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NCT05076370

Safety and Tolerability of Cannabidiol Among Persons With Opioid Use Disorder Receiving Methadone or Buprenorphine

Completed EARLY_PHASE1 Results posted Last updated 26 November 2025
What this trial tests

EARLY_PHASE1 trial testing CBD Day 1 in Addiction in 7 participants. Completed in 28 June 2024.

Timeline
8 December 2021
Primary endpoint
28 June 2024
28 June 2024

Quick facts

Lead sponsorYale University
PhaseEARLY_PHASE1
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designcrossover
Maskingnone
Primary purposetreatment
Enrollment7
Start date8 December 2021
Primary completion28 June 2024
Estimated completion28 June 2024
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

Yale University

Who can join

Adults 18 to 70, any sex, with Addiction. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Agitation Calmness Evaluation Scale (ACES) Primary · 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)

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)
GroupValue95% CI
CBD 400mg4± 0
CBD 800mg4± 0
CBD 1200mg4± 0
+270 Minutes
GroupValue95% CI
CBD 400mg4.07± 0.40
CBD 800mg4± 0
CBD 1200mg4.01± 0.11
+330 Minutes
GroupValue95% CI
CBD 400mg4.02± 0.24
CBD 800mg4± 0
CBD 1200mg4± 0
+390 Minutes
GroupValue95% CI
CBD 400mg4± 0
CBD 800mg4± 0
CBD 1200mg4± 0
+450 Minutes
GroupValue95% CI
CBD 400mg4± 0
CBD 800mg4± 0
CBD 1200mg4± 0
Mini Mental Status Examination (MMSE) Primary · 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)

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 impairme

Baseline (-30 minutes)
GroupValue95% CI
CBD 400mg29.43± 0.98
CBD 800mg29.33± 1.21
CBD 1200mg29.50± 0.55
+270 Minutes
GroupValue95% CI
CBD 400mg29.86± 0.38
CBD 800mg29.33± 0.82
CBD 1200mg29.83± 0.41
+330 Minutes
GroupValue95% CI
CBD 400mg29.57± 0.79
CBD 800mg29.57± 0.53
CBD 1200mg29.14± 1.46
+390 Minutes
GroupValue95% CI
CBD 400mg30± 0
CBD 800mg29.33± 1.03
CBD 1200mg29.43± 0.53
+450 Minutes
GroupValue95% CI
CBD 400mg29.50± 0.58
CBD 800mg29.50± 0.58
CBD 1200mg29.67± 0.58
Systematic Assessment of Side Effects (SAFTEE) Primary · baseline and 4.5 hours after the administration of CBD

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 n

GroupValue95% CI
CBD 400mg5
CBD 800mg5
CBD 1200mg5
Quantitative Sensory Testing (QST)- Threshold and Tolerance Secondary · baseline, 2 hours and 4 hours after the administration of CBD.

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 repre

Threshold Baseline
GroupValue95% CI
CBD 400mg40.29± 5.6
CBD 800mg40.55± 4.3
CBD 1200mg41.435± 4.36
Threshold 2 hours
GroupValue95% CI
CBD 400mg39.65± 3.85
CBD 800mg40.47± 4.27
CBD 1200mg40.63± 4.3
Threshold 4 hours
GroupValue95% CI
CBD 400mg39.95± 3.99
CBD 800mg40.47± 3.9
CBD 1200mg39.94± 4.33
Tolerance Baseline
GroupValue95% CI
CBD 400mg46.17± 3.57
CBD 800mg46.33± 3.4
CBD 1200mg47.08± 2.76
Tolerance 2 hours
GroupValue95% CI
CBD 400mg46.70± 2.66
CBD 800mg45.82± 3.9
CBD 1200mg45.07± 4.35
Tolerance 4 hours
GroupValue95% CI
CBD 400mg45.74± 3.62
CBD 800mg46.66± 2.86
CBD 1200mg45.81± 3.88
Change in Quantitative Sensory Testing (QST) Conditioned Pain Modulation (CPM) Secondary · Baseline (-30 minutes), 2 hours (+120 minutes), and 4 hours (+240 minutes) after the administration of CBD.

