Cannabis Dependence
Conditions
Brief summary
Cannabis dependence is associated with changes in the brain's cannabinoid system. When cannabis dependent individuals try to quit using cannabis, some of them experience problems that make it difficult for them to achieve and maintain abstinence. Therefore, reducing the problems related to quitting cannabis may facilitate abstinence. One way to do this is by harnessing the brain's capacity to make its own cannabis-like substances - endocannabinoids. One of the main endocannabinoids is anandamide. The study is based on the hypothesis that the problems related to quitting cannabis use will be reduced by increasing the brain levels of anandamide. Furthermore, by reducing the problems related to quitting cannabis, people will be less likely to relapse. Brain anandamide levels will be increased by blocking the breakdown of anandamide using a fatty acid amide hydrolase inhibitor (FAAH-I). The effects of a novel FAAH-I cannabis withdrawal and relapse in cannabis dependent subjects will be studied in a double-blind, randomized, controlled, proof-of-concept study. Cannabis-dependent subjects will receive placebo or the FAAH-inhibitor PF-04457845 in a 2:1 randomization. The trial consists of a 1 week inpatient stay to achieve abstinence, a 3 week outpatient treatment phase. Cannabis withdrawal will be measured during the inpatient phase. Cannabis use and urinary THC-COOH levels will be measured during the entire study. The treatment phase will be followed by a safety follow up phase of 8 weeks.
Interventions
DRUGPF-04457845
Study medication will be administered at 4mg by mouth daily for four weeks.
DRUGPlacebo
Sugar pill
Sponsors
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Male 2. Ages 18-55 (inclusive) 3. Cannabis Dependence
Exclusion criteria
1. Allergies or intolerance to FAAH-Inhibitors 2. Current significant medical or other comorbidities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Marijuana Withdrawal Checklist (MWC) | The MWC was administered on Day 0, Day 1, Day 2, Day 3, and Day 4 (during the inpatient phase when withdrawal peaks) to assess change from baseline (Day 0). The scores from each time point and subject were calculated to report the mean score for each arm. | 32-item checklist evaluating potential symptoms of cannabis withdrawal, lower values reflect lesser severity of withdrawal symptoms (lower scores represent a better outcome). Min: 0 Max: 96 |
| Change in Self Reported Cannabis Use at the End of 4 Weeks | Administered weekly for 4 weeks to assess change from baseline (Day 0). The scores from each time point and subject were calculated to report the mean score for each arm. | Subject quantifies and reports frequency of cannabis use prior to study participation and during the 4 week period. Lower scores reflect less cannabis usage, while higher scores reflect more frequent usage. Min: 0 Max: undeterminable, varies per patient and their usage. |
| Change in THC-COOH Quantification at the End of 4 Weeks | Samples obtained weekly for 4 weeks to assess change from baseline (Day 0). The results from each time point and subject were calculated to report the mean score for each arm. | Subjects provide urine samples to quantify levels of THC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Polysomnography | Polysomnography was collected two nights prior to baseline visit, for three nights during study treatment and two nights after four weeks of study treatment. A mean was calculated to assess change from baseline (Day 0). | Polysomnography (PSG) is a comprehensive reading of biophysiological changes that occur during sleep, including identification of sleep stage. A mean and standard deviation of their data points during sleep stages were calculated to determine change from baseline to the end of study treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Feeling States | Administered on Day 0, Day 1, Day 2, Day 3, and Day 4 (Once pre-treatment and during the inpatient phase 'acute abstinence') to assess change from baseline (Day 0) | Visual analog scale for feeling states (depression, anxiety, irritability) |
| Plasma Endocannabinoid Levels | Samples obtained at the following study visits: Day -1, Day 0, Day 2, Day 4, Week 2, Week 3, Week 4 to assess change from baseline (Day 0) | Measurement of circulating plasma Anandamide |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-04457845 (4mg by Mouth Daily for 4 Weeks) 2/3 of subjects will be randomized to fatty acid amide hydrolase (FAAH) inhibitor 4mg
PF-04457845: Study medication will be administered at 4mg by mouth daily for four weeks. | 46 |
| Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) 1/3 of subjects will be randomized to placebo
Placebo: Sugar pill | 24 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 3 |
Baseline characteristics
| Characteristic | PF-04457845 (4mg by Mouth Daily for 4 Weeks) | Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 24 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 20 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 12 Participants | 36 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 9 Participants | 27 Participants |
| Region of Enrollment United States | 46 Participants | 24 Participants | 70 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 24 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 24 |
| other Total, other adverse events | 31 / 46 | 14 / 24 |
| serious Total, serious adverse events | 0 / 46 | 0 / 24 |
Outcome results
Primary
Change in Marijuana Withdrawal Checklist (MWC)
32-item checklist evaluating potential symptoms of cannabis withdrawal, lower values reflect lesser severity of withdrawal symptoms (lower scores represent a better outcome). Min: 0 Max: 96
Time frame: The MWC was administered on Day 0, Day 1, Day 2, Day 3, and Day 4 (during the inpatient phase when withdrawal peaks) to assess change from baseline (Day 0). The scores from each time point and subject were calculated to report the mean score for each arm.
