Cannabis Dependence
Conditions
Keywords
cannabis, marijuana, pharmacotherapy
Brief summary
Despite a benign public perception, marijuana use disorders represent a significant public health problem. The development of safe and effective pharmacotherapies for marijuana dependence is an important unmet public health need. Quetiapine, an effective atypical antipsychotic that acts by blocking serotonin type 2A, dopamine type 2, histamine type 1, and adrenergic receptors, is a promising treatment for substance use disorders. In animal models, quetiapine blocks the enhancement of reward by cocaine, which is likely due to its actions on both dopamine and non-dopamine neurotransmission. Clinical studies of quetiapine have shown benefit for the treatment of alcohol and cocaine use disorders. Conceptually, the clinically prominent effects of quetiapine, namely sedation, anxiolysis, mood stabilization and appetite stimulation, are a good match for the symptoms of marijuana withdrawal. Most importantly, an open-label dose-finding study of quetiapine for the treatment of marijuana dependence conducted by our research group determined that quetiapine was well-tolerated and associated with reductions in marijuana use indicating that it is a promising agent deserving of further study in marijuana-dependent outpatients. The proposed research project is a randomized double-blind placebo-controlled clinical trial to evaluate the efficacy of quetiapine for the treatment of marijuana dependence over a 12-week period. All participants will receive Medical Management, a medication adherence focused psychosocial intervention that facilitates compliance with study medication and other study procedures, promotes abstinence from marijuana and other substances, and encourages mutual-support group attendance. All participants will receive voucher incentives for compliance with study visit attendance, returning study medication bottles, and completing other study procedures, with the objective of achieving a highly compliant sample. The goal of this phase II clinical trial is to build on our promising open-label pilot study results and examine the efficacy of quetiapine on participants' marijuana consumption under placebo-controlled double-blind conditions using an abstinence-initiation model, where participants will be using marijuana regularly at study entry, reduce their use, and then achieve abstinence. The specific aims of the projects are to determine whether quetiapine is superior to placebo in 1) reducing marijuana use and 2) achieving abstinence.
Detailed description
In a 12-week randomized double-blind placebo-controlled clinical trial, we will evaluate the efficacy of quetiapine for the treatment of marijuana dependence in 150 outpatients. Participants will be randomly assigned to treatment under double-blind conditions with either a fixed dosing schedule of quetiapine or placebo. All participants will receive Medical Management, a medication adherence focused psychosocial intervention that facilitates compliance with study medication and other study procedures, and promotes abstinence from marijuana and other substances. All participants will receive progressive voucher incentives for compliance with study visit attendance and completing other study procedures, with the objective of achieving a highly compliant sample. The results of a dose-finding pilot study of quetiapine for the treatment of marijuana dependence (see Preliminary Studies) suggests that the ideal dosing for the proposed project is a single 300 mg dose every evening, achieved after a gradual three-week titration. Clinical experience with this medication for treatment of marijuana dependence indicates that a gradual upward titration of dose is advisable to maximize tolerability and that morning dosing was poorly tolerated. Quetiapine (immediate release formulation) will be administered in 25 and 100 mg capsules; placebo capsules will appear identical to the quetiapine capsules. Participants in both treatment arms will take the same number of pills on the same schedule. Study medication will be dispensed on a weekly basis starting with the baseline visit. Quetiapine will be titrated over a three-week period to the target dose of 300 mg or the maximum tolerated dose. The research psychiatrist will make dose reductions for tolerability if necessary.
Interventions
DRUGQuetiapine
Quetiapine pharmacotherapy for cannabis dependence
DRUGPlacebo
placebo capsules
Sponsors
National Institute on Drug Abuse (NIDA)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Meets DSM-IV-TR criteria for current marijuana dependence 2. Reports using marijuana an average of 5 days per week over the past 28 days 3. Between the ages of 18 and 60 4. Able to provide informed consent and comply with study procedures 5. Seeking treatment for cannabis dependence
Exclusion criteria
1. Lifetime DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder. 2. Current DSM-IV criteria for any other psychiatric disorder that may, according to investigator's judgment, require either pharmacological or non-pharmacological intervention over the course of the study. 3. Patients prescribed psychotropic medications. 4. History of allergic reaction, intolerance, or hypersensitivity to Quetiapine. 5. Pregnancy, lactation, or failure to use adequate contraceptive methods in female patients who are currently engaging in sexual activity with men. 6. Unstable medical conditions, such as poorly controlled hypertension which might make participation hazardous. 7. Diabetes (whether controlled or not), meeting criteria for metabolic syndrome as defined by the NCEP (any 3 of the following: a. obesity \[waist circumference \> 40 inches\], b. hyperglycemia \[fasting glucose \> 100 mg/dl or Rx\], c. dyslipidemia \[TG \> 150 mg/dl or Rx\], d. dyslipidemia \[HDL cholesterol; 40 mg/dl (male), 50 mg/dl (female) or Rx\], e. hypertension \[130 mmHg systolic or \> 85 mmHg diastolic or Rx\]. Participants with a BMI \> 35 will be excluded. 8. Current DSM-IV diagnosis of an alcohol or substance use disorder (abuse or dependence) other than marijuana or nicotine dependence. 9. Positive confirmed result on urine toxicology screen. 10. Are legally mandated to participate in a substance use disorder treatment program. 11. Increased risk for suicide. 12. QTc prolongation (screening electrocardiogram with Qtc \> 450 msec for men, QTc \> 470 msec for women) or history of QTc prolongation or using concomitant medications which prolong QTc interval.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | 12 weeks or length of participants involvement | The median daily dollar value of marijuana used averaged over a one-week period for each of the 12 weeks as recorded by the Timeline Followback method |
| Number of Participants Stratified by Marijuana Abstinence Days Per Week | 12 weeks or length of participation | The number of abstinent days per week over the 12 weeks of study as recorded by the Timeline Followback method. High Use group defined as 0-2 abstinent days per week, Medium Use Group as 3-5 abstinent days per week and Low Use Group as 6-7 abstinent days per week. |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomized to one of the treatment arms at time of enrollment
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo medication
Placebo: placebo capsules | 64 |
| Quetiapine Quetiapine treatment
Quetiapine: Quetiapine pharmacotherapy for cannabis dependence | 66 |
| Total | 130 |
Baseline characteristics
| Characteristic | Total | Quetiapine | Placebo |
|---|---|---|---|
| Age, Continuous | 32.9 years STANDARD_DEVIATION 9.1 | 32.7 years STANDARD_DEVIATION 9.5 | 33.1 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 17 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 98 Participants | 49 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Marijuana using days past 28 days | 26.6 days STANDARD_DEVIATION 2.3 | 26.4 days STANDARD_DEVIATION 2.5 | 26.8 days STANDARD_DEVIATION 2.1 |
