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Agonist Replacement Therapy for
Marijuana Dependence
CDR Steven Sparenborg, Ph.D., Lian Hu, Ph.D.,
CAPT Betty Tai, Ph.D.
The Center for the Clinical Trials Network
National Institute on Drug Abuse
National Institutes of Health
Bethesda, Maryland
The Problem
 Majority of users realize no significantly
deleterious effects. They quit on their own, some
with no withdrawal symptoms
 SAMHSA estimates that at least 8% of those who
use at least once develop cannabis dependence
 Heavy, long-time users much less able to quit
 They want out but cannot find the door
 6-16% of drug treatment seekers state marijuana is
the drug they want help with
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Alan J. Budney, et al. 2007
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An increasing Threat
THC content of marijuana today is many
times greater than past decades
 Skunk is a new herbal product with high
THC and low cannabidiol
 Early-onset of use leads to psychoses
 Quitting cannabis is as hard as quitting
heroin, tobacco
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Symptoms and Effects of Cannabis
 Respiratory problems (COPD, asthma, wheezing,
coughing)
 Anxiety, Depression, Panic
 Paranoia, Depersonalization
 Legal or employment problems
 Difficulty focusing at school, on the job, in
relationships
 Can’t stop using
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Physiological Effects of Cannabis
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Increased appetite
Increased heart rate, decreased blood pressure
Dry mouth
Impaired psychomotor coordination
Sedation
Euphoria - mellow
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Psychological Effects of Cannabis Use
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Sense of euphoria and relaxation
Perceptual and time distortions
Intensification of sensory experiences
Feelings of greater emotional and physical
sensitivity
 Impaired cognitive activities such as: attention,
ST memory, concentration, reaction time,
information processing
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Alan J. Budney et al. 2008
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Psychotherapy of Cannabis Dependence
 Aversion Therapy
 Relapse Prevention/Social Support
 Motivational Enhancement
 Cognitive Behavioral Therapy
 Contingency Management
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Source: Budney et al. 2006
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Pharmacotherapy of Cannabis Dependence
 Dozens of types of cannabinoids in cannabis
 ∆9-tetrahydrocannabinol (THC) is the
cannabinoid of most interest
 THC is primary psychoactive component
 CB1 (central) and CB2 (peripheral) receptors
 Anandamide and 2-AG are the naturally
occurring ligands
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Pharmacotherapy of Cannabis Dependence
Failed attempts to reduce cannabis use
by
 fluoxetine
 bupropion
 nefazodone
 divalproex
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Agonist Pharmacotherapy of Cannabis
Dependence
 Methadone and buprenorphine for opiate
addiction
 Nicotine for tobacco addiction
 Nothing available for stimulants, yet
 Could an agonist (at CB1) work for
cannabis?
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CB1 Agonists
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MARINOL® (dronabinol)
Synthetically produced THC
Capsules for oral administration
From Unimed Pharmaceuticals (Solvay)
Indicated for the treatment of anorexia associated
with weight loss in patients with AIDS, and nausea
and vomiting in cancer patients
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CESAMET® (nabilone)
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Synthetic cannabinoid almost identical to THC
Capsules for oral administration
 Marketed by Valeant Pharmaceuticals, Inc. of
California
 Indicated for the treatment of nausea and vomiting
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associated with cancer chemotherapy
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SATIVEX®
Extract of purposefully bred marijuana plants
 Manufactured and marketed by GW Pharma in UK
 Metered dose oro-mucosal spray
 Each 100µL spray contains 2.7mg THC and 2.5mg
cannabidiol (CBD)
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Approved in Canada for relief from neuropathic pain
from MS and pain from cancer
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Clinical Trial of Marinol®
Randomized, double-blind, placebo controlled
 NY State Psychiatric Institute
 200 Tx-seeking patients using marijuana at
least 5 days/wk
 Relatively high dose of dronabinol
 12 weeks of Tx with FU at 6 months
 Self report and urine testing for cannabinoids
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Clinical Trial of Marinol®
Retention in the study was increased by
dronabinol
 Abstinence not improved by SR or urine
 Wanted to cut down use of cannabis, not quit
 Wanted problems to go away
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What next? Cannabidiol?
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Rats trained to self-administer heroin
Heroin cues normally reinstate drug seeking
and self-administration
Cannabidiol blocked addicted rats from
seeking heroin
As in rats, marijuana with high CBD content
reduced attention to cues in human smokers
Compared CBD:THC ratios of 1:2 vs. 1:100
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Celia JA Morgan et al. 2010
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What Next? Alpha Antagonists?
Combination Tx with THC and lofexidine
 Human residential lab study
 8 males, non-Tx-seeking, 12 joints/day
 The combination was superior to single
drugs in most endpoints
 Clinical trial ongoing now of combination
Tx - Marinol and lofexidine
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Margaret Haney et al. 2008
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Margaret Haney et al. 2008
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Questions to Ask Users
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How many joints do you smoke a day?
How many days a week do you smoke?
Do you mix cannabis use with tobacco?
Do you smoke cigarettes?
Does cannabis use cause you problems, such as
Anxiety, cough, interference with sleep or appetite?
Does smoking interfere with your studying or
working?
Have you thought about stopping or cutting down?
Have you tried to stop? How did you feel?
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At a minimum….
Advise gradual reduction in use before cessation
 Advise to delay first daily use until later in the
day
 Advise good sleep hygiene, no caffeine
 Suggest relaxation techniques, distraction,
progressive muscular relaxation
 Prep the user and family/friends on the nature,
duration, and severity of withdrawal symptoms
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At a minimum….cont.
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Avoid the cues and triggers of use
If irritability and restlessness are marked,
consider prescribing very low dose diazepam for
a few days
Sedatives and analgesics might be necessary,
temporarily
If quitting tobacco use in conjunction with
quitting marijuana, use smoking cessation
products, but bupropion use must start at least
one week before initiation of marijuana
abstinence
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For copy of this slide set
[email protected]
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