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| ID | Type | Description | Link |
|---|---|---|---|
| 1K23DA052682-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Drug Abuse (NIDA) | NIH |
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The overarching goal of this study is to evaluate the potential of Cannabidiol (CBD) as an adjunctive treatment for comorbid opioid use disorder (OUD) and chronic pain. This is a randomized, placebo-controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects of CBD on measures of pain and opioid craving in outpatients with OUD receiving methadone or buprenorphine.
An initial safety pilot phase will recruit six participants: three receiving treatment with methadone and three receiving treatment with buprenorphine. If the results of the pilot study support the safety of CBD administration in this clinical sample, the general study will recruit participants with comorbid OUD and chronic pain, with half the subjects receiving methadone and half receiving buprenorphine. Both sub-studies will enroll participants who do not currently require an inpatient hospitalization.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CBD 400mg | Active Comparator | CBD 400mg |
|
| CBD 800mg | Active Comparator | CBD 800mg |
|
| CBD 1200mg | Active Comparator | CBD 1200mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CBD Day 1 | Drug | CBD 400mg |
| |
| CBD Day 2 |
| Measure | Description | Time Frame |
|---|---|---|
| Agitation Calmness Evaluation Scale (ACES) | The ACES consists of a single item that rates overall agitation and sedation of the participant at the time of evaluation, where 1 indicates marked agitation; 2: moderate agitation; 3: mild agitation; 4: normal behavior; 5: mild calmness; 6: moderate calmness; 7: marked calmness; 8: deep sleep; and 9: unarousable. Clinically significant sedation was a priori defined as an ACES score of 7 (marked calmness) or higher at any point during the session. A score was averaged across all time intervals. | Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 minutes after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD) |
| Mini Mental Status Examination (MMSE) | The MMSE is a 30-point scale ranging from 0 to 30 that measures five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. Each scale is summed to compute a total score. The MMSE is used extensively in clinical and research settings to measure cognitive impairment. A score of 24 or higher is generally considered within the normal range, while lower scores suggest potential cognitive impairment. Scores are often interpreted as follows: 25-30 = normal cognition, 21-24 = mild impairment, 10-20 = moderate impairment, and below 10 = severe impairment. | Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD) |
| Systematic Assessment of Side Effects (SAFTEE) | The SAFTEE is a multi-symptom checklist that has been used successfully in our previous studies to assess and monitor any adverse events and possible side effects of study medications. It includes information regarding the severity of any presenting symptoms (0= none, 1= mild, 2= moderate, and 3= severe), as well as the course of action taken by the study staff in response. The SAFTEE was administered before the administration of CBD at baseline, (timepoint -30 minutes) and 4.5 hours after the administration of CBD (timepoint +240 minutes) during each test session. Data presented here is the number of participants that reported symptoms on SAFTEE. |
| Measure | Description | Time Frame |
|---|---|---|
| Quantitative Sensory Testing (QST)- Threshold and Tolerance | Pain threshold and tolerance will be assessed using a comprehensive QST battery. This is a reliable, dynamic, and computerized method of quantifying distinct mechanisms of the pain experience. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. Threshold: the temperature the participant first begins to feel pain (average pain threshold), and when the participant can no longer tolerate the stimuli (Tolerance). The temperature ranges from 37 degrees celsius to 50 degrees celsius. A lower temperature represents a lower pain threshold and a higher temperature represents a higher pain threshold. A lower temperature represents a lower pain tolerance and a higher temperature represents a higher pain tolerance. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) | The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) consists of 14 statements about the respondent's feelings and thoughts about using heroin as he or she is completing the questionnaire (i.e., right now). Each of the 14 items is scored on a scale from 1 (Strongly Disagree) to 7 (Strongly Agree). The HCQ-SF-14 score is obtained by adding the scores of all 14 statements and dividing the total by 14. Higher scores on the HCQ-SF-14 indicate a stronger craving for heroin. The HCQ-14 was administered before (+150 minutes) and after (+155 minutes) participants watched a cue-induced craving video. The difference of the two HCQ-14 scores (post - pre) will be used to index cue-elicited craving. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joao De Aquino, M.D. | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Veteran Affairs Hospital | West Haven | Connecticut | 06516 | United States |
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Participants were recruited through responses to fliers, craigslist, clinicaltrials.gov, BuildClinical and through local mental health and substance use disorder treatment facilities
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| ID | Title | Description |
|---|---|---|
| FG000 | CBD Overall | Using a dose-escalation paradigm, crossover assignment, participants were administered single doses of 400 mg, 800 mg, and 1200 mg of CBD, across 3 test sessions. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Per protocol population. Defined as participants completing the experimental drug conditions.