Population: Missing data and the removal of outliers led to differences between the total number of participants and the sample for this variable
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-04457845 (4mg by Mouth Daily for 4 Weeks) | Change in Marijuana Withdrawal Checklist (MWC) | 6.04 score on a scale |
| Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) | Change in Marijuana Withdrawal Checklist (MWC) | 11 score on a scale |
Primary
Change in Self Reported Cannabis Use at the End of 4 Weeks
Subject quantifies and reports frequency of cannabis use prior to study participation and during the 4 week period. Lower scores reflect less cannabis usage, while higher scores reflect more frequent usage. Min: 0 Max: undeterminable, varies per patient and their usage.
Time frame: Administered weekly for 4 weeks to assess change from baseline (Day 0). The scores from each time point and subject were calculated to report the mean score for each arm.
Population: Missing data and the removal of outliers led to differences between the total number of participants and the sample for this variable
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-04457845 (4mg by Mouth Daily for 4 Weeks) | Change in Self Reported Cannabis Use at the End of 4 Weeks | 0.40 joints per day |
| Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) | Change in Self Reported Cannabis Use at the End of 4 Weeks | 1.27 joints per day |
Primary
Change in THC-COOH Quantification at the End of 4 Weeks
Subjects provide urine samples to quantify levels of THC.
Time frame: Samples obtained weekly for 4 weeks to assess change from baseline (Day 0). The results from each time point and subject were calculated to report the mean score for each arm.
Population: Missing data and the removal of outliers led to differences between the total number of participants and the sample for this variable
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PF-04457845 (4mg by Mouth Daily for 4 Weeks) | Change in THC-COOH Quantification at the End of 4 Weeks | 265.55 ng/mL |
| Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) | Change in THC-COOH Quantification at the End of 4 Weeks | 657.92 ng/mL |
Secondary
Change in Polysomnography
Polysomnography (PSG) is a comprehensive reading of biophysiological changes that occur during sleep, including identification of sleep stage. A mean and standard deviation of their data points during sleep stages were calculated to determine change from baseline to the end of study treatment.
Time frame: Polysomnography was collected two nights prior to baseline visit, for three nights during study treatment and two nights after four weeks of study treatment. A mean was calculated to assess change from baseline (Day 0).
Population: The units analyzed reflects the number of data points (sum of participants per drug condition across time) was 42 in the placebo group and 82 in the PF-04457845 group.~Missing data and the removal of outliers led to differences between the total number of participants and the sample for this variable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-04457845 (4mg by Mouth Daily for 4 Weeks) | Change in Polysomnography | 89.56 minutes | Standard Deviation 35.2 |
| Placebo (Sugar Pill, by Mouth Daily for 4 Weeks) | Change in Polysomnography | 69.29 minutes | Standard Deviation 27 |
Other Pre-specified
Feeling States
Visual analog scale for feeling states (depression, anxiety, irritability)
Time frame: Administered on Day 0, Day 1, Day 2, Day 3, and Day 4 (Once pre-treatment and during the inpatient phase 'acute abstinence') to assess change from baseline (Day 0)
Other Pre-specified
Plasma Endocannabinoid Levels
Measurement of circulating plasma Anandamide
Time frame: Samples obtained at the following study visits: Day -1, Day 0, Day 2, Day 4, Week 2, Week 3, Week 4 to assess change from baseline (Day 0)