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Agonist Replacement Therapy for Marijuana Dependence CDR Steven Sparenborg, Ph.D., Lian Hu, Ph.D., CAPT Betty Tai, Ph.D. CAPT Betty Tai, Ph.D. The Center.

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Presentation on theme: "Agonist Replacement Therapy for Marijuana Dependence CDR Steven Sparenborg, Ph.D., Lian Hu, Ph.D., CAPT Betty Tai, Ph.D. CAPT Betty Tai, Ph.D. The Center."— Presentation transcript:

1 Agonist Replacement Therapy for Marijuana Dependence 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 Network National Institute on Drug Abuse National Institutes of Health Bethesda, Maryland

2 Majority of users realize no significantly deleterious effects. They quit on their own, some with no withdrawal symptoms 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 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 Heavy, long-time users much less able to quit They want out but cannot find the door They want out but cannot find the door 6-16% of drug treatment seekers state marijuana is the drug they want help with 6-16% of drug treatment seekers state marijuana is the drug they want help with 2 The Problem

3 3 Alan J. Budney, et al. 2007

4 n THC content of marijuana today is many times greater than past decades n Skunk is a new herbal product with high THC and low cannabidiol n Early-onset of use leads to psychoses n Quitting cannabis is as hard as quitting heroin, tobacco 4 An increasing Threat

5 Symptoms and Effects of Cannabis Respiratory problems (COPD, asthma, wheezing, coughing) Respiratory problems (COPD, asthma, wheezing, coughing) Anxiety, Depression, Panic Anxiety, Depression, Panic Paranoia, Depersonalization Paranoia, Depersonalization Legal or employment problems Legal or employment problems Difficulty focusing at school, on the job, in relationships Difficulty focusing at school, on the job, in relationships Cant stop using Cant stop using 5

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

7 Psychological Effects of Cannabis Use Sense of euphoria and relaxation Sense of euphoria and relaxation Perceptual and time distortions Perceptual and time distortions Intensification of sensory experiences Intensification of sensory experiences Feelings of greater emotional and physical sensitivity Feelings of greater emotional and physical sensitivity Impaired cognitive activities such as: attention, ST memory, concentration, reaction time, information processing Impaired cognitive activities such as: attention, ST memory, concentration, reaction time, information processing 7

8 8 Alan J. Budney et al. 2008

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

10 10 Source: Budney et al. 2006

11 Pharmacotherapy of Cannabis Dependence Dozens of types of cannabinoids in cannabis Dozens of types of cannabinoids in cannabis 9-tetrahydrocannabinol (THC) is the cannabinoid of most interest 9-tetrahydrocannabinol (THC) is the cannabinoid of most interest THC is primary psychoactive component THC is primary psychoactive component CB1 (central) and CB2 (peripheral) receptors CB1 (central) and CB2 (peripheral) receptors Anandamide and 2-AG are the naturally occurring ligands Anandamide and 2-AG are the naturally occurring ligands 11

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

13 Agonist Pharmacotherapy of Cannabis Dependence Methadone and buprenorphine for opiate addiction Methadone and buprenorphine for opiate addiction Nicotine for tobacco addiction Nicotine for tobacco addiction Nothing available for stimulants, yet Nothing available for stimulants, yet Could an agonist (at CB1) work for cannabis? Could an agonist (at CB1) work for cannabis? 13

14 CB1 Agonists (dronabinol) MARINOL ® (dronabinol) Synthetically produced THC Synthetically produced THC Capsules for oral administration Capsules for oral administration From Unimed Pharmaceuticals (Solvay) 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 Indicated for the treatment of anorexia associated with weight loss in patients with AIDS, and nausea and vomiting in cancer patients 14

15 CESAMET ® (nabilone) n Synthetic cannabinoid almost identical to THC n Capsules for oral administration n Marketed by Valeant Pharmaceuticals, Inc. of California n Indicated for the treatment of nausea and vomiting associated with cancer chemotherapy 15

16 SATIVEX ® n Extract of purposefully bred marijuana plants n Manufactured and marketed by GW Pharma in UK n Metered dose oro-mucosal spray n Each 100µL spray contains 2.7mg THC and 2.5mg cannabidiol (CBD) n Approved in Canada for relief from neuropathic pain from MS and pain from cancer 16

17 Clinical Trial of Marinol ® n Randomized, double-blind, placebo controlled n NY State Psychiatric Institute n 200 Tx-seeking patients using marijuana at least 5 days/wk n Relatively high dose of dronabinol n 12 weeks of Tx with FU at 6 months n Self report and urine testing for cannabinoids 17

18 Clinical Trial of Marinol ® n Retention in the study was increased by dronabinol n Abstinence not improved by SR or urine n Wanted to cut down use of cannabis, not quit n Wanted problems to go away 18

19 What next? Cannabidiol? n Rats trained to self-administer heroin n Heroin cues normally reinstate drug seeking and self-administration n Cannabidiol blocked addicted rats from seeking heroin n As in rats, marijuana with high CBD content reduced attention to cues in human smokers n Compared CBD:THC ratios of 1:2 vs. 1:100 19

20 20 Celia JA Morgan et al. 2010

21 What Next? Alpha Antagonists? n Combination Tx with THC and lofexidine n Human residential lab study n 8 males, non-Tx-seeking, 12 joints/day n The combination was superior to single drugs in most endpoints n Clinical trial ongoing now of combination Tx - Marinol and lofexidine 21

22 22 Margaret Haney et al. 2008

23 23 Margaret Haney et al. 2008

24 Questions to Ask Users n How many joints do you smoke a day? n How many days a week do you smoke? n Do you mix cannabis use with tobacco? n Do you smoke cigarettes? n Does cannabis use cause you problems, such as n Anxiety, cough, interference with sleep or appetite? n Does smoking interfere with your studying or working? n Have you thought about stopping or cutting down? n Have you tried to stop? How did you feel? 24

25 At a minimum…. n Advise gradual reduction in use before cessation n Advise to delay first daily use until later in the day n Advise good sleep hygiene, no caffeine n Suggest relaxation techniques, distraction, progressive muscular relaxation n Prep the user and family/friends on the nature, duration, and severity of withdrawal symptoms 25

26 At a minimum….cont. n Avoid the cues and triggers of use n If irritability and restlessness are marked, consider prescribing very low dose diazepam for a few days n Sedatives and analgesics might be necessary, temporarily n 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 26

27 For copy of this slide set 27


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