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| ID | Title | Description |
|---|---|---|
| BG000 | Buprenorphine | Completers (3 receiving buprenorphine) |
| BG001 | Methadone | Completers (4 receiving methadone) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Agitation Calmness Evaluation Scale (ACES) | The ACES consists of a single item that rates overall agitation and sedation of the participant at the time of evaluation, where 1 indicates marked agitation; 2: moderate agitation; 3: mild agitation; 4: normal behavior; 5: mild calmness; 6: moderate calmness; 7: marked calmness; 8: deep sleep; and 9: unarousable. Clinically significant sedation was a priori defined as an ACES score of 7 (marked calmness) or higher at any point during the session. A score was averaged across all time intervals. | Posted | Mean | Standard Error | score on a scale | Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 minutes after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD) |
|
baseline up to 6 hours post CBD
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CBD 400mg | CBD 400mg CBD Day 1: CBD 400mg | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Unrelated Serious Adverse Event | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Agitation | General disorders | SAFTEE | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joao De Aquino, M.D. | Yale University, Department of Psychiatry | 203-932-5711 | 12916 | joao.deaquinolima@yale.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 5, 2025 | Jun 21, 2025 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 17, 2021 | Jun 21, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D016739 | Behavior, Addictive |
| ID | Term |
|---|---|
| D003192 | Compulsive Behavior |
| D007175 | Impulsive Behavior |
| D001519 | Behavior |
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Initial safety pilot phase of 6 participants,(3 methadone and 3 on Buprenorphine) The general study is a randomized, placebo-controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects of CBD on measures of pain and opioid craving in outpatients with OUD receiving methadone or buprenorphine.
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| Drug |
CBD 800mg |
|
| CBD Day 3 | Drug | CBD 1200mg |
|
| baseline and 4.5 hours after the administration of CBD |
| baseline, 2 hours and 4 hours after the administration of CBD. |
| Change in Quantitative Sensory Testing (QST) Conditioned Pain Modulation (CPM) | CPM indexes top-down pain inhibition, by leveraging the "pain inhibits pain phenomena". In CPM, a test stimulus is rated on a -100 to +100 Numeric Rating Scale (NRS) for pain both alone and during a concurrent conditioning stimulus applied elsewhere on the body. The CPM Score is the difference between these two ratings. CPM score is a Difference (Delta): Pain rating (test stimulus alone) - Pain rating (test stimulus with conditioning stimulus) Interpretation: Higher (more positive) values indicate greater pain inhibition. | Baseline (-30 minutes), 2 hours (+120 minutes), and 4 hours (+240 minutes) after the administration of CBD. |
| Quantitative Sensory Testing (QST) Temporal Summation of Pain (TSP) | Pain will be assessed using a comprehensive QST battery. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. TSP involves the repeated administration of noxious stimuli, indexing bottom-up pain facilitation. Therefore, TSP measures the increase in pain perception with repeated noxious stimuli, calculated as the area under the curve (AUC) of pain ratings over time during repeated stimulation. Higher TSP scores indicate worse outcomes (greater pain facilitation/central sensitization), while lower TSP scores indicate better outcomes (less pain facilitation/central sensitization). The TSP AUC values represent the cumulative pain experience during repeated stimulation (VAS units*seconds), where larger values reflect greater temporal summation of pain, which is associated with central nervous system sensitization and chronic pain conditions. | Baseline, 2 hours and 4 hours after the administration of CBD. |
| Average difference of scores from before cue-induced craving video (+150 minutes) and after cue-induced craving video (+155 minutes) |
| BG002 |
| Total |
Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Buprenorphine or Methadone Dose | Participants received buprenorphine or methadone. | Mean | Standard Deviation | milligrams |
|
| Weight | Mean | Standard Deviation | Pounds (lbs) |
|
| Brief Pain Index (BPI) | The BPI Severity and Interference each have a total score range of 0-10 where: 0 = no pain, 1-3 = mild pain, 4-6 = moderate pain, 7-10 = severe pain. | Mean | Standard Deviation | score on a scale |
|
| Clinical Pain Location | Count of Participants | Participants |
|
| OG001 | CBD 800mg | CBD 800mg CBD Day 2: CBD 800mg |
| OG002 | CBD 1200mg | CBD 1200mg CBD Day 3: CBD 1200mg |
|
|
| Primary | Mini Mental Status Examination (MMSE) | The MMSE is a 30-point scale ranging from 0 to 30 that measures five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. Each scale is summed to compute a total score. The MMSE is used extensively in clinical and research settings to measure cognitive impairment. A score of 24 or higher is generally considered within the normal range, while lower scores suggest potential cognitive impairment. Scores are often interpreted as follows: 25-30 = normal cognition, 21-24 = mild impairment, 10-20 = moderate impairment, and below 10 = severe impairment. | Posted | Mean | Standard Error | score on a scale | Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD) |
|
|
|
| Primary | Systematic Assessment of Side Effects (SAFTEE) | The SAFTEE is a multi-symptom checklist that has been used successfully in our previous studies to assess and monitor any adverse events and possible side effects of study medications. It includes information regarding the severity of any presenting symptoms (0= none, 1= mild, 2= moderate, and 3= severe), as well as the course of action taken by the study staff in response. The SAFTEE was administered before the administration of CBD at baseline, (timepoint -30 minutes) and 4.5 hours after the administration of CBD (timepoint +240 minutes) during each test session. Data presented here is the number of participants that reported symptoms on SAFTEE. | Posted | Count of Participants | Participants | baseline and 4.5 hours after the administration of CBD |
|
|
|
| Secondary | Quantitative Sensory Testing (QST)- Threshold and Tolerance | Pain threshold and tolerance will be assessed using a comprehensive QST battery. This is a reliable, dynamic, and computerized method of quantifying distinct mechanisms of the pain experience. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. Threshold: the temperature the participant first begins to feel pain (average pain threshold), and when the participant can no longer tolerate the stimuli (Tolerance). The temperature ranges from 37 degrees celsius to 50 degrees celsius. A lower temperature represents a lower pain threshold and a higher temperature represents a higher pain threshold. A lower temperature represents a lower pain tolerance and a higher temperature represents a higher pain tolerance. | Posted | Mean | Standard Deviation | degrees Celsius | baseline, 2 hours and 4 hours after the administration of CBD. |
|
|
|
| Secondary | Change in Quantitative Sensory Testing (QST) Conditioned Pain Modulation (CPM) | CPM indexes top-down pain inhibition, by leveraging the "pain inhibits pain phenomena". In CPM, a test stimulus is rated on a -100 to +100 Numeric Rating Scale (NRS) for pain both alone and during a concurrent conditioning stimulus applied elsewhere on the body. The CPM Score is the difference between these two ratings. CPM score is a Difference (Delta): Pain rating (test stimulus alone) - Pain rating (test stimulus with conditioning stimulus) Interpretation: Higher (more positive) values indicate greater pain inhibition. | Posted | Mean | Standard Deviation | units on a scale | Baseline (-30 minutes), 2 hours (+120 minutes), and 4 hours (+240 minutes) after the administration of CBD. |
|
|
|
| Secondary | Quantitative Sensory Testing (QST) Temporal Summation of Pain (TSP) | Pain will be assessed using a comprehensive QST battery. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. TSP involves the repeated administration of noxious stimuli, indexing bottom-up pain facilitation. Therefore, TSP measures the increase in pain perception with repeated noxious stimuli, calculated as the area under the curve (AUC) of pain ratings over time during repeated stimulation. Higher TSP scores indicate worse outcomes (greater pain facilitation/central sensitization), while lower TSP scores indicate better outcomes (less pain facilitation/central sensitization). The TSP AUC values represent the cumulative pain experience during repeated stimulation (VAS units*seconds), where larger values reflect greater temporal summation of pain, which is associated with central nervous system sensitization and chronic pain conditions. | Posted | Mean | Standard Deviation | AUC (VAS units*seconds) | Baseline, 2 hours and 4 hours after the administration of CBD. |
