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Cannabidiol on Reward- and Stress-related Neurocognitive Processes in Individuals With Opioid Use Disorder

Cannabidiol on reward-and Stress-related Neurocognitive Processes in Individuals With Opioid Use Disorder: A Double-blind, Placebo-controlled, Cross-over Trial

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT04982029
Enrollment
15
Registered
2021-07-29
Start date
2022-04-14
Completion date
2022-12-02
Last updated
2023-10-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Opioid-use Disorder

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

DRUGPlacebo

Matching placebo

Sponsors

Harvard Medical School (HMS and HSDM)
CollaboratorOTHER
Brigham and Women's Hospital
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)

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

Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No

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

MeasureTime frameDescription
Change in Cue-reactivityVisit 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

MeasureTime frameDescription
Delayed DiscountVisit 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 MakingVisit 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 BiasVisit 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-reactivityVisit 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

ArmCount
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
Total15

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyLost to Follow-up23

Baseline characteristics

CharacteristicTotalCannabidiol 600mg First and Placebo SecondNot RandomizedPlacebo First and Cannabidiol 600mg Second
Age, Continuous41.75 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 Participants1 Participants0 Participants0 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
14 Participants4 Participants5 Participants5 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants
Generalized Anxiety Disorder 77.6 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 Cravings3.31 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 Questionnaire8.07 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 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
15 Participants5 Participants5 Participants5 Participants
Region of Enrollment
United States
15 participants5 participants5 participants5 participants
Sex: Female, Male
Female
9 Participants4 Participants3 Participants2 Participants
Sex: Female, Male
Male
6 Participants1 Participants2 Participants3 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 Drinks2.05 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 typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 150 / 15
other
Total, other adverse events
0 / 150 / 15
serious
Total, serious adverse events
0 / 150 / 15

Outcome results

Primary

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)

ArmMeasureGroupValue (MEAN)Dispersion
Cannabidiol 600mgChange in Cue-reactivityPre-cue0.7 score on a scaleStandard Deviation 1.3
Cannabidiol 600mgChange in Cue-reactivityPost-drug cue0.9 score on a scaleStandard Deviation 1.1
Cannabidiol 600mgChange in Cue-reactivityPost-neutral cue0.5 score on a scaleStandard Deviation 1.3
Cannabidiol 600mgChange in Cue-reactivityCue-induced craving0.2 score on a scaleStandard Deviation 0.79
PlaceboChange in Cue-reactivityCue-induced craving1.3 score on a scaleStandard Deviation 1.9
PlaceboChange in Cue-reactivityPre-cue1.1 score on a scaleStandard Deviation 2
PlaceboChange in Cue-reactivityPost-neutral cue1.1 score on a scaleStandard Deviation 2
PlaceboChange in Cue-reactivityPost-drug cue2.4 score on a scaleStandard Deviation 1.7
Secondary

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)

ArmMeasureGroupValue (MEAN)Dispersion
Cannabidiol 600mgAttentional BiasAutomatic orienting-80.4 milisecondsStandard Deviation 298.8
Cannabidiol 600mgAttentional BiasControlled attention145.2 milisecondsStandard Deviation 392.3
PlaceboAttentional BiasAutomatic orienting100.3 milisecondsStandard Deviation 123.5
PlaceboAttentional BiasControlled attention-93.1 milisecondsStandard Deviation 268.5
Secondary

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)

ArmMeasureValue (MEAN)Dispersion
Cannabidiol 600mgDecision Making2.2 units on a scaleStandard Deviation 9.3
PlaceboDecision Making-6.4 units on a scaleStandard Deviation 18.9
Secondary

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)

ArmMeasureValue (MEAN)Dispersion
Cannabidiol 600mgDelayed Discount0.020 units on a scaleStandard Deviation 0.024
PlaceboDelayed Discount0.039 units on a scaleStandard Deviation 0.075
Secondary

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)

ArmMeasureValue (MEAN)Dispersion
Cannabidiol 600mgStress-reactivity59.00 milisecondsStandard Deviation 37.75
PlaceboStress-reactivity99.83 milisecondsStandard Deviation 100.78
Secondary

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)

ArmMeasureGroupValue (MEAN)Dispersion
Cannabidiol 600mgStress-Reactivity (Physiological)Pre-Paradigm0.0855 mcg/dLStandard Deviation 0.0579
Cannabidiol 600mgStress-Reactivity (Physiological)Post-Paradigm0.0745 mcg/dLStandard Deviation 0.272
Cannabidiol 600mgStress-Reactivity (Physiological)20 Minutes Post Paradigm0.0828 mcg/dLStandard Deviation 0.06
PlaceboStress-Reactivity (Physiological)Pre-Paradigm0.1542 mcg/dLStandard Deviation 0.179
PlaceboStress-Reactivity (Physiological)Post-Paradigm0.0816 mcg/dLStandard Deviation 0.045
PlaceboStress-Reactivity (Physiological)20 Minutes Post Paradigm0.0806 mcg/dLStandard Deviation 0.0429

Source: ClinicalTrials.gov · Data processed: Feb 9, 2026