Opioid-use Disorder
Conditions
Brief summary
The purpose of this study is to determine the impact of cannabidiol on reward- and stress-related neurocognitive processes among individuals with opioid use disorder on buprenorphine or methadone treatment.
Detailed description
Individuals with opioid use disorder (OUD) demonstrate reward- and stress-related neurocognitive changes compared to individuals without OUD, including cravings for opioids in response to exposure to triggers, tendency to make impulsive and disadvantageous decisions, and a strong attentional bias towards drug-related cues. Together, these deficits are significant contributors to relapse and discontinuation of treatment. Cannabidiol (CBD) has been shown to impact some of these cognitive deficits but studies of CBD among individuals with OUD are mostly lacking. Therefore, this study aims to answer whether CBD has any impact on reward-related neurocognitive deficits in individuals with OUD. If successful, this line of research will lay the groundwork for future studies to evaluate CBD's impact on OUD treatment outcomes.
Interventions
600mg
Matching placebo
Sponsors
Study design
Masking description
This is a double-blind cross-over trial, in which the research staff and participants will be blinded.
Intervention model description
The study is a double-blind, placebo-controlled, cross-over trial.
Eligibility
Inclusion criteria
* English speaking * DSM5 diagnosis of opioid use disorder * Receiving buprenorphine or methadone for treatment of opioid use disorder * Agreeable to abstaining from using any cannabis or CBD products for the duration of the trial.
Exclusion criteria
* Any self-reported use of cannabis or CBD products in the past 30 days * Baseline depression (PHQ9) or anxiety (GAD7) scores of greater than 10 * Currently pregnant * Hepatic liver enzymes greater than 3x upper normal limit * Hypersensitivity to cannabinoids or sesame oil (CBD solution comes in sesame oil emulsion) * Currently taking any medications with known significant pharmacokinetic interactions with CBD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cue-reactivity | Visit 2 and 3 (at least 1 week apart) | The primary outcomes is cue-induced cravings (Opioid Craving Scale). This was measured with a single 10-point likert scale asking about cravings, where 0 represented lower levels of craving and 10 indicated higher levels of cravings. This was given at 3 different time points, pre-cue, post-neutral, and post-drug images. Cue-induced craving is the difference between drug cue and pre-cue scores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Delayed Discount | Visit 2 and 3 (at least 1 week apart) | Monetary Choice Questionnaire will be used to calculate impulse decision making. This is a 27-item self-administered questionnaire where participants choose between a smaller, immediate monetary reward and a larger, delayed monetary reward. A participants score is between one of the two endpoints (0.25 or 0.00016). If an individual is more likely to prefer the delayed versus immediate reward, their score is more likely to be closer to the 0.00016 endpoint. Please note the rate of delayed discounting is not the same for each question. |
| Decision Making | Visit 2 and 3 (at least 1 week apart) | Iowa Gambling Task will be used to assess impulsive decision-making. The larger the number, the more safer options were chosen. This is measured by taking the total number of risky choices and subtracting it from the less risky choices. The lower the number, the more high risky options were chosen. If participants chose the less risky option, they received a positive point, if individuals picked the riskier choice, they received a negative point. Negative values indicate a participant chose more riskier decisions than less-risky, whereas positive values indicate participants chose the less riskier decision more often. The lowest score an individual could receive is -100 (very risk) to 100 (least risky). |
| Attentional Bias | Visit 2 and 3 (at least 1 week apart) | Visual probe task will be used to assess attentional bias to drug-related cues. Opioid-related and neutral images will be used. Each trial will begin with a fixation point lasting 500ms. A pair of images then will appear on the left and right of the screen for either a short (200ms) or long (500ms) stimulus duration to assess automatic orientating and controlled attention processing, respectively. Image pairs will be replaced by a probe in the location of either the opioid-related or neutral image. The probe will remain until the participant responds to identify the probe orientation by pressing the response keys as quickly as possible. Attentional bias is calculated as the difference in reaction time (RT) between when the probe replaced the neutral compared with the opioid-related images (i.e. RTneutral - RTopioid). Therefore the more positive the number, the less attentional bias toward drug cue, and a negative number represents more attentional bias toward the drug cue. |
| Stress-reactivity | Visit 2 and 3 (at least 1 week apart) | Physiologic and subjective stress will be assessed. Stress-reactivity was measured by participants mirror tracing an image on a compute screen where a loud beeping noise would occur if a participant took too long or went outside the lines. It's measured in ms and the longer someone stayed on the task, the better ability they have to react stress. |
| Stress-Reactivity (Physiological) | Visit 2 and 3 (at least 1 week apart) | For this outcome, participants received a salivary cortisol test prior to, immediately after, and 20 minutes after the cue-reactivity paradigm. Lower levels indicate lower levels of salivary cortisol in the sample. |
Countries
United States
Participant flow
Recruitment details
This study took place from April 2022 - December 2022 at Brigham and Women's Hospital in Boston and Rutland Medical Clinic in Rutland VT. Participants were recruited through clinics and patient registries.
Participants by arm
| Arm | Count |
|---|---|
| Cannabidiol 600mg First and Placebo Second All subjects will receive 600mg of oral cannabidiol in a double-blind fashion. Cannabidiol will be provided using Epidiolex™ oral solution 100mg/mL. Following administration, a battery of tests will be conducted to examine reward- and stress-related neurocognitive processes.
Cannabidiol 100 MG/ML \[Epidiolex\]: 600mg
All subjects will receive a matching placebo in a double-blind fashion. Following administration, a battery of tests will be conducted to examine the impact on reward- and stress-related neurocognitive processes.
Placebo: Matching placebo
In this arm, participants received CBD first and placebo second. | 5 |
| Placebo First and Cannabidiol 600mg Second All subjects will receive 600mg of oral cannabidiol in a double-blind fashion. Cannabidiol will be provided using Epidiolex™ oral solution 100mg/mL. Following administration, a battery of tests will be conducted to examine reward- and stress-related neurocognitive processes.
Cannabidiol 100 MG/ML \[Epidiolex\]: 600mg
All subjects will receive a matching placebo in a double-blind fashion. Following administration, a battery of tests will be conducted to examine the impact on reward- and stress-related neurocognitive processes.
Placebo: Matching placebo
In this arm, participants received placebo first and CBD second. | 5 |
| Not Randomized In this condition, participants only completed the baseline visit and were lost to follow-up prior to randomization. Therefore, only baseline characteristics are reported for these individuals. | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
Baseline characteristics
| Characteristic | Total | Cannabidiol 600mg First and Placebo Second | Not Randomized | Placebo First and Cannabidiol 600mg Second |
|---|---|---|---|---|
| Age, Continuous | 41.75 years STANDARD_DEVIATION 9.33 | 44.2 years STANDARD_DEVIATION 6.98 | 33.6 years STANDARD_DEVIATION 3.78 | 46 years STANDARD_DEVIATION 11.4 |
| Brief Pain Inventory Interference | 3.60 units on a scale STANDARD_DEVIATION 3 | 3.51 units on a scale STANDARD_DEVIATION 3.57 | 3.69 units on a scale STANDARD_DEVIATION 3.16 | 3.2 units on a scale STANDARD_DEVIATION 3.28 |
| Brief Pain Inventory Severity | 2.82 units on a scale STANDARD_DEVIATION 2.97 | 3 units on a scale STANDARD_DEVIATION 2.5 | 1.95 units on a scale STANDARD_DEVIATION 1.87 | 3.8 units on a scale STANDARD_DEVIATION 2.69 |
| COWS | .93 units on a scale STANDARD_DEVIATION 1.19 | 0.4 units on a scale STANDARD_DEVIATION 0.55 | 1.6 units on a scale STANDARD_DEVIATION 1.52 | 0.8 units on a scale STANDARD_DEVIATION 0.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 4 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Generalized Anxiety Disorder 7 | 7.6 units on a scale STANDARD_DEVIATION 6.16 | 9.2 units on a scale STANDARD_DEVIATION 6.87 | 10.2 units on a scale STANDARD_DEVIATION 6.46 | 3.4 units on a scale STANDARD_DEVIATION 3.21 |
| Opioid Cravings | 3.31 units on a scale STANDARD_DEVIATION 3.66 | 1.2 units on a scale STANDARD_DEVIATION 1.3 | 8.2 units on a scale STANDARD_DEVIATION 1.48 | 2.4 units on a scale STANDARD_DEVIATION 3.29 |
| Patient Health Questionnaire | 8.07 units on a scale STANDARD_DEVIATION 6.17 | 7.2 units on a scale STANDARD_DEVIATION 6.18 | 10.4 units on a scale STANDARD_DEVIATION 8.35 | 5.6 units on a scale STANDARD_DEVIATION 2.61 |
| Positive and Negative Affect Schedule Negative PANAS | 21.67 units on a scale STANDARD_DEVIATION 7.98 | 24.8 units on a scale STANDARD_DEVIATION 10.64 | 21.6 units on a scale STANDARD_DEVIATION 7.8 | 16.6 units on a scale STANDARD_DEVIATION 2.79 |
| Positive and Negative Affect Schedule Positive PANAS | 26.47 units on a scale STANDARD_DEVIATION 6.83 | 26.2 units on a scale STANDARD_DEVIATION 9.96 | 22.2 units on a scale STANDARD_DEVIATION 2.59 | 31 units on a scale STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 5 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 15 participants | 5 participants | 5 participants | 5 participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 2 Participants | 3 Participants |
| Timeline Follow Back Alcohol | 1.47 Average days of substance use STANDARD_DEVIATION 5.14 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0.2 Average days of substance use STANDARD_DEVIATION 0.45 | 4.2 Average days of substance use STANDARD_DEVIATION 8.84 |
