Cannabis – Biology to Policy ! Timmen Cermak, MD

Cannabis Biology to Policy

September 5, 2014 CSAM Review Course

Timmen Cermak, MD CSAM Past President

I have no conflicts of interest to disclose

Co-Chair Youth, Educaon and Prevenon work group Blue Ribbon Commission on Marijuana Law and Policy

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Sammy, the Sensive Son

q 16-year-old, sullen, easily wounded

q Clothes, mood and friends changed and darkened on entering high school

q Insomnia worsened

q Dropped out of sports

q Grades worsened and school neglected

q Marijuana touted as the only help

The Clinical Queson

How much of the problem does marijuana Cause? Complicate? Cure?

And what do you need to know to help patients answer this question?

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Objecves

q Basic Science Review

q Clinical Ramifications

q Downregulation of Receptor Sites

q Dependence/Withdrawal

q Developmental Vulnerability

q Structural changes

q Cognitive changes

q Affect and Temperament changes

The Impact of Cannabis Two Studies

q Cognition – Cortical

q Affect - Limbic

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

1. The Dunedin Study

Meier, M, et al, “Persistent cannabis users show neuropsychological decline from childhood to midlife,” www.pnas.org/cgi/doi/10.1073/pnas.1206820109

Protocol

q 1,037 individuals followed from birth (1972/1973) to age 38 y.o. – New Zealand q Neuropsychological tesng at age 13 y.o. (before iniaon of cannabis use) and at age 38 y.o. q Cannabis use evaluaon at ages 18, 21, 26, 32, and 38 y.o.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Results

q Adolescent onset users (weekly) showed greater IQ decline than adult-onset cannabis users q Cannabis dependence at three or more evaluaons experienced −0.38 Standard Deviaons = a loss of 6 IQ points at 38 years old q The most persistent adolescent-onset cannabis users had an average 8-point IQ decline from childhood to adulthood.

Cumulave Effect on IQ

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Subtests

Impairment was detectable across five domains of neuropsychological funconing • Execuve Funconing • Processing Speed • Memory • Perceptual Reasoning • Verbal Comprehension

Informants reported observing significantly more aenon and memory problems among those with more persistent cannabis dependence

2. Masked Faces Paradigm

Gruber et al, “Altered affecve response in marijuana smokers: An FMRI study,” Drug and Alcohol Dependence 105 (2009)

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Subliminal Affecve Smulus

Angry Neutral

30 msec 170 msec

Response in MJ Smokers

• Heavy MJ Users Defined:

• Ave. 25.6 joints/week, at least 4 of last 7 days

• Ave. onset 14.9 y.o.; Current ave. age = 25

• Result: MJ smokers have decreased mygdala acvity during masked affecve smuli compared to controls

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

fMRI

Control

Chronic Marijuana

Gruber’s Conclusion

Marijuana smokers process emoonal informaon differently in the amygdala from those who do not smoke, even when smuli are presented below the level of conscious processing.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Marijuana Demysfied

1. How does marijuana affect the brain (and the mind)?

2. Why does regular use of marijuana lead to cognive and affecve deficits?

The magic is in the brain, not in the herb

Summary of Cannabis Basic Science

Retracing the Endorphin Story

q Start with Psychoacve Plants (Poppy/ Cannabis) q Extract Botanical Essence (Opiates/THC) q Label Acve Molecule to Reveal Receptor Sites q Discover Naturally Occurring Ligand (Endorphin Neurotransmiers/ Endocannabinoid Neuromodulators)

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

CB1 and the Endocannabinoid System - 1988

Discovery of CB1 Receptor (with graduate student William Devane)

Devane WA, et al. “Determinaon and characterizaon of a cannabinoid receptor in rat brain”, Mol Pharmacol, 1988, Vol 34 (5), pp 605-13

Allyn Howle

Miles Herkenham 1990

Radioacve labeled cannabinoid used to begin localizing CB1 receptor in the brain

Miles Herkenham, et al, “Cannabinoid receptor localizaon in brain”, Proc. Nat. Acad. Sci. USA, Vol. 87, pp. 1932-1936, March 1990

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Distribuon of CB1 Receptors

q Hippocampus – Memory and Learning q Amygdala – Novelty, Emoon, Appetes q Basal Ganglia – MotorCerebellum – Real Time Coordinaon, Selecve Aenon and Time Sense q Nucleus Accumbens - Reward Mechanism (Addicon) q Cortex (Anterior > Posterior) – Frontal Lobe Execuve Funcons

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

William A. Devane 1992

q Joined Raphael Anandamide Mechoulam’s research lab q Discovered the first endogenous cannabinoid ligand (with Raphael Mechoulam and Lumir Devane WA, Hanus L, Breuer A, et Hanus) al. “Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946-1949.

Drugs can “mimic” Neurotransmiers

Anandamide THC

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

EndoCannabinoids (ECBs)

q Anandamide (arachidonolyethanolamide, AEA, or AnNH) q 2-AG (2-arachidonylglycerol) q 2-AGE (Noladin ether, or 2-arachidonyl glyceryl ether)

NOT stored in Synapc Vesicles – but rather produced from cellular membranes as needed

Endocannabinoids as Pre-Synapc Neuromodulators

Arachidonic Acid

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Conceptualizing ECB Function

q The endocannabinoid signaling machinery exerts negave feedback on demand in a synapse-specific manner q Brain can synthesize and release enough ECBs to serve as a synapc circuit breaker q ECBs are tonic neuromodulators, keeping neuronal acvity in balance, neither over- or under-acve

Katona & Freund, “Endocannabinoid signaling as a synaptic circuit breaker in neurological dise Nature Medicine, Vol 14 | Number 9 | Sept 2008

Ramificaons

1. Down-regulation of CB1 Receptors

2. Dependence / Reward Circuitry

3. Developmental Vulnerability

4. Structural Changes

5. Cognitive Disturbances

6. Affect & Temperament Changes

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

1. CB1 Downregulaon (in rats)

Chronic exposure to delta-9-THC (5 days) decreases the specific binding of CB1 receptors from ~20-60%, depending on the specific brain area measured with the basolateral nucleus of the amygdala reduced 24% aer 14 days

Downregulaon begins with the first dose of THC in the hippocampus and cerebral cortex

J. Romero, “Effect of chronic exposure to delta9-tetrahydrocannabinoloin cannabinoid receptor binding and mRNA levels in several rat brain regions,” Brain Res Mol Brain Res 1997 Jun;46 (1-2):100-8 J. Romero, “Time-Course of the Cannabinoid Receptor Down-Regulaon in the Adult Rat Brain Caused by Repeated Exposure to D9-Tetrahydrocannabinol “Synapse 30:298–308 (1998)

CB1 Downregulaon (in humans)

q Binding is ~20% lower in neocortex and limbic cortex in daily cannabis smokers than in control subjects

q Binding increased in cannabis smokers after ~4 weeks of abstinence

q Decreased binding reflects either decreased CB1 density or affinity

Hirvonen, J. et al; “Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers” Molecular Psychiatry (2011), 1–8

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

2. Cannabis Dependence & Withdrawal

q Reliability and validity established

q Clear and transient me course

q Pharmacological specificity Alan Budney q Syndrome is not rare Budney and Hughes, “The cannabis q Has clinical importance withdrawal syndrome.” Curr Opin Psychiatry. 2006 May;19(3):233-8.

DSM Criteria for Dependence

q Tolerance/Withdrawal q Loss of Control/Desire to Control q Preoccupaon q Connued Use in the Face of Serious Adverse Consequences q Cognive Distorons/Denial

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Mulple Lines of Evidence for Addicon

q Elevated Dopamine in Reward Center q Animal Models & Cannabinoid Blockers q Clinical Reports of Withdrawal q Epidemiology 9% - with inial use at 18 y.o. or greater

Endocannabinoids in the Nucleus Accumbens

q Cannabinoid agonists increase the efflux of dopamine seen with other drugs of addicon

q NA plascity in response to endocannabinoid induced dopamine increase

q Infusion of cannabinoid blocker leads to withdrawal symptoms aer 8 days of THC administraon

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

MJ Withdrawal (proposed by Alan Budney) 3 (or more) of the following within several days of cessaon 1. Irritability, anger, or increased aggression 2. Nervousness or anxiety 3. Sleep difficulty (insomnia) 4. Decreased appete or weight loss 5. Restlessness 6. Depressed mood 7. At least 1 physical symptom causing significant discomfort (stomach pain, shakiness/tremors, sweang, fever, chills, headache)

Withdrawal Symptom Severity

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Cannabis Withdrawal Epidemiology

Among frequent cannabis users q 59% report 1 or more symptoms q 44% report 2 or more q 34% report 3 or more

Clinical Epidemiology NCS Study (Anthony et al. 1994)

Lifetime Dependence Conditional Dependence**

Cannabis 4.2% Heroin 23.1% Cocaine 2.7% Cocaine 16.7% Stimulants 1.7% Stimulants 11.2% Heroin 0.4% Cannabis 9.1% Tobacco 24.1% Tobacco 31.9% Alcohol 14.1% Alcohol 15.4%

** %of those who have used that develop dependence

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Clinical Importance

§ Those aempng to quit complain of withdrawal and indicate it makes quing difficult § Cannabis users report using cannabis (and other substances) to relieve Withdrawal § Significant Others observe withdrawal symptoms that disrupt daily funconing § Similar in magnitude and severity to Tobacco Withdrawal

Budney et al, “Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse,” J Subst Abuse Treat. 2008 Dec;35(4):362-8. Epub 2008 Mar 14.

Marijuana vs Tobacco

Chemical Marijuana Tobacco

q THC 820.0 mic -----

q Nicotine ----- 2850.0 mic

q Phenol 76.8 mic 138.5 mic

q Naphthalene 3.0 mic 1.2 mic

q Benzanthracene 75.0 ng 43.0 ng

q Benzopyrene 31.0 ng 21.1 ng

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Marijuana vs Tobacco

Chemical Marijuana Tobacco

q Carbon Monoxide 17.6 mg 20.2 mg

q Ammonia 0.3 mg 0.2 mg

q Hydrogen Cyanide 532.0 mic 498.0 mic

q Acetaldehyde 1200.0 mic 980.0 mic

q Acetone 443.0 mic 578.0 mic

q Benzene 76.0 mic 67.0 mic

q Toluene 112.0 mic 108.0 mic

Physical Impact of MJ

q Pulmonary – Chronic Bronchitis

q Heart – Tachycardia & Vasoconstrictive

q Gut - Constipating

Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc 2013;10:239-47. Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Am J Cardiol 2014;113:187-90

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

3. DEVELOPMENTAL VULNERABILITY

How often do adolescents develop cannabis dependence?

Adolescent Epidemiology Monitoring the Future

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Comparave Marijuana Use Rates by Ethnicity

ADDICTION Percentages of past year cannabis use disorder among those with a recent onset (prior 2 years)

Winters & Lee, “Likelihood of developing an alcohol and cannabis use disorder during youth: association with recent use and age,” Drug Alcohol Depend. 2008 Jan 1;92(1-3): 239-47. Epub 2007 Sep 20.

%

12 13 14 15 16 17 18 19 20 21 22-26 Age of Person in Years

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

CHDS Prospecve Study: Cannabis Dependence in Lifeme

Christchurch Health and Development Study (CHDS), Birth to Age 35. 50 691 cannabis users among 1,265 children born in 1977. 45 John Horwood, Personal Communication (July 15, 2014) 40 Cumulative 35 Rate at: 30 Age 18 Age 21 25 Age 25 20 ~Identical Age 30 15 10 Percent of Age-Cohort with of Age-Cohort with Percent 5 Lifetime h/o Cannabis Dependence h/o Cannabis Lifetime 0 13 14 15 16 17 18 19 20 >20 Age of Onset of Cannabis Use

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

CHDS Prospecve Study: Cannabis Dependence in Prior 12 Months

Christchurch Health and Development Study (CHDS), Birth to Age 35. 35.0 691 cannabis users among 1,265 children born in 1977. John Horwood, Personal Communication (July 15, 2014) 30.0

Cumulative 25.0 Rate at:

20.0 Age 18 Age 21 15.0 Age 25 Age 30 10.0

Percent of Age-Cohort Percent ~3-5% remain 5.0 chronic cannabis with Cannabis Dependence Cannabis with users into their 30’s 0.0 13 14 15 16 17 18 19 20 >20 Age of Onset of Cannabis Use

6 College Trajectories

Caldeira et al, “Marijuana use trajectories during the post- college transition: Health outcomes in young adulthood” Drug and Alcohol Dependence (2012)

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Relaonship between Frequency & Amount

Burns et al, “Statistics on cannabis users skew perceptions of cannabis use” http:// www.frontiersin. org/

4. Structural changes

q CB1 receptors contribute to cell migration and differentiation, neurite outgrowth, axonal pathfinding and synaptogenesis

q Brain structure goes through explosive changes during the teen years, with myelination, synaptogenesis and then pruning

Gaffuri et al, “Type-1 Cannabinoid Receptor Signaling in Neuronal Development“ Pharmacology 2012;90:19–39 Giedd, “Structural magnetic resonance imaging of the adolescent brain,” Ann N Y Acad Sci, 2004

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Hippocampal Volume

0.0023

0.0022 Medina et al, “Abnormal cerebellar morphometry in 0.0021 absnent adolescent marijuana users.” Psychiatry Res. 2010 0.0020 May 30;182(2):152-9. Epub 2010 Apr 21.

0.0019

0.0018 Left Hippocampus / CraniumRatio / Hippocampus Left

0.0017 Control Alc MJ+Alc (n=16) (n=21) (n=26)

MJ & PFC Structure

Gender moderated affects of MJ

Medina et al, “Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects.” Addict Biol. 2009 Sep;14 (4):457-68. Epub 2009 Jul 24

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

MJ & Cerebellar Structure

controlled alcohol, gender, ethnicity, reading level

Medina et al, “Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry.” Neurotoxicol Teratol. 2007 Jan-Feb;29(1): 141-52. Epub 2006 Dec 12.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

5. Cognive Disturbances

Adolescents aer One Month Absnence

Krista Medina

Medina et al, “Neuropsychological funconing in adolescent marijuana users: subtle deficits detectable aer a month of absnence.” J Int Neuropsychol Soc. 2007 Sep;13(5):807-20.

Hanson et al, “Longitudinal study of cognion among adolescent marijuana users over three weeks of absnence.” Addict Behav. 2010 Nov;35(11):970-6. Epub 2010 Jun 13.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Execuve Funcons with Early-Onset MJ

Wisconsin Card Sort Stroop

4 20

-a c19 o= o 6 c-^? =t6 c c F g a c- o c '6 Ev c ,a ts1 o 16 o

15 Eariy-onset Late{nset Control Early'onset Lateonset Control group group gfoup group Sroup group

, E5trbAS 95%cmfidentr imeryais. ,.JIY3: 9516 cffifidffie inteffils

Execuve Funcons, Cont.

Frontal Assessment Battery Fontes, et al, “Cannabis use before age 15 and brz subsequent executive 6 functioning,” The British 6 Journal of Psychiatry Era (2011) 198, 442–447.

Early-onset Late-onset Control 8ro$p group group

Eror bars:95% confidence inteMls.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Educaonal Achievement

q Early use more damaging than later onset of use q Lower GPA’s, more negave atudes toward, and reduced sasfacon with school, increased absenteeism, expulsions, suspensions, dropouts and unemployment q Those who have smoked more than 100 mes:

q Rates of leaving school 5.8 mes higher

q Rates of entering college 3.3 mes lower

q Rates of college degree 4.5 me lower

Fergusson et al, “Cannabis and educaonal achievement.” Addicon. 2003 Dec;98(12):1681-92

Altered Risk Assessment Iowa Gambling Task

MJ users are under-influenced by loss magnitude and more influenced by gains q May result in inefficient strategies used to solve problems q i.e., Heavy MJ users fail to respond to the negave consequences and persist in reacng only to large immediate rewards on the Iowa Gambling Task

Wesley et al., “Poor decision-making by chronic marijuana users is associated with decreased funconal responsiveness to negave consequences,” Psychiatry Research: Neuroimaging 191 (2011) Bolla, et al., “Neural substrates of faulty decision-making in absnent marijuana users” NeuroImage 26 (2005)

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

6. Affect & Temperament Changes

Exncon of Condioned Fear

q SR141716A (cannabinoid antagonist) decreases exncon of fear potenated startle

q AM404 (inhibits FAAH) enhances exncon

Giovanni Marsicano q SR141716A blocks AM404 Italy Marsicano G, et.al., “The endogenous cannabinoid system controls exncon of aversive memories.” Nature. 2002 Aug 1;418(6897):530-4.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

MJ and Depression

q Past year cannabis dependence q 1 in 7 (14%) - affecve disorder (vs 6% in non-users) q 1 in 6 (17%) - anxiety (vs 5% in non-users) q But, there is a lack of support for a direct causal relaonship q Daily users were twice as likely to report an anxiety or mood disorder as abstainers

Degenhardt L, Hall W, LynskeyM. The relationship between cannabis use, depression and anxiety among Australian adults: Findings from the National Survey of Mental Health and Well-Being. Soc Psychiatry Psychiatric Epidem 2001; 36:219–227. Cheung et al., “Anxiety and Mood Disorders and Cannabis Use,” The American Journal of Drug and Alcohol Abuse, 36:118–122, 2010

