Cannabidiol on Reward- and Stress-related Neurocognitive Processes in Individuals With Opioid Use Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cannabidiol on Reward- and Stress-related Neurocognitive Processes in Individuals With Opioid Use Disorder (NCT04982029), a randomized phase 2 study. The primary outcome is Change in Cue-reactivity.

2. Clinical Question

In clinical-trial terms, the question is whether the measured craving response differs across the cannabidiol and placebo conditions in the enrolled population. The study also lists outcomes related to delayed discounting, decision making, attentional bias, and stress reactivity. Those outcomes broaden the neurocognitive topics under study, but the registry record does not provide their numerical results or analyses.

The primary measure is a score rather than a clinical event. Its interpretation depends on the scale, the timing of the assessments, and the contrast used to define cue-induced craving. The record describes a pre-cue assessment and assessments following neutral and drug images. It states that cue-induced craving is calculated using the drug-cue and pre-cue scores. It does not give a treatment-effect estimate, an uncertainty interval, or a test of the cannabidiol-placebo comparison. Consequently, the stated research question can be described, but its answer cannot be determined from the results recorded.

3. Trial Design

The registry identifies this as a phase 2, randomized, triple-masked, placebo-controlled crossover trial. Its status is completed, and the recorded enrollment is 15. The sponsor is Brigham and Women's Hospital. The record lists a start date of 2022-04-14 and a primary completion date of 2022-12-02.

The active condition was cannabidiol 600mg, given orally as Epidiolex solution. The comparison condition was a matching placebo. The arm descriptions say that tests of reward- and stress-related neurocognitive processes followed administration. The intervention names identify cannabidiol 100 MG/ML [Epidiolex] and placebo. The registry does not describe the order in which participants received conditions, the allocation sequence, or the procedures used to preserve masking.

In general, a crossover design exposes participants to more than one study condition, so comparisons can account for measurements made within the same participant. This structure can be useful when the outcome is a repeated score and when participants can serve as their own comparison. It also means that treatment order, the interval between conditions, and possible carryover can matter to interpretation. The record specifies that visits 2 and 3 were at least 1 week apart, but it does not report a washout rationale, an assessment of carryover, or the treatment sequence. Those details should not be inferred from the design label alone.

Randomization indicates that treatment assignment involved a random process, but the registry record does not describe how it was implemented. Triple masking indicates masking of three roles or groups, but the specific roles are not reported in the registry record. The arm descriptions themselves call the study double-blind. The record does not explain this difference in terminology. It also does not report a sample-size justification or the planned statistical model. Completion status and enrollment describe the trial record, not the magnitude or precision of any treatment effect.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change in Cue-reactivity, measured over Visit 2 and 3 (at least 1 week apart).

The primary outcome is titled “Change in Cue-reactivity.” Its description focuses on cue-induced cravings measured with an Opioid Craving Scale item. Participants rated craving on a 10-point Likert scale, with 0 representing lower levels of craving and 10 indicating higher levels. The assessment was made at three time points: pre-cue, post-neutral, and post-drug images.

The registry defines cue-induced craving as the difference between the drug-cue score and the pre-cue score. This contrast is intended to distinguish craving associated with drug cues from the participant's pre-cue level. It is a score-based measure of response to an experimental cue task, rather than a direct measure of a clinical event or a long-term treatment outcome. A larger or smaller contrast would need to be interpreted using the direction and scale definition, as well as the comparison between study conditions.

The stated timeframe is visits 2 and 3, at least 1 week apart. That timing is relevant in a crossover study because measurements may be obtained under different conditions for the same participant. The record does not report how scores from the assessments or visits were combined into the primary analysis, nor does it give a numerical result. The reason for using cue reactivity is to study a reward- and stress-related neurocognitive process in the population of interest; the registry does not establish how closely this score corresponds to other outcomes that matter to participants.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods determine how measurements from a trial are converted into estimates and how uncertainty around those estimates is represented. In this record, the outcome is continuous and described in terms of a mean and standard deviation. However, no outcome analyses are reported, so the statistical concepts below explain how such data are generally interpreted; they do not describe a confirmed analysis used in this trial.

What does a mean describe?

For a continuous score, the mean describes the average score for a defined group or condition. The registry identifies the primary outcome as a score and names the mean as its parameter. A mean can give a concise account of the location of the scores, but it does not show how widely individual scores vary. It also does not by itself indicate whether a difference between conditions is precise or clinically important.

In a crossover study, the same participant may contribute measurements under multiple conditions. A comparison can therefore be based on changes within participants rather than treating each condition as if it involved entirely separate people. This can account for stable participant-level differences, but the exact model and contrast need to be specified. The registry record does not report whether the primary analysis used paired differences, a repeated-measures model, or another approach.

What does a standard deviation describe?