| Timeline Follow Back Amphetamine | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Benzodiazepines | 0.07 Average days of substance use STANDARD_DEVIATION 0.26 | 0.2 Average days of substance use STANDARD_DEVIATION 0.45 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Cannabis | 2 Average days of substance use STANDARD_DEVIATION 7.21 | 6 Average days of substance use STANDARD_DEVIATION 12.33 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Crack/Cocaine | 0.6 Average days of substance use STANDARD_DEVIATION 1.18 | 0 Average days of substance use STANDARD_DEVIATION 0 | 1.4 Average days of substance use STANDARD_DEVIATION 1.67 | 0.4 Average days of substance use STANDARD_DEVIATION 0.89 |
| Timeline Follow Back Hallucinogen | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Heroin | 2.27 Average days of substance use STANDARD_DEVIATION 3.97 | 0 Average days of substance use STANDARD_DEVIATION 0 | 6.8 Average days of substance use STANDARD_DEVIATION 4.1 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Inhalants | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Opioid Analgesic | 1.13 Average days of substance use STANDARD_DEVIATION 3.95 | 0 Average days of substance use STANDARD_DEVIATION 0 | 1 Average days of substance use STANDARD_DEVIATION 2.24 | 2.4 Average days of substance use STANDARD_DEVIATION 5.37 |
| Timeline Follow Back Sedatives | 0.07 Average days of substance use STANDARD_DEVIATION 0.26 | 0 Average days of substance use STANDARD_DEVIATION 0 | 0.2 Average days of substance use STANDARD_DEVIATION 0.45 | 0 Average days of substance use STANDARD_DEVIATION 0 |
| Timeline Follow Back Alcohol Drinks | 2.05 numbers of drinks per drinking day STANDARD_DEVIATION 0.22 | 0 numbers of drinks per drinking day STANDARD_DEVIATION 0 | 2 numbers of drinks per drinking day STANDARD_DEVIATION 0 | 2.05 numbers of drinks per drinking day STANDARD_DEVIATION 0.22 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Change in Cue-reactivity
The primary outcomes is cue-induced cravings (Opioid Craving Scale). This was measured with a single 10-point likert scale asking about cravings, where 0 represented lower levels of craving and 10 indicated higher levels of cravings. This was given at 3 different time points, pre-cue, post-neutral, and post-drug images. Cue-induced craving is the difference between drug cue and pre-cue scores.
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabidiol 600mg | Change in Cue-reactivity | Pre-cue | 0.7 score on a scale | Standard Deviation 1.3 |
| Cannabidiol 600mg | Change in Cue-reactivity | Post-drug cue | 0.9 score on a scale | Standard Deviation 1.1 |
| Cannabidiol 600mg | Change in Cue-reactivity | Post-neutral cue | 0.5 score on a scale | Standard Deviation 1.3 |
| Cannabidiol 600mg | Change in Cue-reactivity | Cue-induced craving | 0.2 score on a scale | Standard Deviation 0.79 |
| Placebo | Change in Cue-reactivity | Cue-induced craving | 1.3 score on a scale | Standard Deviation 1.9 |
| Placebo | Change in Cue-reactivity | Pre-cue | 1.1 score on a scale | Standard Deviation 2 |
| Placebo | Change in Cue-reactivity | Post-neutral cue | 1.1 score on a scale | Standard Deviation 2 |
| Placebo | Change in Cue-reactivity | Post-drug cue | 2.4 score on a scale | Standard Deviation 1.7 |
Attentional Bias
Visual probe task will be used to assess attentional bias to drug-related cues. Opioid-related and neutral images will be used. Each trial will begin with a fixation point lasting 500ms. A pair of images then will appear on the left and right of the screen for either a short (200ms) or long (500ms) stimulus duration to assess automatic orientating and controlled attention processing, respectively. Image pairs will be replaced by a probe in the location of either the opioid-related or neutral image. The probe will remain until the participant responds to identify the probe orientation by pressing the response keys as quickly as possible. Attentional bias is calculated as the difference in reaction time (RT) between when the probe replaced the neutral compared with the opioid-related images (i.e. RTneutral - RTopioid). Therefore the more positive the number, the less attentional bias toward drug cue, and a negative number represents more attentional bias toward the drug cue.
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabidiol 600mg | Attentional Bias | Automatic orienting | -80.4 miliseconds | Standard Deviation 298.8 |
| Cannabidiol 600mg | Attentional Bias | Controlled attention | 145.2 miliseconds | Standard Deviation 392.3 |
| Placebo | Attentional Bias | Automatic orienting | 100.3 miliseconds | Standard Deviation 123.5 |
| Placebo | Attentional Bias | Controlled attention | -93.1 miliseconds | Standard Deviation 268.5 |
Decision Making
Iowa Gambling Task will be used to assess impulsive decision-making. The larger the number, the more safer options were chosen. This is measured by taking the total number of risky choices and subtracting it from the less risky choices. The lower the number, the more high risky options were chosen. If participants chose the less risky option, they received a positive point, if individuals picked the riskier choice, they received a negative point. Negative values indicate a participant chose more riskier decisions than less-risky, whereas positive values indicate participants chose the less riskier decision more often. The lowest score an individual could receive is -100 (very risk) to 100 (least risky).
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol 600mg | Decision Making | 2.2 units on a scale | Standard Deviation 9.3 |
| Placebo | Decision Making | -6.4 units on a scale | Standard Deviation 18.9 |
Delayed Discount
Monetary Choice Questionnaire will be used to calculate impulse decision making. This is a 27-item self-administered questionnaire where participants choose between a smaller, immediate monetary reward and a larger, delayed monetary reward. A participants score is between one of the two endpoints (0.25 or 0.00016). If an individual is more likely to prefer the delayed versus immediate reward, their score is more likely to be closer to the 0.00016 endpoint. Please note the rate of delayed discounting is not the same for each question.
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol 600mg | Delayed Discount | 0.020 units on a scale | Standard Deviation 0.024 |
| Placebo | Delayed Discount | 0.039 units on a scale | Standard Deviation 0.075 |
Stress-reactivity
Physiologic and subjective stress will be assessed. Stress-reactivity was measured by participants mirror tracing an image on a compute screen where a loud beeping noise would occur if a participant took too long or went outside the lines. It's measured in ms and the longer someone stayed on the task, the better ability they have to react stress.
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol 600mg | Stress-reactivity | 59.00 miliseconds | Standard Deviation 37.75 |
| Placebo | Stress-reactivity | 99.83 miliseconds | Standard Deviation 100.78 |
Stress-Reactivity (Physiological)
For this outcome, participants received a salivary cortisol test prior to, immediately after, and 20 minutes after the cue-reactivity paradigm. Lower levels indicate lower levels of salivary cortisol in the sample.
Time frame: Visit 2 and 3 (at least 1 week apart)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cannabidiol 600mg | Stress-Reactivity (Physiological) | Pre-Paradigm | 0.0855 mcg/dL | Standard Deviation 0.0579 |
| Cannabidiol 600mg | Stress-Reactivity (Physiological) | Post-Paradigm | 0.0745 mcg/dL | Standard Deviation 0.272 |
| Cannabidiol 600mg | Stress-Reactivity (Physiological) | 20 Minutes Post Paradigm | 0.0828 mcg/dL | Standard Deviation 0.06 |
| Placebo | Stress-Reactivity (Physiological) | Pre-Paradigm | 0.1542 mcg/dL | Standard Deviation 0.179 |
| Placebo | Stress-Reactivity (Physiological) | Post-Paradigm | 0.0816 mcg/dL | Standard Deviation 0.045 |
| Placebo | Stress-Reactivity (Physiological) | 20 Minutes Post Paradigm | 0.0806 mcg/dL | Standard Deviation 0.0429 |