| mood/anxiety disorder | 28 Participants | 14 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 56 Participants | 24 Participants | 32 Participants |
| Race (NIH/OMB) More than one race | 11 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) White | 43 Participants | 25 Participants | 18 Participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 14 Participants |
| Sex: Female, Male Male | 102 Participants | 52 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 66 |
| other Total, other adverse events | 34 / 64 | 46 / 66 |
| serious Total, serious adverse events | 0 / 64 | 0 / 66 |
Outcome results
Primary
Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study
The median daily dollar value of marijuana used averaged over a one-week period for each of the 12 weeks as recorded by the Timeline Followback method
Time frame: 12 weeks or length of participants involvement
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 2 | 10.00 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 7 | 3.70 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 4 | 6.43 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 8 | 2.86 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 1 | 14.00 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 9 | 6.43 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 5 | 6.43 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 10 | 5.35 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 11 | 3.21 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 3 | 7.14 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 12 | 1.00 dollars |
| Placebo | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 6 | 5.71 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 12 | 2.14 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 1 | 7.00 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 2 | 8.00 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 3 | 5.86 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 4 | 5.71 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 5 | 4.29 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 6 | 4.11 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 7 | 3.57 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 8 | 3.43 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 9 | 3.00 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 11 | 2.86 dollars |
| Quetiapine | Marijuana Use, Daily Dollar Averaged Over 7 Days During Each of 12 Weeks of Study | week 10 | 2.86 dollars |
Primary
Number of Participants Stratified by Marijuana Abstinence Days Per Week
The number of abstinent days per week over the 12 weeks of study as recorded by the Timeline Followback method. High Use group defined as 0-2 abstinent days per week, Medium Use Group as 3-5 abstinent days per week and Low Use Group as 6-7 abstinent days per week.
Time frame: 12 weeks or length of participation
Population: participants were included in the weekly analysis who were still active in the trial at each given week.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | medium use | 7 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | high use | 12 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | high use | 8 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | medium use | 9 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | low use | 40 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | low use | 17 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | medium use | 9 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | high use | 12 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | low use | 34 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | medium use | 9 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | low use | 23 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | low use | 17 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | medium use | 9 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | high use | 13 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | high use | 10 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | medium use | 7 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | high use | 9 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | low use | 18 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | medium use | 7 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | high use | 14 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | high use | 8 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | medium use | 5 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | low use | 22 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | low use | 17 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | medium use | 5 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | high use | 15 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | high use | 13 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | medium use | 5 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | high use | 5 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | low use | 16 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | medium use | 4 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | high use | 17 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | medium use | 3 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | low use | 28 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | low use | 14 Participants |
| Placebo | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | low use | 22 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | low use | 11 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | high use | 4 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | medium use | 9 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 1 | low use | 46 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | high use | 4 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | medium use | 7 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 2 | low use | 44 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | high use | 5 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | medium use | 14 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 3 | low use | 33 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | high use | 8 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | medium use | 15 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 4 | low use | 26 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | high use | 10 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | medium use | 16 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 5 | low use | 21 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | high use | 10 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | medium use | 13 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 6 | low use | 23 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | high use | 11 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | medium use | 15 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 7 | low use | 17 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | high use | 10 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | medium use | 16 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 8 | low use | 17 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | high use | 13 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | medium use | 15 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 9 | low use | 15 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | high use | 13 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | medium use | 13 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 10 | low use | 15 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | high use | 14 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | medium use | 12 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 11 | low use | 11 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | medium use | 11 Participants |
| Quetiapine | Number of Participants Stratified by Marijuana Abstinence Days Per Week | Week 12 | high use | 15 Participants |