A standard deviation describes the spread of observations around their mean. A relatively wide spread means that scores vary more across observations; a narrower spread means they cluster more closely around the mean. It is not the same as the uncertainty in the estimated mean or the uncertainty in a treatment comparison. Those quantities also depend on the analysis structure and the information available. The registry identifies standard deviation as the dispersion measure, but reports no values for it.

How should a treatment contrast be interpreted?

A treatment contrast expresses how an outcome differs between conditions under a specified analysis. For the primary measure, the score is defined from drug-cue and pre-cue craving ratings, and the conditions are cannabidiol and placebo. A useful report would state the estimated contrast, its direction, and its uncertainty, with enough detail to make clear which condition is subtracted from which. The registry record does not report that contrast or define a subtraction order for the cannabidiol-placebo comparison.

A confidence interval is a statistical range used to express uncertainty about an estimated effect under a model. A narrower interval generally indicates greater precision than a wider interval. The interval should be interpreted together with its estimate and the study design; it is not a guarantee that the true effect lies inside the reported range. No confidence interval is reported for this primary outcome, so precision cannot be assessed from the registry results.

Why does the crossover structure matter?

General crossover analyses must account for the fact that outcomes from the same participant are related. Treating repeated measurements as independent can misrepresent uncertainty. Period, order, and carryover can also affect interpretation if a condition's influence persists or if measurements differ systematically by visit. The registry gives the visit timeframe as visits 2 and 3, at least 1 week apart, but does not report the treatment sequence, a washout period, or methods for evaluating period or carryover effects. No specific concern about these effects can be established from the record alone.

What can a p-value tell the reader?

In general, a p-value is a measure of how compatible observed data are with a specified null model, under the assumptions of the analysis. It does not give the probability that the null hypothesis is true, and it does not describe the size or practical importance of an effect. A p-value is most informative alongside an effect estimate and an uncertainty interval. No p-value or statistical test for the primary outcome is reported in the registry record.

The record also contains no reported model specification, covariate adjustment, treatment-order term, missing-data procedure, analysis population, or multiplicity adjustment. These omissions prevent a detailed appraisal of how the planned or conducted statistical analysis handled the repeated outcomes and study structure. General explanations of means, standard deviations, contrasts, confidence intervals, and p-values should not be mistaken for evidence that any particular method was used in this trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists secondary outcomes involving delayed discounting, decision making, attentional bias, stress reactivity, and physiological stress reactivity. The primary craving description also includes more than one assessment time point. When investigators assess multiple outcomes or contrasts, the chance of finding an apparently notable result by chance can increase if no multiplicity strategy is used. General approaches include designating a primary endpoint in advance, adjusting tests, or interpreting secondary analyses as exploratory. The registry record does not report a multiplicity plan, a hierarchy of tests, or adjusted results.

The record lists six outcome measures and zero analyses. It does not report which outcomes were analyzed, whether all planned outcomes were collected, or whether any analyses were omitted. No results are available for the secondary outcomes, and no explanation of their status is reported in the registry record.

Missing-data handling is also not reported. The record does not state whether outcome data were missing, how missing scores were handled, or whether any sensitivity analyses were planned or conducted. In a crossover design, missing measurements in one condition can affect the paired comparison and the participants represented in an analysis. The actual impact cannot be assessed without information about completeness and analysis methods.

Likewise, the analysis population is not described. The registry gives enrollment and group-level safety denominators, but does not say which participants contributed to the primary-outcome analysis or how exclusions were handled. The randomization method, analysis model, and assumptions for any inferential test are not reported. These gaps limit reproducibility and make it impossible to evaluate whether the reported analysis, if any, addressed all randomized participants and the planned outcomes.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry records serious adverse events for the cannabidiol and placebo conditions separately. For each condition, 15 participants are listed as at risk and 0 as affected by a serious adverse event. The other adverse-event category also lists 15 at risk and 0 affected in each condition. Deaths are listed as 0 in both conditions. No serious adverse event terms are listed.

These figures are counts as recorded, not estimates of comparative risk with uncertainty intervals. The record does not provide additional detail about how adverse events were defined, collected, or assessed, or whether the categories capture every event of interest. A zero count means that no events in that category are recorded for the listed group; it does not establish that the intervention is free from risk. Safety counts also do not answer the primary question about cue-induced craving, which is a separate score-based outcome.

12. What the Result Does, and Does Not, Mean

The registry record describes a randomized, triple-masked crossover comparison of cannabidiol and placebo in a study of reward- and stress-related neurocognitive processes among individuals with opioid use disorder. It specifies an oral cannabidiol dose of 600mg and defines a primary craving measure based on ratings before cues and after drug images. This information establishes what the study set out to examine, but not what the comparison found.

