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, Educa on and Preven on 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 Sensi ve 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 Ques on
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
Objec ves
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 tes ng at age 13 y.o. (before ini a on of cannabis use) and at age 38 y.o. q Cannabis use evalua on 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 evalua ons experienced −0.38 Standard Devia ons = 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.
Cumula ve 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 func oning • Execu ve Func oning • Processing Speed • Memory • Perceptual Reasoning • Verbal Comprehension
Informants reported observing significantly more a en on and memory problems among those with more persistent cannabis dependence
2. Masked Faces Paradigm
Gruber et al, “Altered affec ve 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 Affec ve S mulus
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 ac vity during masked affec ve s muli 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 emo onal informa on differently in the amygdala from those who do not smoke, even when s muli 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 Demys fied
1. How does marijuana affect the brain (and the mind)?
2. Why does regular use of marijuana lead to cogni ve and affec ve deficits?
The magic is in the brain, not in the herb
Summary of Cannabis Basic Science
Retracing the Endorphin Story
q Start with Psychoac ve Plants (Poppy/ Cannabis) q Extract Botanical Essence (Opiates/THC) q Label Ac ve Molecule to Reveal Receptor Sites q Discover Naturally Occurring Ligand (Endorphin Neurotransmi ers/ 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. “Determina on and characteriza on of a cannabinoid receptor in rat brain”, Mol Pharmacol, 1988, Vol 34 (5), pp 605-13
Allyn Howle
Miles Herkenham 1990
Radioac ve labeled cannabinoid used to begin localizing CB1 receptor in the brain
Miles Herkenham, et al, “Cannabinoid receptor localiza on 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
Distribu on of CB1 Receptors
q Hippocampus – Memory and Learning q Amygdala – Novelty, Emo on, Appe tes q Basal Ganglia – MotorCerebellum – Real Time Coordina on, Selec ve A en on and Time Sense q Nucleus Accumbens - Reward Mechanism (Addic on) q Cortex (Anterior > Posterior) – Frontal Lobe Execu ve Func ons
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” Neurotransmi ers
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 Synap c Vesicles – but rather produced from cellular membranes as needed
Endocannabinoids as Pre-Synap c 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 nega ve feedback on demand in a synapse-specific manner q Brain can synthesize and release enough ECBs to serve as a synap c circuit breaker q ECBs are tonic neuromodulators, keeping neuronal ac vity in balance, neither over- or under-ac ve
Katona & Freund, “Endocannabinoid signaling as a synaptic circuit breaker in neurological dise Nature Medicine, Vol 14 | Number 9 | Sept 2008
Ramifica ons
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 Downregula on (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% a er 14 days
Downregula on 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-Regula on in the Adult Rat Brain Caused by Repeated Exposure to D9-Tetrahydrocannabinol “Synapse 30:298–308 (1998)
CB1 Downregula on (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 Preoccupa on q Con nued Use in the Face of Serious Adverse Consequences q Cogni ve Distor ons/Denial
Addiction Medicine: Review Course / September 3-6, 2014 / Anaheim, CA Cannabis – Biology to Policy ! Timmen Cermak, MD
Mul ple Lines of Evidence for Addic on
q Elevated Dopamine in Reward Center q Animal Models & Cannabinoid Blockers q Clinical Reports of Withdrawal q Epidemiology 9% - with ini al 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 addic on
q NA plas city in response to endocannabinoid induced dopamine increase
q Infusion of cannabinoid blocker leads to withdrawal symptoms a er 8 days of THC administra on
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 cessa on 1. Irritability, anger, or increased aggression 2. Nervousness or anxiety 3. Sleep difficulty (insomnia) 4. Decreased appe te or weight loss 5. Restlessness 6. Depressed mood 7. At least 1 physical symptom causing significant discomfort (stomach pain, shakiness/tremors, swea ng, 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 a emp ng to quit complain of withdrawal and indicate it makes qui ng difficult § Cannabis users report using cannabis (and other substances) to relieve Withdrawal § Significant Others observe withdrawal symptoms that disrupt daily func oning § 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
Compara ve 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 Prospec ve Study: Cannabis Dependence in Life me
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 Prospec ve 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
Rela onship 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 abs nent 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. Cogni ve Disturbances
Adolescents a er One Month Abs nence
Krista Medina
Medina et al, “Neuropsychological func oning in adolescent marijuana users: subtle deficits detectable a er a month of abs nence.” J Int Neuropsychol Soc. 2007 Sep;13(5):807-20.
Hanson et al, “Longitudinal study of cogni on among adolescent marijuana users over three weeks of abs nence.” 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
Execu ve Func ons 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
Execu ve Func ons, 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
Educa onal Achievement
q Early use more damaging than later onset of use q Lower GPA’s, more nega ve a tudes toward, and reduced sa sfac on 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 educa onal achievement.” Addic on. 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 nega ve consequences and persist in reac ng only to large immediate rewards on the Iowa Gambling Task
Wesley et al., “Poor decision-making by chronic marijuana users is associated with decreased func onal responsiveness to nega ve consequences,” Psychiatry Research: Neuroimaging 191 (2011) Bolla, et al., “Neural substrates of faulty decision-making in abs nent 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
Ex nc on of Condi oned Fear
q SR141716A (cannabinoid antagonist) decreases ex nc on of fear poten ated startle
q AM404 (inhibits FAAH) enhances ex nc on
Giovanni Marsicano q SR141716A blocks AM404 Italy Marsicano G, et.al., “The endogenous cannabinoid system controls ex nc on 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%) - affec ve 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 rela onship 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 psycho c disorders: systema c review” Br J Psychiatry, Vol 193, 2008 q There is a strong associa on between use of cannabis and earlier age at first psycho c 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, “Rela onship 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 Downregula on 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% a er 14 days
q 7.1% decrease in amygdala volume in chronic MJ users
Romero et al., “Time-Course of the Cannabinoid Receptor Down-Regula on in the Adult Rat Brain Caused by Repeated Exposure toD9-Tetrahydrocannabinol,” SYNAPSE 30:298–308 (1998)
Yucel et al., “Regional Brain Abnormali es 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 – Gabapen n § Mason, et al,” A Proof-of-Concept Randomized Controlled Study of Gabapen n: Effects on Cannabis Use, Withdrawal and Execu ve Func on 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 nega ve urines, )nl I compared with placebo, ruf ,t IJ 0- detectable within a week Baseline I Follow-up of treatment ini a on. Caveat Within a powerful psychosocial treatment pla orm
Gabapen n, 300/300/600 mg
§ Less marijuana use in cannabis dependence over 12 weeks § A enuates withdrawal symptoms, including craving and disturbances in mood and sleep § Greater overall improvement in neurocogni ve execu ve func oning, 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 Bo om 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 Addic on is Real q Quality of Life can be diminished even without developing addic on q Mo va ons for Ini al Use Vs Con nuing 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
Reali es Challenge Current MJ Policy
q The primary Public Health goal - Limi ng access to adolescents (the popula on at highest risk) q De facto legaliza on already exists in CA q Adolescents have unlimited access to marijuana, but very limited access to treatment
Policy Implica ons, cont.
q Policies that rely primarily on enforcement have been tried – and failed q Prohibi on for adults does not appear to be necessary to protect public health q The onus is on adults, who are primarily responsible for crea ng an “a rac ve 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 legaliza on 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