Treatment for Cannabis Withdrawal and Dependence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment for Cannabis Withdrawal and Dependence (NCT01611948), a randomized phase 2 study. The primary outcome is Change From Week 0 in Cannabis Use Using Urinary CN-THCCOOH Levels at Week 8.

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 2, randomized, triple-masked, parallel-group trial. Its listed enrollment is 70, and its status is completed. The record lists The Scripps Research Institute as sponsor. The start date is 2011-05 and the primary completion date is 2015-10. These registry dates describe the recorded trial timeline; they do not supply further details about recruitment, follow-up, or conduct.

Participants were assigned to an aprepitant arm or a matched placebo arm. The active regimen was aprepitant 125mg/day for 8 weeks. The comparator was a placebo pill daily for 8 weeks. Both arm descriptions include 8 weeks of manual-guided behavioral counseling, making counseling a shared component rather than the randomized difference between the arms described in the record.

The term randomized means allocation was assigned by chance, although the registry record does not report the sequence-generation method or allocation concealment. Triple masking indicates masking at three levels as recorded by the trial, but the registry record does not identify which roles were masked or describe how masking was maintained. Parallel design means the arms are concurrent treatment groups, rather than a crossover in which participants switch regimens.

The posted primary outcome is change from Week 0 in urinary CN-THCCOOH at Week 8. Results are reported as arm means and standard deviations, with outcome data for 18 participants in the aprepitant arm and 24 in the matched placebo arm. These are the outcome analysis counts; the registry record does not explain the difference between these counts and the listed enrollment in full. Two placebo participants who completed the double blind portion could not be analyzed for change because Week 0 and/or Week 8 data were missing. The record does not report a detailed analysis-population definition or a participant flow account.

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

Analysis population for the primary outcome, as defined in the registry: Two participants in the matched placebo arm who completed the double blind portion of the trial were unable to be analyzed for change in Urinary CN-THCCOOH Level due to missing data at Week 0 and/or Week 8. One sample was missing source documentation while the other sample was too dilute to return a reliable measurement.

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 From Week 0 in Cannabis Use Using Urinary CN-THCCOOH Levels at Week 8, measured over Week 0 and Week 8.

The primary endpoint is change in urinary CN-THCCOOH from Week 0 to Week 8, expressed in ng/mg. The registry defines change as the Week 8 value minus the Week 0 value. CN-THCCOOH is the creatinine-normalized urinary THC/Cr ratio. It quantifies the cannabis metabolite THC-COOH in urine, with creatinine normalization intended to reduce measurement variability attributable to urine dilution.

The registry describes this assay as a highly sensitive and specific quantitative procedure for assessing current marijuana metabolite levels and new use or abstinence. Negative values indicate decreased use. That direction matters when reading the arm means: both posted mean changes are negative, so both are in the direction of decreased urinary metabolite levels over the measurement interval. The comparison of interest, however, is the difference in mean change between the arms, not whether either arm’s mean is negative by itself.

A urinary biomarker provides a quantitative measure rather than relying only on a participant’s report of use. It is still a measure of metabolite levels, not a direct count of use occasions or a direct measure of withdrawal symptoms. The registry’s stated trial hypothesis emphasizes anxiety, mood, craving, and sleep, while the posted primary endpoint measures cannabis use through urine. The registry record lists one outcome measure and does not report posted secondary outcome results.

7. Results Posted in the Registry

• Aprepitant: 125mg/Day: mean -334.21 versus -359.95 on control; difference 25.74 (95% CI -560.47 to 611.95), standardized effect d = 0.03; z-test p = 0.931.

8. Statistical Interpretation

9. Statistical Methods Explained

What does an arm mean represent?

The primary outcome is continuous: it can take a range of quantitative values rather than being only a category. The registry reports the mean change for each arm. A mean is an average that summarizes the observed outcome values in a group. It is useful for comparing overall levels, but it does not show the full spread or shape of the individual values. In this trial, the mean changes were -334.2 ng/mg for aprepitant and -359.9 ng/mg for matched placebo. Since the outcome is defined as Week 8 minus Week 0, and negative values indicate decreased use, the signs should be interpreted in that direction.

What do standard deviations describe?

The reported standard deviations are 718.8 ng/mg for aprepitant and 1207.0 ng/mg for matched placebo. A standard deviation describes how dispersed participant measurements are around the group mean. A larger standard deviation indicates more variation in the observed measurements. It does not show how precisely the group mean has been estimated; confidence intervals address uncertainty about an estimate. The large spread relative to the mean changes means that arm averages alone do not capture the range of individual outcomes.

In general, over-dispersion means that observed variability is greater than a statistical model would expect under its assumptions. When that occurs, standard errors or confidence intervals based on an overly restrictive variance model can be misleading. The registry record reports standard deviations but does not report a distributional assessment or a model addressing over-dispersion. It is therefore not possible to say from the record whether a particular over-dispersion correction was considered or used.

How should the mean difference be read?

The posted mean difference is 25.74 ng/mg, defined by the comparison as aprepitant minus placebo. This is a contrast between the two arm averages, not a change within either arm. Its positive sign means the aprepitant arm’s mean change is numerically higher than the placebo arm’s mean change. Because negative changes indicate decreased use, the direction of a positive contrast should not be mistaken for a larger decrease in the active arm. The confidence interval and uncertainty are essential to interpreting the contrast, not just its point estimate.

What does the confidence interval contribute?

The reported confidence interval for the mean difference is -560.5 to 611.9 ng/mg. In general, a confidence interval expresses the uncertainty around an estimate under the statistical procedure used to calculate it. A wide interval indicates limited precision: a broad set of underlying differences remains compatible with the data and method. Here it spans negative and positive differences, so the posted estimate does not pin down the direction of a between-arm difference. The registry record does not describe the exact confidence-interval method.

How should the p-value be interpreted?

The posted unadjusted p-value is 0.931. In general, a p-value measures how unusual the data, or data more extreme, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not quantify the size or clinical importance of an effect. The registry record does not state the test used to obtain this p-value, so its underlying calculation cannot be independently characterized from the record. The term unadjusted indicates that the posted value is not presented as adjusted for multiple comparisons.

A p-value should be read alongside the estimated difference and its interval. Here, the p-value does not indicate a clear statistical separation between the arms, while the wide interval shows that the estimate is also imprecise. Neither feature establishes that the arms are equivalent. A formal equivalence or non-inferiority conclusion would require a prespecified margin and an analysis designed for that question; such information is not reported in the registry record.

What is the standardized effect size?

The posted standardized effect size is d = 0.025. In general, a standardized effect expresses a contrast relative to a measure of variability, so it is not in the endpoint’s original ng/mg units. Standardization can help describe the relative scale of a contrast, but it does not replace the original-unit estimate or its confidence interval. The registry record does not report a confidence interval for d. This estimate is also used as the basis of the separate planning illustration, which should not be confused with the trial’s original design calculations.

The registry record does not report a detailed statistical analysis plan, the inferential test, handling of deviations from assumptions, or any adjusted analysis. It lists zero posted analyses. General descriptions of means, standard deviations, confidence intervals, and p-values explain statistical concepts; they do not establish which undisclosed procedures were used. The reported summary statistics remain the basis for interpreting the posted result.

10. Confidence Intervals and Precision

The mean difference in change was 25.74 ng/mg, with a confidence interval from -560.5 to 611.9 ng/mg. This interval is broad relative to the point estimate and includes both negative and positive values. It therefore leaves substantial uncertainty about the direction and magnitude of the between-arm difference. The result is not precise enough to narrow the comparison to a small range of plausible values.

In general, a confidence interval gives a range of values compatible with the observed data and the method used to calculate the interval. It is not a guarantee that the true value lies inside the interval, and it is not a range containing a specified share of individual participants’ results. The interval applies to the estimated difference in arm means, whereas standard deviations describe participant-level spread. Here the arm standard deviations were 718.8 ng/mg and 1207.0 ng/mg, demonstrating notable variability in the outcome measurements.

The interval crosses from negative to positive values, so it does not establish which arm had the more favorable mean change. The posted unadjusted p-value of 0.931 is consistent with the absence of a clear statistical distinction in this comparison, but neither the p-value nor the interval demonstrates equivalence. The registry record does not report the confidence-interval method, so the specific assumptions behind its coverage cannot be assessed from the record. The interval should be read as uncertainty around the posted contrast, not as evidence that any particular value within it is equally likely.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures describe participants per arm, not total events. They are an illustration based on the observed effect, rather than the trial’s original design calculation. The assumptions listed for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set in turn to 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect.

The 80% power column gives the illustrative number of participants per arm that would be required, under those assumptions, for an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column expresses the corresponding planning target for a 90% chance. These are prospective design calculations conditional on assumptions; they are not observed results and do not describe the probability that this completed trial found a real effect. This is not observed power.