No numerical primary-outcome results or statistical analyses are reported. The record therefore does not show the size, direction, or precision of a cannabidiol-placebo difference in cue-induced craving. It also does not provide results for the listed secondary outcomes. Without estimates and uncertainty, it is not possible to distinguish a result that is compatible with little difference from one that is simply too imprecise to interpret.

The reported safety entries are limited to the listed adverse-event categories and groups. Zero recorded events in those categories should not be treated as evidence that no adverse events can occur. Nor do those counts establish a benefit or lack of benefit on the neurocognitive measures.

The population and outcome also define the scope of the research question. The study purpose concerns individuals with opioid use disorder on buprenorphine or methadone treatment, and the primary measure is an experimental craving response to cues. The record does not report enough participant detail or outcome data to extend conclusions beyond that setting. In particular, the registry information does not establish an effect on broader clinical outcomes or long-term treatment experience.

The most supportable conclusion is limited: the record documents the design, intervention conditions, outcome definition, and safety counts, while leaving the primary statistical result unreported. An interpretation of treatment effects would require the analysis estimates and their uncertainty, along with information about the methods used to account for the crossover design and repeated measurements.

13. Why This Trial Matters Statistically

This trial is statistically notable for using a crossover design to study a continuous neurocognitive score. In general, a crossover can make within-participant comparisons possible, which may help separate condition differences from stable differences between participants. At the same time, such a design requires attention to treatment order, visit effects, and possible carryover. The registry identifies the design and assessment visits, but does not report the sequence or the analytical handling of those features.

The primary outcome is also defined through a contrast between craving after drug cues and a pre-cue rating. That construction makes the outcome more specific than a single uncontextualized score, but interpretation depends on how the score is calculated and compared across conditions. The record describes the cue-related difference and scale anchors, yet does not report a treatment-effect estimate or its uncertainty.

These details matter because a clearly stated endpoint and an appropriate design do not, on their own, establish a result. Statistical interpretation requires a transparent link from the measured scores to an analysis, along with information about variability, missing observations, and the intended population for inference. The registry record reports none of the primary analyses and does not specify the statistical plan.

The record therefore illustrates a distinction between trial registration details and result reporting. Design labels and outcome definitions can clarify the scientific question, while estimates and uncertainty are needed to assess what the observed data say. With analyses unreported, the study question is identifiable but the comparative statistical evidence is not available in the registry record.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main trial-specific limitation in interpreting the record is the absence of reported analyses. Although the primary endpoint is described, there are no numerical estimates, dispersion values, confidence intervals, or test results. The record consequently does not permit an assessment of effect size or precision.

The primary outcome description uses the title “Change in Cue-reactivity” and defines cue-induced craving as the difference between drug-cue and pre-cue scores. It does not specify the exact treatment contrast, the direction of subtraction for the cannabidiol-placebo comparison, or how measurements from the visits were combined. The registry gives a timeframe of visits 2 and 3 at least 1 week apart, but does not describe the assessment schedule beyond that information.

The crossover record does not report treatment order, sequence generation, washout procedures, or analysis of period and carryover effects. Masking is described as triple in the design information and double-blind in the arm descriptions; the roles involved and the reason for the differing terms are not reported. These omissions leave important design and analysis details unresolved without demonstrating that a specific flaw occurred.

Participant characteristics beyond the study's stated population are not reported in the registry record. Nor are the sample-size rationale, statistical model, analysis population, missing-data procedures, or multiplicity strategy. The listed safety counts provide limited event information and do not supply additional evidence about the primary outcome. These limitations mean that the available registry information supports a description of the trial, but not an appraisal of its comparative treatment effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Cannabidiol on Reward- and Stress-related Neurocognitive Processes in Individuals With Opioid Use Disorder — NCT04982029.
• Registry record last updated 2023-10-05; status last verified 2023-09.
• Results first posted 2023-10-05.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes NCT04982029, a completed phase 2 randomized, triple-masked, placebo-controlled crossover trial sponsored by Brigham and Women's Hospital. It records enrollment of 15 and dates of 2022-04-14 for study start and 2022-12-02 for primary completion. The study purpose concerns reward- and stress-related neurocognitive processes among individuals with opioid use disorder receiving buprenorphine or methadone treatment.

The intervention conditions were oral cannabidiol 600mg and matching placebo. The primary outcome concerns cue-induced craving on an Opioid Craving Scale item, defined as the difference between drug-cue and pre-cue scores. Visits 2 and 3 were scheduled at least 1 week apart. The record lists secondary outcomes related to delayed discounting, decision making, attentional bias, and stress reactivity.

For both conditions, the registry lists 0 serious adverse events, 0 other adverse events, and 0 deaths. It reports six outcome measures and zero analyses. No numerical primary-outcome estimate, uncertainty interval, or statistical test is reported, so the comparative result cannot be determined from the registry record.