Cannabis and Psychosis

q Cannabis use is associated with a dose dependent increase in schizophrenia, doubling the risk in heavy users and increasing relapse and non- adherence to treatment Zammit et al, “Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study,” BMJ, 2002 November 23; 325 (7374): 1199 Zammit et al, “Effects of cannabis use on outcomes of psychoc disorders: systemac review” Br J Psychiatry, Vol 193, 2008 q There is a strong associaon between use of cannabis and earlier age at first psychoc episode in male schizophrenics (2-6 years). Veen et al, “Cannabis Use and Age at Onset of Schizophrenia,” Am J Psychiatry 2004; 161:501-505 Castle and Murray, Ed. Marijuana and Madness, Cambridge Univ. Press, 2004 Di For et al, “Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users”. Schizophr Bull 2014 March 19

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

CB1 and Temperament Novelty & the Amygdala

q Uninhibited

q Low amygdala response to novelty q Inhibited

q High amygdala response to novelty

Schwartz, et al: “Inhibited and Uninhibited Infants “Grown Up”: Adult Amygdalar Response to Novelty,” Science, Vol 300, June 20, 2003

Temperament, Novelty, the Amygdala & eCBs

Baseline CB1 availability in the amygdala is inversely related to degree of novelty- seeking

• Low CB1 low amygdala response & high novelty seeking temperament

• High CB1 high amygdala response & low novelty seeking temperament

Van Leare, et al, “Relaonship of Type 1 Cannabinoid Receptor Availability in the Human Brain to Novelty-Seeking Temperament,” Arch Gen Psychiatry/Vol 66 (No. 2), Feb 2009

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Chronic Cannabis and CB1 Downregulaon q Chronic exposure to delta-9-THC (5 days) decreases the specific binding of CB1 receptors from ~20-60%, depending on the specific brain area measured with the basolateral nucleus of the amygdala reduced 24% aer 14 days

q 7.1% decrease in amygdala volume in chronic MJ users

Romero et al., “Time-Course of the Cannabinoid Receptor Down-Regulaon in the Adult Rat Brain Caused by Repeated Exposure toD9-Tetrahydrocannabinol,” SYNAPSE 30:298–308 (1998)

Yucel et al., “Regional Brain Abnormalies Associated With Long-term Heavy Cannabis Use,” Arch Gen Psychiatry/Vol 65 (No. 6), June 2008

Pharmacotherapy Approaches

Reduce Use - N-Acetylcysteine § Gray, et al,” A Double-Blind Randomized Controlled Trial of N- Acetylcysteine in Cannabis-Dependent Adolescents”Am J Psychiatry 2012; 169:805–812

Reduce Withdrawal – Gabapenn § Mason, et al,” A Proof-of-Concept Randomized Controlled Study of Gabapenn: Effects on Cannabis Use, Withdrawal and Execuve Funcon Deficits in Cannabis-Dependent Adults”, Neuropsychopharmacology (2012) 37, 1689–1698

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

NAC, 1200 mg BID

60 More than doubled {-tlacebo +NAc

C)a 50 .2- -q the odds of having =,v 40

2330 negave urines, )nl I compared with placebo, ruf ,t IJ 0- detectable within a week Baseline I Follow-up of treatment iniaon. Caveat Within a powerful psychosocial treatment plaorm

Gabapenn, 300/300/600 mg

§ Less marijuana use in cannabis dependence over 12 weeks § Aenuates withdrawal symptoms, including craving and disturbances in mood and sleep § Greater overall improvement in neurocognive execuve funconing, compared with placebo

Caveat Within a powerful psychosocial treatment platform

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

The Boom Line Message to Parents and Adolescents

q Delay is the wisest course q Non-Use is as Normal as Experimental Use q All Use = Risk q Risk is not Evenly Distributed, Increasing with • Heredity • Early Onset • Frequency/Amount q Addicon is Real q Quality of Life can be diminished even without developing addicon q Movaons for Inial Use Vs Connuing Use are always different

Do NOT even try to tell me that marijuana is just an herb.

Oregano, mint and basil are herbs – they do not downregulate receptor sites, are not addictive, do not blunt my affect, decrease cognitive efficiency, affect my ability to weigh losses and gains effectively or alter my temperament.

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Realies Challenge Current MJ Policy

q The primary Public Health goal - Liming access to adolescents (the populaon at highest risk) q De facto legalizaon already exists in CA q Adolescents have unlimited access to marijuana, but very limited access to treatment

Policy Implicaons, cont.

q Policies that rely primarily on enforcement have been tried – and failed q Prohibion for adults does not appear to be necessary to protect public health q The onus is on adults, who are primarily responsible for creang an “aracve nuisance” for youth, to reduce the harm caused by their behavior

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD

Would you support legalizaon of marijuana if profits were taxed to support treatment?

CSAM Member Survey 52.8% Yes 31.1% No 16% Undecided

Discussion

Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA