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Cermak Cannabis.Pdf 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, EDucaLon anD PrevenLon 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 QuesLon 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 evaluaLons experienceD −0.38 StanDarD DeviaLons = 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. CumulaLve 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 funcLoning •# Execuve Funconing •# Processing Speed •# Memory •# Perceptual Reasoning •# Verbal Comprehension Informants reported observing significantly more aen'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 AffecLve SLmulus 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 informaon differently in the amygdala from those who do not smoke, even when s3muli 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 DemysLfieD 1. How does marijuana affect the brain (and the mind)? 2. Why does regular use of marijuana leaD to cognive and affecLve 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 NeurotransmiBers/ 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 HowleB Miles Herkenham 1990 Radioac've 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! DistribuLon of CB1 Receptors q# Hippocampus – Memory and Learning q# AmygDala – Novelty, Emo'on, Appe'tes q# Basal Ganglia – MotorCerebellum – Real Time Coordinaon, Selec've ABen'on 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 SynapLc 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 negaLve 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 RamificaLons 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% aoer 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# 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! MulLple Lines of EviDence for AdDicLon 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
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