1. 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

2. 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

3. Alan J. Budney, et al. 2007

4. 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

5. 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

6. Physiological Effects of Cannabis
Increased appetite
Increased heart rate, decreased blood pressure
Dry mouth
Impaired psychomotor coordination
Sedation
Euphoria - mellow

7. Psychological Effects of Cannabis Use
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

8. Alan J. Budney et al. 2008

9. Psychotherapy of Cannabis Dependence
Aversion Therapy
Relapse Prevention/Social Support
Motivational Enhancement
Cognitive Behavioral Therapy
Contingency Management

10. Source: Budney et al. 2006

11. 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

12. Pharmacotherapy of Cannabis Dependence
Failed attempts to reduce cannabis use by
fluoxetine
bupropion
nefazodone
divalproex

13. 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?

14. CB1 Agonists 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

15. CESAMET® (nabilone) 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 associated with cancer chemotherapy

16. 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)
Approved in Canada for relief from neuropathic pain from MS and pain from cancer

17. 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

18. 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

19. What next? Cannabidiol? 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

20. Celia JA Morgan et al. 2010

21. 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

22. Margaret Haney et al. 2008

23. Margaret Haney et al. 2008

24. Questions to Ask Users 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?

25. 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

26. At a minimum….cont. 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

27. For copy of this slide set