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)
GroupValue95% CI
CBD 400mg3.43± 11.69
CBD 800mg5.29± 12.4
CBD 1200mg5.7± 5.6
+120 Minutes
GroupValue95% CI
CBD 400mg2.14± 5.81
CBD 800mg-4.28± 6.21
CBD 1200mg1.71± 2.98
+240 Minutes
GroupValue95% CI
CBD 400mg-9.86± 22.99
CBD 800mg-6.28± 10.17
CBD 1200mg-4.42± 11.88
Quantitative Sensory Testing (QST) Temporal Summation of Pain (TSP) Secondary · Baseline, 2 hours and 4 hours after the administration of CBD.

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 sco

Baseline (-30 Minutes)
GroupValue95% CI
CBD 400mg522436.5± 784227.4
CBD 800mg333689.75± 596722.19
CBD 1200mg337314.16± 641890.80
+120 Minutes
GroupValue95% CI
CBD 400mg549573± 841674.11
CBD 800mg354263.75± 693645.10
CBD 1200mg390454.3± 670332.51
+240 Minutes
GroupValue95% CI
CBD 400mg445697.91± 697669.30
CBD 800mg260961.4± 399847.43
CBD 1200mg542224.7± 731050.04
Change in The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) Secondary · Average difference of scores from before cue-induced craving video (+150 minutes) and after cue-induced craving video (+155 minutes)

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

GroupValue95% CI
CBD 400mg-0.57± 3.05
CBD 800mg-0.56± 3.69
CBD 1200mg0.33± 2.58

Adverse events — posted to ClinicalTrials.gov

Time frame: baseline up to 6 hours post CBD. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

CBD 400mg
Serious: 0/7 (0%)
Deaths: 0/7
CBD 800mg
Serious: 0/7 (0%)
Deaths: 0/7
CBD 1200mg
Serious: 1/7 (14%)
Deaths: 0/7

Serious adverse events (1 terms)

ReactionSystemCBD 400mgCBD 800mgCBD 1200mg
Unrelated Serious Adverse EventNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Other adverse events (31 terms — click to expand)

ReactionSystemCBD 400mgCBD 800mgCBD 1200mg
Feeling DrowsyGeneral disorders
ConstipationGastrointestinal disorders
Runny noseGeneral disorders
Back, muscle or bone painMusculoskeletal and connective tissue disorders
Depressed moodPsychiatric disorders
Dry mouthGeneral disorders
HeadacheGeneral disorders
HeartburnMetabolism and nutrition disorders
NauseaGastrointestinal disorders
NervousnessGeneral disorders
Problems with urinationGeneral disorders
RestlessnessGeneral disorders
SweatingGeneral disorders
Teary or dry eyesGeneral disorders
AgitationGeneral disorders
Anger or irritabilityGeneral disorders
Chest painCardiac disorders
ChillsGeneral disorders
ConfusionGeneral disorders
Difficulty concentratingGeneral disorders
Excessive hungerGeneral disorders
Extreme thirstGeneral disorders
Feeling dizzy or faint or lightheadedGeneral disorders
Irregular or pounding heartbeatCardiac disorders
Loss of appetiteMetabolism and nutrition disorders
Memory problemsGeneral disorders
Mood swingsPsychiatric disorders
Stomach painGastrointestinal disorders
Tremors or shakinessGeneral disorders
Trouble walkingGeneral disorders
Upset stomachGastrointestinal disorders

Most-reported serious reactions: Unrelated Serious Adverse Event.

Data from ClinicalTrials.gov NCT05076370 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

  1. The therapeutic potential of purified cannabidiol.
    O'Sullivan SE, Jensen SS, Nikolajsen GN, Bruun HZ, et al · · 2023 · cited 37× · PMID 37312194 · DOI 10.1186/s42238-023-00186-9

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Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT05076370.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing