Agonist Replacement Therapy for Agonist Replacement Therapy for Marijuana DependenceMarijuana Dependence

CDR Steven Sparenborg, Ph.D., Lian Hu, Ph.D.,CDR Steven Sparenborg, Ph.D., Lian Hu, Ph.D., CAPT Betty Tai, Ph.D.CAPT Betty Tai, Ph.D.

The Center for the Clinical Trials NetworkThe Center for the Clinical Trials NetworkNational Institute on Drug Abuse National Institute on Drug Abuse

National Institutes of Health National Institutes of Health Bethesda, MarylandBethesda, Maryland

Majority of users realize no significantly Majority of users realize no significantly deleterious effects. They quit on their own, some deleterious effects. They quit on their own, some with no withdrawal symptomswith no withdrawal symptoms

SAMHSA estimates that at least 8% of those who SAMHSA estimates that at least 8% of those who use at least once develop cannabis dependenceuse at least once develop cannabis dependence

Heavy, long-time users much less able to quitHeavy, long-time users much less able to quit They want out but cannot find the doorThey want out but cannot find the door 6-16% of drug treatment seekers state marijuana is 6-16% of drug treatment seekers state marijuana is

the drug they want help withthe drug they want help with

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The ProblemThe Problem

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Alan J. Budney, et al. 2007

THC content of marijuana today is many THC content of marijuana today is many times greater than past decadestimes greater than past decades

Skunk is a new herbal product with high Skunk is a new herbal product with high THC and low cannabidiolTHC and low cannabidiol

Early-onset of use leads to psychosesEarly-onset of use leads to psychoses Quitting cannabis is as hard as quitting Quitting cannabis is as hard as quitting

heroin, tobaccoheroin, tobacco

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An increasing ThreatAn increasing Threat

Symptoms and Effects of CannabisSymptoms and Effects of Cannabis

Respiratory problems (COPD, asthma, wheezing, Respiratory problems (COPD, asthma, wheezing, coughing)coughing)

Anxiety, Depression, PanicAnxiety, Depression, Panic Paranoia, DepersonalizationParanoia, Depersonalization Legal or employment problemsLegal or employment problems Difficulty focusing at school, on the job, in Difficulty focusing at school, on the job, in

relationshipsrelationships Can’t stop usingCan’t stop using

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Physiological Effects of Physiological Effects of CannabisCannabis

Increased appetiteIncreased appetite Increased heart rate, decreased blood pressureIncreased heart rate, decreased blood pressure Dry mouthDry mouth Impaired psychomotor coordinationImpaired psychomotor coordination SedationSedation Euphoria - mellowEuphoria - mellow

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Psychological Effects of Cannabis UsePsychological Effects of Cannabis Use

Sense of euphoria and relaxationSense of euphoria and relaxation Perceptual and time distortionsPerceptual and time distortions Intensification of sensory experiencesIntensification of sensory experiences Feelings of greater emotional and physical Feelings of greater emotional and physical

sensitivitysensitivity Impaired cognitive activities such as: attention, Impaired cognitive activities such as: attention,

ST memory, concentration, reaction time, ST memory, concentration, reaction time, information processinginformation processing

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Alan J. Budney et al. 2008

Psychotherapy of Cannabis DependencePsychotherapy of Cannabis Dependence

Aversion TherapyAversion Therapy Relapse Prevention/Social SupportRelapse Prevention/Social Support Motivational EnhancementMotivational Enhancement Cognitive Behavioral TherapyCognitive Behavioral Therapy Contingency ManagementContingency Management

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Source: Budney et al. 2006

Pharmacotherapy of Cannabis DependencePharmacotherapy of Cannabis Dependence

Dozens of types of cannabinoids in cannabisDozens of types of cannabinoids in cannabis ∆∆9-tetrahydrocannabinol (THC) is the 9-tetrahydrocannabinol (THC) is the

cannabinoid of most interestcannabinoid of most interest THC is primary psychoactive component THC is primary psychoactive component CB1 (central) and CB2 (peripheral) receptorsCB1 (central) and CB2 (peripheral) receptors Anandamide and 2-AG are the naturally Anandamide and 2-AG are the naturally

occurring ligandsoccurring ligands

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Pharmacotherapy of Cannabis DependencePharmacotherapy of Cannabis Dependence

Failed attempts to reduce cannabis use Failed attempts to reduce cannabis use byby

fluoxetinefluoxetine bupropionbupropion nefazodonenefazodone divalproexdivalproex

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Agonist Pharmacotherapy of Cannabis Agonist Pharmacotherapy of Cannabis DependenceDependence

Methadone and buprenorphine for opiate Methadone and buprenorphine for opiate addictionaddiction

Nicotine for tobacco addictionNicotine for tobacco addiction Nothing available for stimulants, yetNothing available for stimulants, yet Could an agonist (at CB1) work for Could an agonist (at CB1) work for

cannabis?cannabis?

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CB1 AgonistsCB1 Agonists

MARINOL® (dronabinol)(dronabinol) Synthetically produced THCSynthetically produced THC Capsules for oral administrationCapsules for oral administration From Unimed Pharmaceuticals (Solvay)From Unimed Pharmaceuticals (Solvay) Indicated for the treatment of anorexia associated Indicated for the treatment of anorexia associated

with weight loss in patients with AIDS, and nausea with weight loss in patients with AIDS, and nausea and vomiting in cancer patients and vomiting in cancer patients

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CESAMETCESAMET®® (nabilone) (nabilone) Synthetic cannabinoid almost identical to THCSynthetic cannabinoid almost identical to THC

Capsules for oral administrationCapsules for oral administration Marketed by Valeant Pharmaceuticals, Inc. of Marketed by Valeant Pharmaceuticals, Inc. of

CaliforniaCalifornia Indicated for the treatment of nausea and vomiting Indicated for the treatment of nausea and vomiting

associated with cancer chemotherapyassociated with cancer chemotherapy 15

SATIVEXSATIVEX®® Extract of purposefully bred marijuana plantsExtract of purposefully bred marijuana plants Manufactured and marketed by GW Pharma in UKManufactured and marketed by GW Pharma in UK Metered dose oro-mucosal sprayMetered dose oro-mucosal spray Each 100µL spray contains 2.7mg THC and 2.5mg Each 100µL spray contains 2.7mg THC and 2.5mg

cannabidiol (CBD)cannabidiol (CBD)

Approved in Canada for relief from neuropathic Approved in Canada for relief from neuropathic pain from MS and pain from cancerpain from MS and pain from cancer

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Clinical Trial of MarinolClinical Trial of Marinol®®

Randomized, double-blind, placebo controlledRandomized, double-blind, placebo controlled NY State Psychiatric InstituteNY State Psychiatric Institute 200 Tx-seeking patients using marijuana at 200 Tx-seeking patients using marijuana at

least 5 days/wkleast 5 days/wk Relatively high dose of dronabinolRelatively high dose of dronabinol 12 weeks of Tx with FU at 6 months12 weeks of Tx with FU at 6 months Self report and urine testing for cannabinoidsSelf report and urine testing for cannabinoids

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Clinical Trial of MarinolClinical Trial of Marinol®®

Retention in the study was increased by Retention in the study was increased by dronabinoldronabinol

Abstinence not improved by SR or urineAbstinence not improved by SR or urine Wanted to cut down use of cannabis, not quitWanted to cut down use of cannabis, not quit Wanted problems to go awayWanted problems to go away

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What next? Cannabidiol?What next? Cannabidiol?

Rats trained to self-administer heroinRats trained to self-administer heroin Heroin cues normally reinstate drug seeking Heroin cues normally reinstate drug seeking

and self-administrationand self-administration Cannabidiol blocked addicted rats from Cannabidiol blocked addicted rats from

seeking heroinseeking heroin As in rats, marijuana with high CBD content As in rats, marijuana with high CBD content

reduced attention to cues in human smokersreduced attention to cues in human smokers Compared CBD:THC ratios of 1:2 vs. 1:100Compared CBD:THC ratios of 1:2 vs. 1:100

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Celia JA Morgan et al. 2010

What Next? Alpha Antagonists?What Next? Alpha Antagonists?

Combination Tx with THC and lofexidineCombination Tx with THC and lofexidine Human residential lab studyHuman residential lab study 8 males, non-Tx-seeking, 12 joints/day8 males, non-Tx-seeking, 12 joints/day The combination was superior to single The combination was superior to single

drugs in most endpointsdrugs in most endpoints Clinical trial ongoing now of combination Clinical trial ongoing now of combination

Tx - Marinol and lofexidineTx - Marinol and lofexidine

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Margaret Haney et al. 2008

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Margaret Haney et al. 2008

Questions to Ask UsersQuestions to Ask Users

How many joints do you smoke a day?How many joints do you smoke a day? How many days a week do you smoke?How many days a week do you smoke? Do you mix cannabis use with tobacco?Do you mix cannabis use with tobacco? Do you smoke cigarettes?Do you smoke cigarettes? Does cannabis use cause you problems, such asDoes cannabis use cause you problems, such as Anxiety, cough, interference with sleep or appetite?Anxiety, cough, interference with sleep or appetite? Does smoking interfere with your studying or Does smoking interfere with your studying or

working?working? Have you thought about stopping or cutting down?Have you thought about stopping or cutting down? Have you tried to stop? How did you feel?Have you tried to stop? How did you feel?

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At a minimum….At a minimum…. Advise gradual reduction in use before cessationAdvise gradual reduction in use before cessation Advise to delay first daily use until later in the Advise to delay first daily use until later in the

dayday Advise good sleep hygiene, no caffeineAdvise good sleep hygiene, no caffeine Suggest relaxation techniques, distraction, Suggest relaxation techniques, distraction,

progressive muscular relaxationprogressive muscular relaxation Prep the user and family/friends on the nature, Prep the user and family/friends on the nature,

duration, and severity of withdrawal symptomsduration, and severity of withdrawal symptoms

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At a minimum….cont.At a minimum….cont.

Avoid the cues and triggers of useAvoid the cues and triggers of use If irritability and restlessness are marked, If irritability and restlessness are marked,

consider prescribing very low dose diazepam for consider prescribing very low dose diazepam for a few daysa few days

Sedatives and analgesics might be necessary, Sedatives and analgesics might be necessary, temporarilytemporarily

If quitting tobacco use in conjunction with If quitting tobacco use in conjunction with quitting marijuana, use smoking cessation quitting marijuana, use smoking cessation products, but bupropion use must start at least products, but bupropion use must start at least one week before initiation of marijuana one week before initiation of marijuana abstinenceabstinence

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For copy of this slide setFor copy of this slide set

sparenborgs@nida.nih.gov

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