The displayed planning values are 25,066 and 33,557 participants per arm for 100% of the observed effect; 44,562 and 59,656 for 75% of the observed effect; and 100,264 and 134,225 for 50% of the observed effect, respectively for the 80% and 90% power targets. Smaller effects require more participants to detect under a fixed set of assumptions, because a smaller contrast is harder to distinguish from random variation. The registry record does not report the trial’s original sample-size justification or planning assumptions, so these illustrations should not be treated as those original calculations.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 25.740; pooled standard deviation σ = 1028.565.
2. n = 2 × (1.96 + 0.842)² × 1028.565² / 25.740² = 25,065.9, rounded up to 25,066 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 25.74                      # observed difference in means
sigma <- 1028.56464420084                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1611948)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 25,066 (80% power), 33,557 (90% power)
 75% of observed effect: n per arm = 44,562 (80% power), 59,656 (90% power)
 50% of observed effect: n per arm = 100,264 (80% power), 134,225 (90% power)
power.t.test: 25066.9 
Simulated power at n = 25,066 per arm: 0.805 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when analyses examine multiple outcomes, time points, comparisons, or subgroups. Repeated opportunities to test hypotheses can increase the chance of obtaining an apparently notable result by chance. The registry record lists one outcome measure and zero posted analyses, and it provides one primary outcome result. It does not report a multiplicity-adjustment plan or say whether additional analyses were conducted but not posted. The posted p-value is explicitly unadjusted, so it should not be represented as corrected for multiple testing.

The registry’s brief summary identifies withdrawal symptoms, including anxiety, mood, craving, and sleep, as central to the trial hypothesis. The posted primary outcome instead measures change in urinary CN-THCCOOH. No secondary results are posted in the record. The absence of those results means the primary urinary finding cannot stand in for results on withdrawal symptoms or other outcomes.

Missing data affect the interpretation of the primary outcome. The outcome description says two participants in the matched placebo arm completed the double blind portion but could not be analyzed for change because Week 0 and/or Week 8 data were missing. One sample was missing source documentation, and the other was too dilute to return a result. The record does not state whether additional data were missing in other circumstances, what imputation or sensitivity methods were considered, or how the analysis population was defined beyond the posted arm counts.

The posted outcome counts are 18 in the aprepitant arm and 24 in the placebo arm. These counts should not be treated as a complete account of participant disposition. The registry record does not explain all differences between listed enrollment and the outcome counts, or report a full flow of participants by stage. It also does not report whether the primary comparison followed an intention-to-treat principle, a per-protocol principle, or another analysis-population definition. Consequently, the posted estimate is best understood as the reported comparison among the participants represented in the outcome results, with limitations from unreported analysis and missing-data details.

14. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The safety record reports serious adverse events for 32 participants at risk in the aprepitant group and 38 participants at risk in the matched placebo group. Serious adverse events affected 0 in each group. No serious adverse-event terms are listed. These figures describe the reported serious-event results and do not establish that no event of any kind occurred.

The record also reports other adverse events affecting 20 participants in the aprepitant group and 28 in the matched placebo group. Those are not the serious adverse-event figures and should not be combined with them. The safety at-risk counts differ from the posted primary-outcome counts; the registry record does not explain the difference, so the denominators should be kept specific to each result rather than treated as interchangeable.

Death counts are not reported in the registry record. The listed safety figures do not give event timing, severity beyond the serious classification, causal attribution, or statistical comparisons between groups. They are descriptive registry counts, not proof of equal safety or a complete assessment of risk.

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

The posted primary result is an uncertain comparison of average urinary CN-THCCOOH change from Week 0 to Week 8. Both arm means are negative, consistent with decreased use under the endpoint definition, while the estimated between-arm difference is 25.74 ng/mg. Its confidence interval, -560.5 to 611.9 ng/mg, spans values in both directions, and the unadjusted p-value is 0.931. Taken together, the posted statistics do not show a clear difference between the arms, but they also do not establish equivalence or rule out potentially meaningful differences.

The result applies to the specific urinary measure and time point reported. It is not a direct finding about anxiety, mood, craving, sleep, or other withdrawal symptoms, even though those are central to the trial’s stated hypothesis. The registry record does not post secondary outcome results. It also does not report longer-term outcomes, so the Week 8 comparison cannot answer whether any change persisted beyond the measured interval.