|
|
|
| Other Pre-specified | Change in The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) | The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) consists of 14 statements about the respondent's feelings and thoughts about using heroin as he or she is completing the questionnaire (i.e., right now). Each of the 14 items is scored on a scale from 1 (Strongly Disagree) to 7 (Strongly Agree). The HCQ-SF-14 score is obtained by adding the scores of all 14 statements and dividing the total by 14. Higher scores on the HCQ-SF-14 indicate a stronger craving for heroin. The HCQ-14 was administered before (+150 minutes) and after (+155 minutes) participants watched a cue-induced craving video. The difference of the two HCQ-14 scores (post - pre) will be used to index cue-elicited craving. | Posted | Mean | Standard Deviation | units on a scale | Average difference of scores from before cue-induced craving video (+150 minutes) and after cue-induced craving video (+155 minutes) |
|
|
|
| 7 |
| 0 |
| 7 |
| 5 |
| 7 |
| EG001 | CBD 800mg | CBD 800mg CBD Day 2: CBD 800mg | 0 | 7 | 0 | 7 | 6 | 7 |
| EG002 | CBD 1200mg | CBD 1200mg CBD Day 3: CBD 1200mg | 0 | 7 | 1 | 7 | 5 | 7 |
| Anger or irritability | General disorders | SAFTEE | Systematic Assessment |
|
| Back, muscle or bone pain | Musculoskeletal and connective tissue disorders | SAFTEE | Systematic Assessment |
|
| Chest pain | Cardiac disorders | SAFTEE | Systematic Assessment |
|
| Chills | General disorders | SAFTEE | Systematic Assessment |
|
| Confusion | General disorders | SAFTEE | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | SAFTEE | Systematic Assessment |
|
| Depressed mood | Psychiatric disorders | SAFTEE | Systematic Assessment |
|
| Difficulty concentrating | General disorders | SAFTEE | Systematic Assessment |
|
| Dry mouth | General disorders | SAFTEE | Systematic Assessment |
|
| Excessive hunger | General disorders | SAFTEE | Systematic Assessment |
|
| Extreme thirst | General disorders | SAFTEE | Systematic Assessment |
|
| Feeling dizzy or faint or lightheaded | General disorders | SAFTEE | Systematic Assessment |
|
| Feeling Drowsy | General disorders | SAFTEE | Systematic Assessment |
|
| Headache | General disorders | SAFTEE | Systematic Assessment |
|
| Heartburn | Metabolism and nutrition disorders | SAFTEE | Systematic Assessment |
|
| Irregular or pounding heartbeat | Cardiac disorders | SAFTEE | Systematic Assessment |
|
| Loss of appetite | Metabolism and nutrition disorders | SAFTEE | Systematic Assessment |
|
| Memory problems | General disorders | SAFTEE | Systematic Assessment |
|
| Mood swings | Psychiatric disorders | SAFTEE | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | SAFTEE | Systematic Assessment |
|
| Nervousness | General disorders | SAFTEE | Systematic Assessment |
|
| Problems with urination | General disorders | SAFTEE | Systematic Assessment |
|
| Restlessness | General disorders | SAFTEE | Systematic Assessment |
|
| Runny nose | General disorders | SAFTEE | Systematic Assessment |
|
| Stomach pain | Gastrointestinal disorders | SAFTEE | Systematic Assessment |
|
| Sweating | General disorders | SAFTEE | Systematic Assessment |
|
| Teary or dry eyes | General disorders | SAFTEE | Systematic Assessment |
|
| Tremors or shakiness | General disorders | SAFTEE | Systematic Assessment |
|
| Trouble walking | General disorders | SAFTEE | Systematic Assessment |
|
| Upset stomach | Gastrointestinal disorders | SAFTEE | Systematic Assessment |
|
Not provided
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| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
| +330 Minutes |
|
| +390 Minutes |
|
| +450 Minutes |
|
|
| Threshold 4 hours |
|
| Tolerance Baseline |
|
| Tolerance 2 hours |
|
| Tolerance 4 hours |
|
|
| +240 Minutes |
|
|
| +240 Minutes |
|