more strongly • SE: ↑HR, N/V, agitation, confusion, hallucinations • Extreme cases: ↑BP, MI, myocardial ischemia

Case Report CC: “my body is under an external locus of control” HPI: 20 yo community college student with PPH sig for mushroominduced psychosis BIB EMS following a high-speed MVA and admitted to trauma surgery. Psychiatry consult placed for evaluation of agitation and SI. Four days prior to the MVA, pt smoked “earwax; ” he became paranoid anxious and was unable to sleep in the days preceding the MVA due to “strange noises” and feeling like he “was being robbed. ” Pt had crashed into parked cars driving at 100 mph. Methamphetamine was found in his car. Case obtained from Misty Richards, M. D. , MS PGY-3, UCLA Adult Psychiatry Resident

PPH: One prior hospitalization in high school for mushroom-induced psychosis (< 1 week, given one dose of unknown antipsychotic; resolved). Never seen an outpatient psychiatrist. No use of psychotropic meds. SH: Born and raised in Dallas, Texas; parents divorced; one brother Attends community college; student body president No prodrome: Popular, studies environmental policy, transfer to state university Lives w roommate in apt off campus Recently broke up with girlfriend of > 1 year No prior arrests

FH: No mental illness SA Hx: Drinks ETOH socially (once a month) Mushrooms once in high school (hospitalization) Marijuana a “handful of times” with no bad reaction “Earwax” 4 days prior to MVA No other use of illicit substances No tobacco use Allergies: NKDA Meds (On admission): None

Back to the Case 2 days after discharge by surgery, pt re-presented as: Well groomed, eyes closed, during “spell” exhibited agitation, posturing including rounding of his back, odd speech; monotone. Paucity of content. Mood “fine” and affect euphoric. Thought process disorganized, tangential with loose associations. Negative SI, HI; grandiose delusions. Internally preoccupied. No insight and judgment. “I have transcended and found the truth…I am God…I was conscious during that seizure and transcended to a different state…Mom, I just want peace…I want to fly. ” PEC’d started Latuda discharged 7 days later

Acknowledgements Yifrah Kaminer, M. D. , MBA Robert Milin, M. D. , FRCPC (Director Division of Addiction and Mental Health, Royal Ottawa Mental Health Centre) Misty Richards, M. D. , MA (PGY-3, UCLA Department of Psychiatry) Bagot KS, Milin R, Kaminer Y. Adolescent initiation of cannabis use and early-onset psychosis. Substance Abuse Journal; in press , 2015.

Definitions-Cannabis Cannabis: refers to the plant (Cannabis sativa) its components Marijuana: comprises the dried flowering tops & leaves of the plant Hashish: consists of dried cannabis resin (THC content 2 -20%) THC: Delta 9 -Tetrahydrocannabinol is the primary psychoactive component of cannabis preparations Cannabinoids: refers to any chemical compounds that include or are related to THC Endocannabinoids: synthesized in the body Synthethic cannabinoids: manufactured in the lab

“Medical” Cannabis Policy and Teens Use A higher prevalence of adolescent CU and a lower perception of risk in states with MM laws compared with those without (Wall MM, et al. , Ann Epidemiol, 2011) The majority (74%) of teens (N=164; mean age-16) in treatment (Colorado 2. 3%of adult pop. Have a MM registration) used MM with a median frequency of 50 times and mean of 117 (Samuelson-Sautel, JAACAP, 2012) Those using MM had earlier age of regular use, more symptoms of abuse and dependence, and more conduct symptoms compared with those NOT using MM