The trial compared aprepitant with matched placebo while both arms received manual-guided behavioral counseling. The posted contrast therefore concerns the difference between those regimens against that shared counseling background, as recorded. It does not isolate the effect of counseling, and the record does not report counseling adherence or delivery details. The outcome analysis includes 18 aprepitant participants and 24 placebo participants; two placebo participants who completed the double blind portion could not be analyzed for change because data were missing or unusable.

These observations should be understood as a registry result with important limits in precision and reporting detail. The registry record does not report a full analysis plan, detailed missing-data approach, or original sample-size rationale. The findings describe the posted data; they do not by themselves establish that aprepitant works or does not work, nor do they support medical advice.

16. Why This Trial Matters Statistically

This trial illustrates why a mean difference should be read together with its uncertainty. The arm means are both negative, but the primary scientific comparison is the contrast between them. That contrast is 25.74 ng/mg, with a confidence interval extending from -560.5 to 611.9 ng/mg. A reader who focused only on the direction of the arm means could miss how uncertain the between-arm estimate is; a reader who focused only on the p-value could miss the range of effects still compatible with the interval.

It also illustrates the distinction between an outcome’s clinical framing and its statistical measurement. The registry describes a trial motivated by cannabis withdrawal and names anxiety, mood, craving, and sleep in its hypothesis. Its posted primary measure is instead a creatinine-normalized urinary metabolite change. The endpoint gives a quantitative measure related to cannabis use, but it does not directly report those symptoms. Keeping the distinction clear prevents a result for one measure from being generalized to another.

The outcome and safety denominators also illustrate why analysis populations matter. The primary outcome counts are 18 and 24, while the safety record uses at-risk counts of 32 and 38. These sets of counts serve different results, and the registry does not provide a full explanation of participant flow. The documented missing outcome data in the placebo arm further shows why missingness and analysis rules are relevant to interpreting a result, even when the posted summary statistics are available.

Finally, the planning illustration makes the scale of a proposed future study depend strongly on the assumed effect. Smaller effects require more participants under the stated assumptions. Such calculations are not the original trial design rationale and are not observed power. This distinction is central to sound statistical interpretation: study-planning scenarios, posted findings, and unreported design decisions answer different questions.

17. 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 posted mean difference is imprecise, with a confidence interval that spans negative and positive values. The arm standard deviations are large relative to the mean changes, indicating substantial spread in the observed outcome. The registry record does not report the interval method or the inferential test, limiting assessment of the assumptions behind the reported uncertainty and p-value.

Outcome data were not analyzable for two placebo participants who completed the double blind portion because Week 0 and/or Week 8 data were missing. The description identifies missing source documentation for one sample and excessive dilution for the other. The registry record does not describe a missing-data strategy, sensitivity analyses, or the full analysis-population definition. It reports 18 aprepitant and 24 placebo participants for the primary outcome but does not provide a complete participant flow explanation.

The primary result is for urinary CN-THCCOOH at Week 8 relative to Week 0. It does not directly answer the trial’s stated questions about anxiety, mood, craving, or sleep, and no secondary results are posted. The record does not report outcomes beyond the stated timeframe, adherence to the assigned regimen, counseling attendance, or details of how counseling was delivered.

Although the trial is described as randomized and triple-masked, the registry record does not describe sequence generation, concealment, which roles were masked, or how masking was maintained. It does not report a detailed statistical analysis plan or the trial’s original sample-size assumptions. Safety counts are descriptive; the record does not provide deaths, event attribution, or comparative safety analyses. These reporting limits mean the posted summaries cannot answer every question about trial conduct, missingness, or the broader clinical effects of the regimens.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Treatment for Cannabis Withdrawal and Dependence — NCT01611948.
• Registry record last updated 2017-05-01; status last verified 2017-03.
• Results first posted 2017-03-27.
• 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.

21. Record Summary

NCT01611948 is a completed Phase 2 randomized, triple-masked, parallel trial sponsored by The Scripps Research Institute. It compared aprepitant 125mg/day for 8 weeks with matched placebo, with manual-guided behavioral counseling in both arms. Listed enrollment was 70.

The primary outcome was change in urinary CN-THCCOOH from Week 0 to Week 8, measured in ng/mg. Mean changes were -334.2 for aprepitant and -359.9 for placebo. The estimated mean difference was 25.74, with a confidence interval from -560.5 to 611.9 and an unadjusted p-value of 0.931. Outcome analysis counts were 18 and 24, respectively. The registry record reports no secondary results and does not report a detailed analysis plan or original sample-size justification.