Abstract
Background
Comorbidity between alcohol use disorder (AUD) and post‐traumatic stress disorder (PTSD) exacerbates symptom severity and worsens treatment outcomes. Limited clinical research suggests that cannabidiol (CBD) may have therapeutic effects on anxiety disorders and addictive behavior, but efficacy has not been established.
Methods
Two proof‐of‐concept trials of CBD were conducted simultaneously. In Study 1, 27 adults with moderate to severe AUD were randomized to CBD [600 mg/day for 4 weeks, then 1200 mg/day for 4 weeks] versus placebo. In Study 2, 30 adults with AUD plus DSM‐5 PTSD or subthreshold post‐traumatic stress disorder (PTSD) were randomized to CBD 600 mg/day vs. placebo for 6 weeks. The trials assessed CBD pharmacokinetics, safety and tolerability, alcohol consumption, craving, mood and anxiety symptoms, and, in Study 2, PTSD symptom severity. Efficacy analyses used mixed‐effects models, and the primary drinking outcome was the average number of drinks per day during treatment.
Results
CBD was rapidly absorbed, achieving near‐steady‐state trough levels by week 1, with dose‐dependent increases during weeks 5–8 in Study 1. Mean trough and estimated peak CBD levels at week 4 (n = 20) were 31.15 (SD: 21.22) ng/mL and 130.75 (SD: 152.57) ng/mL, respectively. Few safety concerns emerged, but 7/31 (22.6%) of participants assigned to CBD experienced dose‐limiting side effects. In both studies, participants in both treatment groups showed large reductions in drinks per day and percentage heavy drinking days during treatment (Cohen's dz. > 0.9). Neither trial demonstrated superiority of CBD over placebo for drinking outcomes, craving, mood, anxiety, or PTSD symptoms.
Conclusions
These findings support the feasibility and tolerability of twice‐daily oral CBD up to 1200 mg/day in actively drinking individuals but do not demonstrate efficacy at the CBD levels that were achieved in this study. Further dose finding and larger, well‐powered trials are needed to clarify CBD's therapeutic potential in AUD and comorbid PTSD.
Keywords: alcohol use disorder, cannabidiol, comorbidity, post‐traumatic stress disorder
Two small placebo‐controlled trials evaluated the effects of cannabidiol (CBD) in patients with alcohol use disorder (AUD), with and without co‐occurring post‐traumatic stress disorder (PTSD). CBD was rapidly absorbed and generally well tolerated in dosages of up to 1200 mg/day. Both treatment groups showed large reductions in drinking. However, neither trial demonstrated superiority of CBD over placebo for AUD or PTSD symptoms. Well‐powered trials are needed to clarify CBD's therapeutic potential in AUD and comorbid PTSD.
INTRODUCTION
High rates of comorbidity have been consistently observed between alcohol use disorder (AUD) and post‐traumatic stress disorder (PTSD; Baker et al., 2009, Jacobsen et al., 2001, Kessler et al., 1997, McCarthy & Petrakis, 2010, Pietrzak et al., 2011), and evidence suggests that this comorbidity exacerbates symptomatology and results in less favorable treatment outcomes, relative to each disorder alone. Animal models show that circuitry within the extended amygdala plays a central role in both the stress response and alcohol craving, and that pharmacological inhibition of stress or ethanol‐withdrawal‐associated activity in this circuit simultaneously reduces both anxiety and ethanol‐seeking behaviors (de Guglielmo et al., 2016; Gilpin, 2012; Gilpin & Roberto, 2012). In AUD patients who report drinking alcohol to cope with negative emotions, higher amygdala reactivity predicts future problem drinking (Nikolova et al., 2016). In PTSD/subthreshold PTSD patients, PTSD symptoms predict alcohol craving and use (Freeman & Kimbrell, 2004; Saladin et al., 2003). Furthermore, patients with PTSD/subthreshold PTSD demonstrate exaggerated amygdala response and heightened sympathetic physiological arousal in response to threat, relative to healthy controls (Garfinkel et al., 2014; Milad et al., 2009; Pole, 2006). Among patients with comorbid PTSD and AUD, exposure to trauma imagery elicits negative emotion, physiological arousal, and alcohol craving (Coffey et al., 2006, 2010; Kwako et al., 2015; Nosen et al., 2014; Petrakis et al., 2016).
Cannabidiol (CBD) has attracted considerable interest as a potential medical treatment for substance use disorders (Bhardwaj et al., 2024; Kohne et al., 2024; Paulus et al., 2022), anxiety disorders (Blessing et al., 2015; Han et al., 2024), and stress‐related disorders (Lookfong et al., 2023), due to its ability to act on neurobiological targets that are relevant to all of these conditions. In animal models, CBD produces anxiolytic, anti‐compulsive, anti‐fear‐conditioning, and pro‐fear‐extinction effects, by acting at serotonin 1A (5‐HT1A) and CB1 receptors within extended amygdala areas [the central nucleus (Hsiao et al., 2012), bed nucleus of the stria terminalis (Alves et al., 2010, Gomes et al., 2013), and nucleus accumbens shell (Norris et al., 2016)] and within functionally connected brain regions including the periaqueductal gray (Soares Vde et al., 2010), prelimbic (Lemos et al., 2010), and infralimbic (Do Monte et al., 2013) regions of the medial prefrontal cortex and hippocampus (Campos et al., 2013). CBD also potently reduced ethanol seeking in animal models of relapse during 7 days of treatment, and drug seeking remained fully attenuated up to 5 months following treatment termination (Gonzalez‐Cuevas et al., 2018). A recently published placebo‐controlled human laboratory study in 28 non‐treatment‐seeking participants with AUD demonstrated that a single 800 mg dose of CBD (n = 14) significantly attenuated nucleus accumbens activation and alcohol craving during an fMRI alcohol cue exposure task, as well as reducing alcohol craving induced by a combined stress/alcohol cue exposure task (Zimmermann et al., 2024).
In spite of these suggestive findings, results of clinical trials of CBD for treatment of SUDs and anxiety disorders have yielded mixed results (Dammann et al., 2024). To date, the only published trial evaluating the effects of CBD in patients with AUD is a feasibility study that demonstrated the tolerability of CBD dosages of approximately 150 mg/day, but did not provide strong evidence for or against efficacy (Mueller et al., 2025). There have been no trials published evaluating the effects of CBD in PTSD. To begin to address this knowledge gap, we conducted two small, double‐blind, randomized trials to explore the effects of CBD in AUD and in AUD with co‐occurring PTSD (Studies 1 and 2, respectively), relative to inactive placebo. Both studies aimed to (1) evaluate circulating CBD levels observed over 6–8 weeks of twice‐daily dosing; (2) evaluate the safety and tolerability of CBD at the dosages administered; (3) evaluate the effects of CBD on self‐report measures of craving, anxiety, mood, and self‐efficacy; and (4) evaluate the effects of CBD on drinking outcomes. Study 2 also investigated the effects of CBD on symptoms of PTSD. Because of the high degree of overlap in the aims and measures of the two studies, and because both were small and exploratory in nature, we have chosen to present the primary results of both studies together in a single paper.
MATERIALS AND METHODS
Trial oversight
The studies were reviewed and approved by NIAAA, the FDA, the DEA, and the institutional review board of New York University Grossman School of Medicine. One of the authors (MPB) was the IND holder for both trials. The studies were pre‐registered at clinicaltrials.gov (NCT03252756 and NCT03248167 for studies 1 and 2, respectively) and were overseen by the same Data and Safety Monitoring Board. Cannabidiol was provided by Tilray Canada. All participants provided written informed consent. The funders played no role in the design, conduct, analysis, and reporting of the trial.
Trial design
Overview
Both studies were double‐blind, randomized, placebo‐controlled trials evaluating the efficacy of CBD in the treatment of alcohol use disorder. Study 1 included only AUD patients without PTSD, while Study 2 included only AUD patients with PTSD or subthreshold PTSD. The studies were conducted simultaneously at the same facility, and the protocols were almost identical in many respects, allowing data to be pooled for some analyses. The salient similarities and differences between the two studies are described below.
Participants
Participants were recruited at New York University from August 28, 2019, to January 4, 2022, for Study 1 and from September 6, 2019, to February 8, 2022, for Study 2, using advertisements in local media and social media. Participants in both studies were adults with moderate to severe AUD who had at least 6 (AUD study) or 4 (AUD‐PTSD study) heavy drinking days in the 30 days preceding screening (defined as ≥56 g of ethanol in a day for a woman, ≥70 g for a man), were not currently in treatment for AUD or PTSD, reported a desire to stop or reduce drinking alcohol, and agreed to abstain from cannabis and any other non‐study cannabinoid for the duration of the study. Participants in Study 2 were also required to have a DSM‐5 diagnosis of PTSD or meet criteria for subthreshold PTSD, defined as having at least six symptoms of PTSD across criteria B–E but not meeting all criteria. Participants were excluded from the study at screening if they had clinically significant alcohol withdrawal; exclusionary medical conditions including significant hepatic dysfunction and type I diabetes; exclusionary psychiatric conditions including schizophrenia, schizoaffective disorder, bipolar disorder, current suicidality or homicidality, history of severe traumatic brain injury, other current moderate to severe non‐nicotine substance use disorder or any current cannabis use disorder, current pregnancy or lactation, urine drug screen positive for THC, cocaine or opioids or current use of exclusionary medications, including any pharmacotherapy for alcohol use disorder or any medication with possibly significant pharmacokinetic interactions with CBD.
Source of study medication
cGMP study medication was obtained for both studies from Tilray Canada. Study medication was provided as capsules for oral administration. CBD capsules contained CBD 200 mg in an oil‐based formulation. Placebo capsules were identical in appearance and contained the same ingredients, minus the CBD. The CBD was hemp‐derived and had a THC content of <0.1%. Therefore, a 600‐mg dose of CBD contained less than 0.6 mg of THC.
Randomization and blinding
An unblinded study statistician assigned participants to a treatment group in the order they qualified for each study, using separate pre‐existing allocation sequences for each study. In Study 1, participants were randomized to CBD versus placebo in the ratio 1:1, while in Study 2, the ratio was 5:3. Randomization was stratified by AUD severity (moderate vs. severe) in each study. Medication was dispensed by an unblinded study team member who had no interaction with study participants. All other study team members and participants remained blind to treatment assignment until study data had been locked.
Dosage and administration of study medication
In Study 1, participants assigned to active treatment were prescribed CBD 600 mg/day (400 mg in the morning and 200 mg in the evening) for 4 weeks, followed by CBD 1200 mg/day (600 mg twice daily) for 4 weeks (8 weeks total). Medical management (MM) visits were scheduled at baseline (start of medication), 1 week, 4 weeks, 5 weeks, 8 weeks, and 9 weeks (post‐treatment follow‐up). In Study 2, participants received CBD 600 mg/day (dosage divided as in Study 1) for 6 weeks, with MM visits at Baseline, 1 week, 2 weeks, 4 weeks, 6 weeks, and 7 weeks (post‐treatment follow‐up).
Participants in both studies were evaluated by a physician or nurse practitioner at each MM visit. MM visits were conducted using manualized procedures based on those used in the COMBINE trial (Anton et al., 2006). The first dose of study medication was administered on‐site in the morning, following the completion of baseline assessments. At each visit, participants received enough study medication to last until the next study visit, plus several days extra in case of scheduling difficulties. Both protocols allowed the dosage to be reduced or titrated if participants were unable to tolerate the full dosage.
Adherence monitoring
Adherence was monitored using pill counts and cell phone‐based video monitoring (emocha Mobile Health Inc.). Participants were instructed to make a video recording of their consumption of each dose of study medication, and these videos were reviewed by study clinicians prior to each study visit.
Measures
Diagnoses
In both studies, trained staff administered the Structured Clinical Interview for DSM‐5 (SCID) (First et al., 2015) to determine substance use disorder diagnoses and exclusionary psychiatric disorders. In Study 2, the Clinician Administered PTSD Scale for DSM‐5 (CAPS‐5) (Weathers et al., 2018) was used to determine PTSD or subthreshold PTSD.
Trough and estimated peak cannabinoid levels
Plasma levels of CBD, Delta‐9 Carboxy THC, Delta‐9 THC, and 11‐Hydroxy Delta‐9 THC were determined via high‐performance liquid chromatography/tandem mass spectrometry (LC–MS/MS) at Dr. Thomas Neubert's Lab at the Department of Cell Biology at NYU Langone Health. Levels were obtained at baseline and at specified time points for each of the study protocols. Depending on the time point, blood samples were obtained prior to participants taking their morning dose of study medication (trough levels) and/or 45 min after taking their morning dose, which was chosen to approximate peak CBD levels based on the reported pharmacokinetics of the CBD formulation used in both trials.
Drinking and AUD‐related measures
Alcohol consumption was assessed primarily with Time‐line Follow‐back (TLFB) (Sobell et al., 1988). Percent carbohydrate‐deficient transferrin (CDT) in serum (assayed at ARUP Laboratories) was used as a secondary, objective measure of alcohol use. CDT levels of 1.7% or greater were considered abnormal and suggestive of chronic heavy drinking (at least 40 g of ethanol per day for at least 2 weeks). The Penn Alcohol Craving Scale (PACS) (Flannery et al., 1999) was used to assess alcohol craving. The Clinical Institute Withdrawal Scale‐Alcohol, revised (CIWA‐Ar) (Sullivan et al., 1989) was used to assess alcohol withdrawal, with clinically significant withdrawal defined as a score ≥8. An immunoassay‐based urine drug screen (UDS) was obtained at in‐person study visits to verify lack of recent use of cannabis (THC > 50 ng/mL) and other drugs of abuse. Breath alcohol concentration (BAC) was also measured at each visit.
PTSD, depression, and anxiety outcomes
In Study 2, PTSD symptoms were assessed with the PTSD checklist for the DSM‐5 (PCL‐5) (Bovin et al., 2016), assessed before CBD or placebo treatment (baseline), at weeks 2, 4, and 6 of treatment, and 1 week after the completion of treatment (week 7). In both studies, depression and anxiety were measured with the Beck Anxiety Inventory (BAI) (Beck et al., 1997) and Beck Depression Inventory‐II (BDI‐II) (Beck, 1961) scales, respectively.
Safety and tolerability outcomes
Adverse events (AEs) were solicited during all visits occurring after randomization, using the General Inquiry from the Systemic Assessment for Treatment of Emergent Events (SAFTEE) (Johnson et al., 2005). To assess liver function, liver enzymes were measured in blood samples obtained at screening, during treatment, and 1 week after completion of study treatment. Suicidality was assessed by a licensed Clinical Psychologist, Nurse Practitioner, or MD as part of each MM visit, using the Columbia‐Suicide Severity Rating Scale (C‐SSRS) (Posner et al., 2011).
Statistical analysis
Sample size and power
Studies 1 and 2 were designed as proof‐of‐concept studies rather than well‐powered efficacy studies. With planned sample sizes of 40 and 48 randomized participants, respectively, the studies had adequate power to provide reasonable estimates of average blood levels and to detect large (Cohen's d > 0.9) between‐group effects. However, recruitment for both studies was delayed due to challenges in obtaining cGMP CBD. The onset of the COVID‐19 pandemic resulted in further delays as recruitment was suspended from March to August 2020, then restarted under significant restrictions. Therefore, the final sample sizes were somewhat smaller than planned. Because both studies used identical dosages of medication for weeks 1–4, we conducted analyses of week 1–4 outcomes for the combined sample as well as for both studies separately. The larger sample size (n = 54 evaluable subjects: 29 receiving CBD and 25 receiving placebo) yielded 80% power to detect an effect of d = 0.78 for analyses of 4‐week outcomes for the combined sample. Due to the exploratory nature of the study, we chose to report nominal p‐values with the significance level set at p < 0.05, without correction for multiplicity.
Cannabinoid levels
All analyses were conducted in SPSS version 28.0.1.1. For each study and for the combined sample (weeks 1–4), trough and estimated peak levels of CBD were plotted for each participant who received CBD and provided samples for plasma level determination. Mean values and standard deviations were computed for Study 1 participants, Study 2 participants, and the combined sample for weeks 1–4. Time points within each group were contrasted using paired t‐tests.
Efficacy for AUD
The primary self‐reported drinking outcome was the average number of standard drinks per day, with 1 standard drink defined as 14 g ethanol. The secondary drinking outcomes were the percentage of heavy drinking days (PHDD) during each week of follow‐up and carbohydrate‐deficient transferrin (CDT) levels. A heavy drinking day was defined as four or more standard drinks in a day for female participants and five or more standard drinks in a day for male participants. Paired t‐tests were used to compute within‐group effect sizes (Cohen's dz. with Hedges' correction for small samples) for change from baseline. Efficacy analyses used mixed models for repeated measures (MMRMs) to evaluate the effect of treatment assignment on outcomes during active treatment (weeks 1–8 for study 1, weeks 1–6 for study 2). MMRMs included all randomized participants who received one dose of study medication. For self‐reported drinking outcomes from the TLFB, levels of time were included for each week of treatment, and time, treatment group (CBD vs. placebo), the time‐by‐treatment interaction, and the pretreatment value of the dependent variable were included as fixed effects. Analyses combining participants from both trials included only outcome data for weeks 1–4. CDT levels were modeled analogously, except that only two post‐randomization measurements were available for each study (weeks 4 and 8 for Study 1; weeks 4 and 6 for Study 2). To evaluate the effect of treatment on CDT levels in the combined sample (week 4 only), ANCOVA was used, with baseline CDT value included as the covariate. 95% confidence intervals were computed for all efficacy outcomes.
Efficacy for PTSD, depression, and anxiety
For Study 2, the PTSD outcome was the total PCL‐5 score during treatment. For both studies, the effect of treatment on mood and anxiety symptoms was evaluated based on total scores on the BDI‐II and BAI, respectively. These outcomes were analyzed using MMRM models analogous to those described for the drinking outcomes above.
Exploratory analyses
Due to the considerable variability in CBD levels among participants assigned to CBD, exploratory analyses evaluated the relationship between CBD levels and clinical response. First, we computed Pearson correlations between week 4 trough and estimated peak CBD levels and observed change in measures of drinking (DPD, PHDD), alcohol craving (PACS), depression, (BDI‐II), anxiety (BAI), and PTSD symptoms (PCL‐5, Study 2 only). Change was defined as the mean of the week 4 value minus the pretreatment value of the outcome variable. Second, we divided the participants treated with CBD into two groups (high level and low level) using median splits with respect to their peak and trough CBD levels at week 4. t‐tests were then used to compare change in the same clinical outcomes across the two groups.
Safety
AEs occurring after drug exposure were coded using MedDRA Version 25.1 and tabulated by treatment group for each study and for both studies combined.
RESULTS
Participants
Figure 1 summarizes recruitment of participants, treatment exposure, and retention. In Study 1, 27 participants were randomized, 14 to CBD, and 13 to placebo. One participant randomized to CBD withdrew before receiving study medication and was excluded from both the safety sample and the efficacy sample. One participant randomized to placebo received study medication but did not provide any post‐randomization efficacy data. This participant was included in the safety sample but excluded from the efficacy sample. In Study 2, 30 participants were randomized, 17 to CBD, and 13 to placebo. One participant randomized to CBD received study medication but did not provide any post‐randomization efficacy data. This participant was included in the safety sample but excluded from the efficacy sample.
FIGURE 1.
Consort flow diagram.
Table 1 summarizes characteristics of and disposition of the efficacy samples in each condition of each study. Among the 54 evaluable participants across the two studies, 26 participants (48.1%) were female. Participants averaged 39.7 (SD: 10.5) years of age, 4.98 (SD: 2.45) drinks per day, and 53.0 (SD: 27.1) PHDD in the month prior to screening. In Study 2, 20 participants (66.7%) met full diagnostic criteria for PTSD, and the mean PCL score was 45.6 (SD: 13.9), in the moderate range of PTSD severity. No significant differences in demographics or drinking behavior were observed between the two studies or between treatment conditions. However, baseline mood and anxiety symptoms were significantly greater in Study 2 participants (BDI‐II: t(41.2) = 5.350, p < 0.001; BAI: t(42.7) = 4.171, p < 0.001).
TABLE 1.
Baseline sample characteristics.
| Study 1 | Study 2 | Studies combined | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CBD (n = 13) | Placebo (n = 12) | Total (n = 25) | CBD (n = 16) | Placebo (n = 13) | Total (n = 29) | CBD (n = 29) | Placebo (n = 25) | Total (n = 54) | ||||||||||
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | |
| Gender | ||||||||||||||||||
| Male | 8 | 61.5% | 9 | 75.0% | 17 | 68.0% | 5 | 31.3% | 6 | 46.2% | 11 | 37.9% | 13 | 44.8% | 15 | 60% | 28 | 51.9% |
| Female | 5 | 38.5% | 3 | 25.0% | 8 | 32.0% | 11 | 68.8% | 7 | 53.8% | 18 | 62.1% | 16 | 55.2% | 10 | 40% | 26 | 48.1% |
| Race and ethnicity | ||||||||||||||||||
| Black | 7 | 53.8% | 2 | 16.7% | 9 | 36.0% | 8 | 50.0% | 4 | 30.8% | 12 | 41.4% | 15 | 51.7% | 6 | 24% | 21 | 38.9% |
| White | 5 | 38.5% | 8 | 66.7% | 13 | 52.0% | 6 | 37.5% | 7 | 53.8% | 13 | 44.8% | 13 | 44.8% | 15 | 60% | 26 | 48.1% |
| Other | 1 | 7.7% | 2 | 16.7% | 3 | 12.0% | 2 | 12.5% | 2 | 15.4% | 4 | 13.8% | 3 | 10.3% | 4 | 16% | 7 | 13.0% |
| Hispanic/Latinx | 2 | 15.4% | 4 | 33.3% | 6 | 24.0% | 8 | 50.0% | 4 | 30.8% | 12 | 41.4% | 10 | 33.5% | 8 | 32% | 18 | 33.3% |
| Non‐Hispanic | 11 | 84.6% | 8 | 66.7% | 19 | 76.0% | 8 | 50.0% | 9 | 69.2% | 17 | 58.6% | 19 | 65.5% | 17 | 68% | 36 | 66.7% |
| Elevated CDT | 6 | 60.0% | 4 | 40.0% | 10 | 50.0% | 2 | 15.4% | 5 | 50.0% | 7 | 30.4% | 8 | 34.8% | 9 | 45.0% | 17 | 39.5% |
| Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | 39.2 | 11.6 | 43.2 | 10.0 | 41.1 | 10.8 | 39.3 | 10.6 | 37.7 | 10.1 | 38.6 | 10.2 | 39.2 | 10.9 | 40.3 | 10.2 | 39.7 | 10.5 |
| DPD | 4.61 | 2.17 | 5.38 | 2.40 | 4.98 | 2.27 | 4.67 | 2.85 | 5.36 | 2.39 | 4.98 | 2.63 | 4.65 | 2.53 | 5.37 | 2.35 | 4.98 | 2.45 |
| PHDD | 46.7 | 28.3 | 58.6 | 30.1 | 52.4 | 29.2 | 50.6 | 24.0 | 57.7 | 28.0 | 53.8 | 25.7 | 48.9 | 25.6 | 58.1 | 28.4 | 53.0 | 27.1 |
| CDT | 1.78 | 1.04 | 3.03 | 3.60 | 2.41 | 2.66 | 1.13 | 0.59 | 2.57 | 2.84 | 1.76 | 2.01 | 1.41 | 0.86 | 2.80 | 3.17 | 2.06 | 2.33 |
| BAI score | 8.0 | 7.4 | 6.9 | 5.1 | 7.5 | 6.3 | 14.9 | 13.3 | 22.9 | 10.2 | 18.5 | 12.5 | 11.8 | 114 | 15.2 | 11.4 | 13.4 | 11.4 |
| BDI Score | 9.9 | 7.9 | 9.3 | 7.2 | 9.6 | 7.4 | 26.3 | 16.7 | 28.0 | 14.9 | 27.0 | 15.6 | 18.9 | 15.6 | 19.0 | 15.0 | 19.0 | 15.2 |
| PACS Score | 17.8 | 5.5 | 14.2 | 4.6 | 16.1 | 5.3 | 17.0 | 7.9 | 19.2 | 7.0 | 18.0 | 7.5 | 17.3 | 6.8 | 16.9 | 6.4 | 17.1 | 6.6 |
| PCL‐5 Score | 42.8 | 14.9 | 49.2 | 12.0 | 45.6 | 13.9 |
Note: Data for the efficacy sample are shown, that is, the 54 participants who received at least one dose of study medication and provide outcome data for at least one post‐randomization time point. Baseline data were available for all participants with the exception of CDT. Elevan participants (5 in Study 1 and 6 in Study 2) had missing values for CDT because the laboratory reported that results were invalid.
Treatment exposure and retention in efficacy sample
Overall treatment adherence was good across both studies, with 67.7% of participants in Study 1 and 70% of participants in Study 2, respectively, completing the full 8‐ or 6‐week course of treatment (See Figure 1). Medication adherence while in treatment was also good. Based on pill counts, CBD participants in Study 1 took 93.0% (SD: 11.9%) of prescribed doses while remaining in treatment versus 91.6% (SD: 16.9%) of participants receiving placebo. In Study 2, participants took 89.0% (SD: 13.8%) of prescribed doses while remaining in treatment versus 88.7% (SD: 7.4%) of participants receiving placebo. Most participants took the full target dosage of study medication while in treatment throughout the study. However, three participants assigned to CBD in Study 1 took reduced dosages of medication for at least part of the study due to treatment‐emergent AEs. The maximum tolerable daily dosages for these participants were 800, 1000, and 1200 mg. Three participants assigned to CBD in Study 2 also took reduced dosages due to AEs; maximum dosages tolerated among these participants were 400 mg for each.
Of 25 participants, 19 (76%) in Study 1 provided the full 8 weeks of efficacy data. Retention did not differ significantly between the CBD and placebo groups (CBD group: mean 6.2 weeks, SD: 2.9 weeks; placebo group: mean 6.8 weeks, SD: 2.7 weeks). Similarly in Study 2, 21/29 participants (72%) provided the full 6 weeks of efficacy data, and retention did not differ significantly between treatment groups (CBD group: mean 5.1 weeks, SD: 1.6 weeks; placebo group: mean 4.8 weeks, SD: 1.9 weeks).
CBD/cannabinoid levels
Figure 2 illustrates trough and estimated peak CBD levels for each participant assigned to CBD, as well as the mean level at each time point for each study separately and for the combined sample for weeks 1–4, during which participants assigned to CBD in both studies were prescribed CBD 600 mg/day. Table 2 displays mean trough and estimated peak CBD levels (mean, SD) for participants who provided blood samples at each time point. During the first 4 weeks of treatment, when participants in both studies received a CBD dose of 600 mg/day, there were no significant differences between the two studies in mean peak or trough CBD levels (p > 0.05, Welch's t‐tests). For the studies combined, trough and estimated peak CBD levels at week 4 (n = 20) were 31.15 (SD: 21.22) and 130.75 (SD: 152.57) ng/ml, respectively. Paired t‐tests including adherent participants from both studies showed that week 4 trough levels were not significantly higher than week 1 levels (t(18) = 0.840, p = 0.412), suggesting that steady‐state levels were approached within 1 week. Similarly, although week 1 estimated peak CBD levels were significantly higher than day 1 levels (t(26) = 3.233, p = 0.003), week 4 levels were non‐significantly higher than week 1 levels (t(18) = 1.835, p = 0.083). In Study 1, trough CBD levels increased significantly during week 5 following the increase from 600 mg to 1200 mg CBD daily (week 5 vs. week 4: t(7) = 4.939, p = 0.002). However, the increase from week 5 to week 8 did not approach statistical significance (t(5) = 0.511, p = 0.631). Estimated peak CBD levels did not increase significantly from week 4 to week 5 (t(7) =0.232, p = 0.823) or week 8 (t(5) =1.001, p = 0.363). One week after discontinuation of medication, CBD levels remained detectable in both studies (See Table 2).
FIGURE 2.
Trough and estimated peak levels of cannabidiol in Study 1 and Study 2, and the combined sample for weeks 1–4. Individual participants' data are indicated by different colors. Those taking reduced dosages of CBD are shown in gray. The bold red line represents the mean value of observations at each time point. Blood samples for trough levels were drawn in the morning prior to the morning dose of study medication. Estimated peak samples were drawn 45 min after an observed morning dose. The y‐axis represents CBD level in ng/mL.
TABLE 2.
Trough and estimated peak CBD levels (all available data).
| Time point | Study 1 | Study 2 | Studies combined | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Trough | Estimated peak | Trough | Estimated peak | Trough | Estimated peak | |||||||||||||
| N | Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | |
| Day 0 | 12 | 0.70 | 2.41 | 12 | 52.04 | 68.78 | 17 | 0.92 | 3.79 | 17 | 40.33 | 49.48 | 29 | 0.83 | 3.24 | 29 | 45.18 | 57.38 |
| Week 1 | 12 | 22.79 | 16.44 | 12 | 83.67 | 67.34 | 14 | 27.64 | 31.54 | 15 | 67.22 | 70.12 | 26 | 25.40 | 25.34 | 27 | 74.53 | 68.09 |
| Week 2 | 13 | 25.51 | 24.67 | 13 | 91.68 | 108.51 | ||||||||||||
| Week 4 | 9 | 31.21 | 20.91 | 9 | 211.83 | 197.34 | 11 | 31.10 | 22.30 | 11 | 64.42 | 48.13 | 20 | 31.15 | 21.11 | 20 | 130.75 | 152.57 |
| Week 5 | 8 | 74.54 | 44.85 | 8 | 178.91 | 211.35 | ||||||||||||
| Week 6 | 10 | 42.58 | 31.62 | 10 | 74.30 | 46.48 | ||||||||||||
| Week 7 | 11 | 12.71 | 11.93 | |||||||||||||||
| Week 8 | 6 | 100.03 | 45.13 | 6 | 275.01 | 236.42 | ||||||||||||
| Week 9 | 6 | 22.71 | 19.67 | |||||||||||||||
Note: CBD levels are in units of ng/mL. Trough levels were obtained prior to the morning dose of study medication (approximately 10 h after the previous evening dose). Estimated peak levels were obtained 45 min after an observed morning dose.
Table S1 provides individual data for CBD and THC metabolite levels for CBD‐treated participants throughout the study. THC and/or THC metabolites were detected at various time points in 5 Study 1 and 11 Study 2 participants. This could have been due to the small amount of THC present in the drug product or due to the use of cannabis or cannabinoids outside of the study. Although participants were required to test negative for COOH‐THC at screening, during treatment 22/29 CBD participants and 2/25 placebo participants across the two studies had at least one urine drug test positive for COOH‐THC (p < 0.00001, Fisher's exact), suggesting that most of the positive tests in the CBD group were due to the study drug.
Clinical outcomes
Drinking and AUD‐related outcomes
Across both studies, change in CDT levels at week 4 was significantly correlated with self‐reported change in DPD at week 4 (week 4 minus the average for the 30 days prior to enrollment; r = −0.475, n = 30, p = 0.008), providing validation of TLFB self‐report data. Participants in both studies reported decreases in DPD and PHDD during treatment, relative to baseline (See Figure 3). Effect sizes for change in DPD and PHDD were large across treatment groups in both studies (Cohen's dz. ranging from 0.921 to 1.201; see Table 3). However, the primary MMRM outcome analyses summarized in Table 4 did not demonstrate significant effects of treatment or time × treatment interactions for DPD, PHDD, CDT, or alcohol craving in either study or in the combined 4‐week analysis.
FIGURE 3.
Observed outcomes. Graphs depict mean values of all participants providing data for each measure at each time point. Participants randomized to CBD are shown in red, and those randomized to placebo are shown in blue. Numbers indicate the number of observations at each time point.
TABLE 3.
Within‐group changes in drinking outcomes.
| Sample | Baseline | During treatment | Nominal significance | Effect size | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Treatment | N | Mean | SD | Mean | SD | t (df) | p value1 | Cohen's dz2 | 95% CI | ||
| DPD |
Study 1 weeks 1–8 |
CBD | 13 | 4.61 | 2.17 | 2.39 | 1.64 | 4.140 (12) | 0.001 | 1.059 | 0.329 | 1.789 |
| Placebo | 12 | 5.39 | 2.39 | 2.98 | 2.34 | 3.569 (11) | 0.004 | 0.947 | 0.213 | 1.680 | ||
| Total | 25 | 4.99 | 2.27 | 2.67 | 1.99 | 5.518 (24) | <0.001 | 1.045 | 0.546 | 1.545 | ||
|
Study 2 Weeks 1–6 |
CBD | 16 | 4.66 | 2.85 | 2.00 | 2.19 | 4.660 (16) | <0.001 | 0.968 | 0.387 | 1.549 | |
| Placebo | 13 | 5.36 | 2.39 | 2.45 | 2.13 | 4.920 (12) | <0.001 | 1.198 | 0.446 | 1.949 | ||
| Total | 29 | 4.98 | 2.63 | 2.20 | 2.14 | 6.844 (28) | <0.001 | 1.108 | 0.659 | 1.557 | ||
|
Combined Weeks 1–4 |
CBD | 29 | 4.64 | 2.52 | 2.27 | 2.13 | 6.629 (28) | <0.001 | 0.973 | 0.571 | 1.375 | |
| Placebo | 25 | 5.38 | 2.34 | 3.03 | 2.58 | 4.606 (24) | <0.001 | 0.921 | 0.425 | 1.417 | ||
| Total | 54 | 4.98 | 2.45 | 2.62 | 2.35 | 7.834 (53) | <0.001 | 0.968 | 0.656 | 1.279 | ||
| PHDD |
Study 1 Weeks 1–8 |
CBD | 13 | 46.7 | 28.3 | 19.0 | 14.6 | 3.104 (12) | 0.009 | 1.150 | 0.195 | 2.106 |
| Placebo | 12 | 58.6 | 30.1 | 25.7 | 24.8 | 3.788 (11) | 0.003 | 1.103 | 0.279 | 1.927 | ||
| Total | 25 | 52.4 | 29.2 | 22.2 | 20.0 | 4.927 (24) | <0.001 | 1.153 | 0.560 | 1.746 | ||
|
Study 2 Weeks 1–6 |
CBD | 16 | 50.2 | 23.9 | 19.8 | 24.6 | 5.864 (16) | <0.001 | 1.191 | 0.557 | 1.825 | |
| Placebo | 13 | 57.7 | 28.0 | 24.5 | 27.9 | 5.693 (12) | <0.001 | 1.113 | 0.460 | 1.767 | ||
| Total | 29 | 53.6 | 25.6 | 21.9 | 25.7 | 8.299 (28) | <0.001 | 1.201 | 0.758 | 1.643 | ||
|
Combined Weeks 1–4 |
CBD | 29 | 48.6 | 25.5 | 20.1 | 21.4 | 6.279 (28) | <0.001 | 1.171 | 0.672 | 1.669 | |
| Placebo | 25 | 58.1 | 28.4 | 27.3 | 27.0 | 5.734 (24) | <0.001 | 1.078 | 0.575 | 1.582 | ||
| Total | 54 | 53.0 | 27.1 | 23.4 | 24.2 | 8.563 (53) | <0.001 | 1.134 | 0.788 | 1.479 | ||
Note: DPD and PHDD refer to timeline followback reports of drinks per day and percentage heavy drinking days, respectively, as defined in the text. P‐values based on paired t‐tests are not corrected for multiple comparisons and are shown for descriptive purposes only. Hedges' correction for small samples was applied to estimates of Cohen's dz. (standardized effect size for paired samples).
TABLE 4.
Results of outcome analyses.
| Fixed effects (df, F, Sig.) | Estimated marginal means (mean, 95% CI) | Treatment effect size | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | Weeks measured | Intercept | Baseline | Treatment | Time | Time × Tx | CBD | Placebo | Est. diff. | 95% CI | d | ||||||||||||||
| DPD |
Study 1 Weeks 1–8 |
25 | 1, 2, 3, 4, 5, 6, 7, 8 | 1, 25.0 | 0.211 | 0.650 | 1, 26.4 | 7.501 | 0.011 | 1, 25.9 | 0.255 | 0.618 | 7, 143.5 | 1.382 | 0.217 | 7, 143.5 | 1.620 | 0.134 | 2.360 | 1.333 to 3.387 | 2.724 | 1.671 to 3.777 | −0.36 | −1.83 to 1.11 | −0.20 |
|
Study 2 Weeks 1–6 |
29 | 1, 2, 3, 4, 5, 6 | 1, 29.2 | 0.135 | 0.716 | 1, 29.1 | 15.219 | <0.001 | 1, 29.6 | 0.048 | 0.829 | 5, 121.0 | 1.005 | 0.418 | 5, 121.0 | 0.520 | 0.761 | 2.116 | 1.225 to 3.007 | 2.259 | 1.265 to 3.252 | −0.14 | −1.48 to 1.19 | −0.08 | |
| Combined Weeks 1–4 | 54 | 1, 2, 3, 4 | 1, 55.0 | 0.024 | 0.876 | 1, 55.7 | 24.242 | <0.001 | 1, 55.8 | 0.722 | 0.399 | 3, 144.0 | 0.583 | 0.627 | 3, 145.0 | 1.931 | 0.127 | 2.361 | 1.630 to 3.091 | 2.819 | 2.031 to 3.607 | −0.46 | −1.53 to 0.62 | −0.25 | |
| PHDD |
Study 1 Weeks 1–8 |
25 | 1, 2, 3, 4, 5, 6, 7, 8 | 1, 25.2 | 3.514 | 0.073 | 1, 26.8 | 0.757 | 0.392 | 1, 26.0 | 0.526 | 0.475 | 7, 143.5 | 2.934 | 0.007 | 7, 143.4 | 1.211 | 0.300 | 18.145 | 7.166 to 29.125 | 23.803 | 12.369 to 35.237 | −5.66 | −21.51 to 10.19 | −0.29 |
|
Study 2 Weeks 1–6 |
29 | 1, 2, 3, 4, 5, 6 | 1, 29.1 | 3.230 | 0.083 | 1, 28.7 | 24.907 | <0.001 | 1, 29.8 | 0.000 | 0.984 | 5, 121.5 | 3.024 | 0.013 | 5, 121.5 | 0.519 | 0.761 | 22.663 | 12.993 to 32.333 | 22.807 | 12.032 to 33.582 | −0.14 | −14.62 to 14.33 | −0.01 | |
| Combined Weeks 1–4 | 54 | 1, 2, 3, 4 | 1, 54.7 | 0.000 | 0.988 | 1, 55.5 | 16.945 | <0.001 | 1, 55.5 | 0.406 | 0.527 | 3, 145.3 | 8.349 | <0.001 | 3, 145.3 | 1.974 | 0.120 | 21.350 | 13.553 to 29.148 | 25.032 | 16.581 to 33.482 | −3.68 | −15.18 to 7.82 | −0.18 | |
| CDT |
Study 1 Weeks 1–8 |
14 | 4, 8 | 1, 14.3 | 0.950 | 0.0346 | 1, 14.0 | 5.354 | 0.036 | 1, 14.2 | 0.138 | 0.716 | 1, 13.5 | 3.762 | 0.007 | 1, 13.5 | 2.511 | 0.136 | 2.745 | 0.206 to 5.285 | 3.331 | 1.167 to 5.495 | −0.59 | −3.92 to 2.75 | ‐‐0.20 |
|
Study 2 Weeks 1–6 |
16 | 4, 6 | 1, 14.2 | 14.933 | 0.002 | 1, 13.0 | 156.739 | <0.001 | 1, 14.7 | 0.019 | 0.892 | 1, 17.0 | 0.618 | 0.443 | 1, 17.0 | 0.610 | 0.445 | 1.403 | 1.157 to 1.648 | 1.425 | 1.193 to 1.656 | −0.02 | −0.36 to 0.32 | −0.07 | |
| Combined Weeks 1–4 a | 30 | 4 | 1, 0.54 | 1.110 | 0.270 | 1, 0.90 | 4.730 | <0.001 | 1, −0.4 | −0.413 | 0.683 | NA | NA | NA | NA | NA | NA | 1.621 | 1.180 to 2.062 | 3.062 | 1.578 to 4.547 | −1.44 | −2.99 to 0.11 | −0.63 | |
| PACS |
Study 1 Weeks 1–8 |
23 | 1, 4, 5, 8 | 1, 21.2 | 4.079 | 0.056 | 1, 21.2 | 0.710 | 0.409 | 1, 21.4 | 0.020 | 0.888 | 2,34.2 | 2.473 | 0.099 | 2, 34.2 | 1.537 | 0.230 | 11.861 | 8.283 to 15.439 | 12.238 | 8.209 to 16.268 | −0.38 | −5.77 to 5.01 | −0.06 |
|
Study 2 Weeks 1–6 |
29 | 1, 4, 6 | 1, 25.5 | 5.078 | 0.033 | 1, 26.1 | 5.181 | 0.031 | 1, 26.8 | 0.021 | 0.885 | 2, 42.3 | 2.213 | 0.122 | 2, 42.3 | 0.063 | 0.939 | 13.495 | 10.176 to 16.814 | 13.849 | 10.154 to 0.545 | −0.35 | −5.32 to 4.61 | −0.05 | |
| Combined Weeks 1–4 | 52 | 1, 4 | 1, 48.8 | 7.874 | 0.007 | 1, 49.3 | 7.602 | 0.008 | 1, 50.1 | 0.504 | 0.481 | 1, 39.9 | 4.020 | 0.052 | 1, 39.9 | 0.008 | 0.927 | 12.884 | 10.455 to 15.313 | 14.169 | 11.462 to 6.876 | −1.29 | −4.92 to 2.35 | 0.07 | |
| BAI |
Study 1 Weeks 1–8 |
22 | 1, 4, 5, 8 | 1, 19.3 | 0.100 | 0.755 | 1, 18.8 | 31.285 | <0.001 | 1, 20.0 | 3.645 | 0.071 | 3, 52.7 | 2.868 | 0.045 | 3, 52.7 | 1.584 | 0.204 | 7.373 | 4.899 to 9.847 | 4.097 | 1.518 to 6.676 | 3.28 | −0.3 to 6.85 | 0.81 |
|
Study 2 Weeks 1–6 |
28 | 1, 4, 6 | 1, 21.9 | 2.027 | 0.169 | 1, 20.4 | 21.351 | <0.001 | 1, 22.4 | 0.682 | 0.418 | 2, 40.0 | 0.675 | 0.515 | 2, 40.0 | 1.374 | 0.265 | 11.080 | 7.483 to 14.676 | 13.279 | 9.275 to 17.284 | −2.20 | −7.58 to 3.18 | −0.33 | |
| Combined Weeks 1–4 | 50 | 1, 4 | 1, 43.1 | 2.221 | 0.143 | 1, 41.9 | 61.034 | <0.001 | 1, 44.8 | 0.090 | 0.765 | 1, 42.0 | 0.071 | 0.791 | 1, 41.9 | 2.718 | 0.107 | 10.276 | 7.941 to 12.610 | 9.757 | 7.218 to 12.296 | 0.52 | −2.93 to 3.97 | −0.09 | |
| BDI‐II |
Study 1 Weeks 1–8 |
22 | 1, 4, 5, 8 | 1, 20.5 | 0.081 | 0.779 | 1, 20.6 | 25.626 | <0.001 | 1, 21.4 | 1.168 | 0.292 | 3, 57.0 | 0.947 | 0.424 | 3, 57.0 | 0.704 | 0.554 | 7.459 | 4.893 to 10.025 | 5.513 | 2.794 to 8.233 | 1.95 | −1.79 to 5.68 | 0.46 |
|
Study 2 Weeks 1–6 |
28 | 1, 4, 6 | 1, 21.9 | 0.077 | 0.784 | 1, 23.6 | 90.444 | <0.001 | 1, 23.3 | 1.242 | 0.276 | 2, 42.3 | 0.336 | 0.716 | 2, 42.3 | 4.884 | 0.012 | 17.773 | 14.441 to 21.105 | 20.443 | 16.785 to 24.102 | −2.67 | −7.62 to 2.28 | −0.42 | |
| Combined Weeks 1–4 | 50 | 1, 4 | 1, 45.7 | 0.448 | 0.507 | 1, 48.4 | 135.670 | <0.001 | 1, 47.3 | 1.710 | 0.197 | 1, 42.5 | 1.021 | 0.318 | 1, 42.7 | 4.932 | 0.032 | 12.618 | 10.201 to 15.035 | 14.926 | 12.325 to 17.527 | −2.31 | −5.86 to 1.24 | −0.37 | |
| PCL‐5 |
Study 2 Weeks 1–6 |
28 | 2, 4, 6 | 1, 27.0 | 0.233 | 0.633 | 1, 27.1 | 17.059 | <0.001 | 1, 28.0 | 0.116 | 0.736 | 2, 45.6 | 1.082 | 0.347 | 2, 45.6 | 1.007 | 0.373 | 27.459 | 21.415 to 33.502 | 25.899 | 18.935 to 32.863 | 1.56 | −7.66 to 10.78 | 0.13 |
Note: Statistics shown are from Mixed Models for Repeated Measures (MMRM) analyses performed as described in the text.
Abbreviations: BAI, Beck Anxiety Inventory; BDI‐II, Beck Depression Inventory‐II; DPD, standard drinks per day; PACS, Penn Alcohol Craving Scale total score; PCL‐5, PTSD checklist for DSM‐5; PHDD, percentage of heavy drinking.
The analysis for CDT levels in the combined sample used analysis of covariance (ANCOVA) rather than MMRM because there was only one follow‐up time point common to both studies. See text for statistical methods.
Measures related to anxiety, depression, and PTSD
No significant main effects of treatment were observed for anxiety (BAI total score) or depressive symptoms (BDI‐II total score) in either study or in the combined 4‐week analysis (See Table 4). In Study 2, PTSD symptomatology (PCL‐5 total score) also was not significantly related to treatment assignment. Time‐by‐treatment interactions were observed for BDI scores in Study 2 (F[2, 42.3] = 4.884, p = 0.012) and in the combined sample (F[1, 42.7] = 4.932, p = 0.032). Post hoc contrasts showed that BDI scores were lower in the CBD group than in control participants at week 1 in both Study 2 and the combined sample (p = 0.007, p = 0.032, respectively), but not at later time points.
Relationships between Week 4 CBD levels and study outcomes
Table S2 displays correlations between week 4 CBD levels and change in DPD, PHDD, alcohol craving, depression, anxiety, and PTSD symptoms (Study 2 only). In the combined sample (20 participants with valid week 4 CBD levels), a moderately strong correlation was observed between trough CBD levels at week 4 and week 4 change in BDI‐II scores (week 4 minus baseline), with higher CBD levels associated with a greater decrease in depression symptoms (r = −0.522, n = 20, p = 0.018). Correlations between week 4 trough levels and change in DPD, PHDD, alcohol craving, and PCL score (Study 2 only, n = 11) were not significant (p > 0.05). Week 4 estimated peak CBD levels were positively correlated with week 4 change in DPD (r = 0.470, n = 20, p = 0.037) and PHDD (r = 0.634, n = 20, p = 0.003) meaning that higher levels were associated with less improvement in drinking. No other significant correlations were observed between week 4 estimated peak CBD levels and study outcomes in the combined sample. Analyses restricted to the separate study samples showed that week 4 estimated peak CBD levels were robustly correlated with change in PHDD in Study 1 (r = 0.719, n = 9, p = 0.029) and with change in DPD in Study 2 (r = 0.724, n = 11, p = 0.012). No other significant correlations with week 4 CBD levels were observed in the separate study samples. Figure 4 displays scatterplots of the observed nominally significant associations of week 4 CBD levels with BDI‐II scores, PHDD, and DPD.
FIGURE 4.
Scatterplots for outcomes with nominally significant correlations with trough or estimated peak CBD levels at 4 weeks. Regression lines are shown for each study separately as well as for the combined sample. Study 1 participants and regression lines are represented in red; and placebo participants and regression lines are represented in blue. The regression line for the combined sample is represented in purple. (A) Week 4 trough CBD level versus change in BDI‐II score (week 4 minus baseline). (B) Week 4 estimated peak CBD level versus change in DPD (week 4 minus baseline). (C) Week 4 estimated peak CBD level versus change in PHDD (week 4 minus baseline).
Table S3 displays t‐tests for differences in week 4 outcomes between CBD‐treated patients with high versus low CBD levels. Groups were defined in relation to the median of week 4 peak and trough levels. In the combined sample, greater improvement in DPD and PHDD was seen in the participants with lower peak CBD levels. In the individual study samples, Study 1 participants with lower CBD levels showed greater decreases in PHDD. There were no other significant differences in outcomes between the high‐ and low‐level groups.
Safety
Across the two studies, a total of 107 AEs were reported among the 30 CBD participants and 42 among the 26 placebo participants. In the combined sample, there were more AEs per participant in the CBD group than in the placebo group (CBD group mean = 3.57, SD = 3.92; placebo group mean = 1.62, SD = 1.86; p = 0.017, asymptotic significance, Mann–Whitney U‐test). Examining the studies separately, CBD participants reported significantly more AEs in Study 1 (CBD group mean = 5.00, SD = 5.13; placebo group mean = 1.69, SD = 2.14; p = 0.05, exact significance, Mann–Whitney U‐test), but not in Study 2 (CBD group mean = 2.47, SD = 2.27; placebo group mean = 2.54, SD = 1.61; p = 0.123, exact significance, Mann–Whitney U‐test).
Table 5 displays the number of participants experiencing AEs for the two studies separately and combined. The most common AEs in the CBD group were diarrhea (27%, vs. 12% in the placebo group), somnolence (23%, vs. 23% in the placebo group), and nausea (20%, vs. 0% in the placebo group). Only nausea was significantly more common in the CBD group (p = 0.025, exact significance, chi‐squared test). One case of suicidal ideation was observed in each treatment group. Elevated liver enzymes (specifically transaminases, total bilirubin, and/or direct bilirubin ranging from 1.5 to 6.5 times the upper limit of normal) were observed during treatment in two CBD participants and one placebo participant. AEs were almost entirely mild or moderate in severity. The only severe and serious AE reported was a case of diabetic ketoacidosis in a participant who received CBD in the AUD study. Although this patient was hospitalized 25 days after the last dose of CBD and had underlying diabetes, the AE was judged to be possibly related to study medication because cannabis use is known to increase the risk of ketoacidosis in patients with type 1 diabetes.
TABLE 5.
Adverse events.
| Study 1 | Study 2 | Studies combined | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CBD | Placebo | CBD | Placebo | CBD | Placebo | |||||||
| (N = 13) | (N = 13) | (N = 17) | (N = 13) | (N = 30) | (N = 26) | |||||||
| N | % | N | % | N | % | N | % | N | % | N | % | |
| Eye disorders | ||||||||||||
| Conjunctivitis | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Vision blurred | 0 | 0 | 0 | 0 | 1 | 6 | 1 | 8 | 1 | 3 | 1 | 4 |
| Endocrine disorders | ||||||||||||
| Thyroid mass | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Gastrointestinal disorders | ||||||||||||
| Abdominal discomfort | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Abdominal pain | 0 | 0 | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 4 |
| Gastroesophageal reflux disease | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Diarrhea | 5 | 38 | 2 | 15 | 3 | 18 | 1 | 8 | 8 | 27 | 3 | 12 |
| Dry mouth | 2 | 15 | 2 | 15 | 0 | 0 | 0 | 0 | 2 | 7 | 2 | 8 |
| Dyspepsia | 2 | 15 | 0 | 0 | 1 | 6 | 1 | 8 | 3 | 10 | 1 | 4 |
| Frequent bowel movements | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Gingival disorder | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Nausea | 3 | 23 | 0 | 0 | 3 | 18 | 0 | 0 | 6 | 20 | 0 | 0 |
| General disorders and administration site conditions | ||||||||||||
| Chills | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Fatigue | 2 | 15 | 1 | 8 | 2 | 12 | 1 | 8 | 4 | 13 | 2 | 8 |
| Feeling hot | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Pain | 2 | 15 | 0 | 0 | 1 | 6 | 0 | 0 | 3 | 10 | 0 | 0 |
| Pyrexia | 2 | 15 | 0 | 0 | 1 | 6 | 0 | 0 | 3 | 10 | 0 | 0 |
| Hyperhidrosis | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 8 | 0 | 0 | 1 | 4 |
| Thirst | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Infections and infestations | ||||||||||||
| Gingivitis | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Influenza | 1 | 8 | 0 | 0 | 1 | 6 | 0 | 0 | 2 | 7 | 0 | 0 |
| Upper respiratory tract infection | 1 | 8 | 0 | 0 | 0 | 0 | 1 | 8 | 1 | 3 | 1 | 4 |
| Investigations | ||||||||||||
| Heart rate irregular | 0 | 0 | 1 | 8 | 0 | 0 | 1 | 8 | 0 | 0 | 2 | 8 |
| Hepatic enzyme increased | 1 | 8 | 1 | 8 | 1 | 6 | 0 | 0 | 2 | 7 | 1 | 4 |
| Hypotension | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Metabolism and nutrition | ||||||||||||
| Appetite increase | 2 | 15 | 0 | 0 | 2 | 12 | 1 | 8 | 4 | 13 | 1 | 4 |
| Ketoacidosis | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Weight gain | 0 | 0 | 0 | 0 | 3 | 18 | 2 | 15 | 3 | 10 | 2 | 8 |
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Myalgia | 2 | 15 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 7 | 0 | 0 |
| Muscle spasms | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 8 | 0 | 0 | 1 | 4 |
| Orthopedic procedure | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Nervous system disorders | ||||||||||||
| Cognitive disorder | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Disturbance in attention | 2 | 15 | 1 | 8 | 0 | 0 | 0 | 0 | 2 | 7 | 1 | 4 |
| Dizziness | 3 | 23 | 2 | 15 | 1 | 6 | 1 | 8 | 4 | 13 | 3 | 12 |
| Headache | 3 | 23 | 2 | 15 | 2 | 12 | 0 | 0 | 5 | 17 | 2 | 8 |
| Memory impairment | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Somnolence | 1 | 8 | 2 | 15 | 6 | 35 | 4 | 31 | 7 | 23 | 6 | 23 |
| Taste disorder | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Psychiatric disorders | ||||||||||||
| Abnormal dreams | 1 | 8 | 2 | 15 | 1 | 6 | 2 | 15 | 2 | 7 | 4 | 15 |
| Alcoholism | 0 | 0 | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 4 |
| Psychiatric disorders, continued | ||||||||||||
| Anxiety | 1 | 8 | 0 | 0 | 0 | 0 | 1 | 8 | 1 | 3 | 1 | 4 |
| Confusional state | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Depression | 2 | 15 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 7 | 0 | 0 |
| Euphoric mood | 2 | 15 | 1 | 8 | 0 | 0 | 0 | 0 | 2 | 7 | 1 | 4 |
| Illusion | 2 | 15 | 1 | 8 | 1 | 6 | 0 | 0 | 3 | 7 | 1 | 4 |
| Insomnia | 1 | 8 | 1 | 8 | 1 | 6 | 1 | 8 | 2 | 7 | 2 | 8 |
| Irritability | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Lack of motivation | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Stress | 0 | 0 | 0 | 0 | 1 | 6 | 0 | 0 | 1 | 3 | 0 | 0 |
| Suicidal ideation | 0 | 0 | 1 | 8 | 1 | 6 | 0 | 0 | 1 | 3 | 1 | 4 |
| Respiratory, thoracic, and mediastinal disorders | ||||||||||||
| Cough | 2 | 15 | 0 | 0 | 1 | 6 | 0 | 0 | 3 | 10 | 0 | 0 |
| Dyspnea | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Respiration abnormal | 1 | 8 | 0 | 0 | 1 | 6 | 0 | 0 | 2 | 7 | 0 | 0 |
| Rhinorrhea | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||
| Hair disorder | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
| Skin irritation | 1 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 |
Note: Adverse events are tabulated by system order class and preferred term using MedDRA Version 25.1. Totals refer to the number of participants in each group experiencing each adverse event.
A total of seven study participants, all allocated to CBD, reduced or stopped their study medication due to AEs. Three participants in Study 1 decreased due to AEs. With dose titration, all were able to tolerate dosages of at least 800 mg. Due to AEs, three CBD participants in Study 2 decreased their dosage to 400 mg, and a fourth participant withdrew after 1 day of medication.
DISCUSSION
The study demonstrated that CBD as formulated in this study was absorbed adequately. Levels were achieved that approximated the target that had been established based on prior animal studies and clinical trials with CBD for substance use and anxiety disorders. Trough levels after 4 weeks of dosing at either 600 or 1200 mg/day were not significantly higher than those observed after 1 week, suggesting that the levels at 4 weeks were near maximal steady‐state levels.
Safety outcomes suggested that CBD is safe and generally well tolerated in dosages of up to 1200 mg/day with the current formulation, corresponding to steady‐state levels of up to 140 ng/mL and peak levels as high as 600 ng/mL. AEs were mostly mild and consistent with the known side effects of CBD. Since many study participants continued to drink heavily while on CBD, these results suggest that pharmacodynamic interactions between CBD and ethanol are unlikely to preclude the safe use of CBD in actively drinking patients with no other contraindications. This finding is consistent with a human laboratory study demonstrating that CBD in dosages of up to 200 mg had minimal effect on the pharmacokinetics and subjective effects of alcohol (Karoly et al., 2023). Overall, these results are consistent with recent studies demonstrating the safety and tolerability of CBD in AUD patients (Mueller et al., 2025; Zimmermann et al., 2024). However, the fact that seven participants decreased their dosages of CBD due to side effects suggests that dose‐limiting side effects may not be uncommon at dosages of 600 mg or higher.
Regarding the primary therapeutic target (AUD), CBD was not shown to be superior to placebo. Similarly, results did not provide evidence that CBD reduces symptoms of PTSD, depression, or anxiety in patients with co‐occurring AUD. There are several possible explanations. It is possible that CBD is simply not effective in the treatment of AUD or PTSD. However, these findings could also be due to inadequate power to detect small‐ or medium‐sized effects, administration of CBD dosages that were not optimal for efficacy, sample characteristics, or high rates of placebo response.
Regarding dosage of CBD, although the cannabinoid levels that were obtained provide a reasonable estimate of the peak and trough levels that were achieved, they provide an incomplete picture of pharmacokinetics or overall drug exposure. More importantly, the CBD levels obtained may not be the optimal levels for the treatment of AUD or PTSD. It is possible that the selected dosage was too low given the pharmacokinetics of the CBD formulation used in the trial. In a recent human laboratory study which demonstrated significant blunting of alcohol craving and nucleus accumbens activation in response to alcohol cues (Zimmermann et al., 2024), the mean CBD level prior to testing was 257 ng/mL (SD: 215.42 ng/mL), higher than the mean peak level we observed at week 4 on 600 mg (130.75 ng/mL, SD: 152.57 ng/mL) and comparable to the mean peak level achieved on 1200 mg/day in study 1 (275.01 ng/mL, SD: 236.42 ng/mL). The positive associations observed between trough CBD levels and improvement in depression suggest, if anything, that higher dosages could be more effective, at least for depressive symptoms. However, no strong inferences can be made from this post hoc finding. It is also possible that the dosage selected was too high. This possibility is supported by the post hoc observation of less improvement in drinking among participants with higher CBD levels in these studies. Animal studies have found that CBD has anxiolytic effects at moderate dosages, but becomes ineffective at higher dosages (Blessing et al., 2015). However, human trials have reported anxiolytic effects from dosages up to 800 mg/day (Han et al., 2024). Based on current evidence, it would be unwise to assume that the optimal dosage or blood level of CBD is the same across different diagnoses or that the effects of a given dosage or blood level will be the same after a single dose versus longer term treatment.
It is increasingly apparent in AUD treatment and more generally in psychiatry that a medication can be highly effective for subgroups or patients even if its effect in the whole sample or population is not clinically or statistically significant (Bach et al., 2021; Laska et al., 2020; Webb et al., 2019). Our studies recruited a community of participants who were actively drinking and not currently in treatment. Although all met criteria for moderate to severe AUD, their pre‐randomization level of drinking was somewhat low relative to many AUD pharmacotherapy trials, and a floor effect may have further diminished the power of the study to detect treatment effect. It is possible that CBD is effective only for patients with more severe AUD or patients who have already achieved abstinence (i.e., relapse prevention).
The significance of the null efficacy findings is also limited by the relatively high response rate that was observed across conditions. Participants in both treatment groups improved substantially during treatment (Cohen's dz. > 0.9), and roughly half were drinking in the WHO low‐risk range during follow‐up. (Across the two studies, the median DPD during weeks 1–4 was 1.0 and 2.7 for women and men, respectively.) This may have been related to characteristics of the study samples and study design. Participants in both groups received considerable attention in the form of frequent medical management and assessment visits. In any case, the low rates of drinking in the placebo group during treatment left little room for greater improvement in participants treated with CBD.
In conclusion, these studies provided preliminary evidence for the feasibility and safety of CBD in the treatment of AUD with and without co‐occurring PTSD. The studies did not provide evidence for the efficacy of CBD compared with placebo, but the null findings should be interpreted in light of the limitations discussed above. Given the mixed results that have been reported for CBD as a treatment for other substance use disorders and anxiety disorders, further dose finding, mechanistic, and efficacy studies are warranted to determine whether CBD holds promise as a treatment for these disorders.
FUNDING INFORMATION
This work was supported by grants R21AA025748 and R21AA026424 from NIAAA (NIH). Study medication and partial funding for pharmacokinetic analysis were provided by Tilray Canada.
CONFLICT OF INTEREST STATEMENT
MPB has received research funding from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, Tilray Canada, Lykos Therapeutics, B.More, Inc., Ceruvia Life Sciences, Mind Medicine, Inc., the Heffter Research Institute, the Riverstyx Foundation, the Turnbull Family Foundation, the Fournier Family Foundation, Dr. Bronner's Family Foundation, and Bill Linton. He serves on the Advisory Boards of Ajna Labs LLC, Journey Colab, and Bright Minds Biosciences, Inc., and provides consultation to Lilly USA, LLC. CRM has served on advisory boards of Receptor Life Sciences, Otsuka Pharmaceuticals, and Roche Products Limited. He receives support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health, the United States Department of Defense Congressionally Directed Medical Research Programs, the US Army Research Office, the Defense Advanced Research Projects Agency, the Bank of America Foundation, Cohen Veterans Bioscience, the Cohen Veterans Network, the McCormick Foundation, the Home Depot Foundation, the New York City Council, the New York State Department of Health, the Mother Cabrini Foundation, Tilray Pharmaceuticals, Ananda Scientific, and GrayMatters Health.
CONFLICT OF INTEREST STATEMENT
The authors have no conflict of interest to declare.
Supporting information
Tables S1–S3
Bogenschutz, M.P. , Blessing, E. , Dgheim, D. , Cho, D. , Zhang, J. , Laska, E.M. et al. (2026) Effects of cannabidiol in alcohol use disorder patients with and without co‐occurring post‐traumatic stress disorder: Tolerability but no evidence for efficacy in two randomized proof‐of‐concept trials. Alcohol: Clinical and Experimental Research, 50, e70212. Available from: 10.1111/acer.70212
Additional trial information: Both trials were registered on Clinicaltrials.gov prior to the start of enrollment. Study 1 (NCT03252756) Date of Registration: 2017‐08‐15. Study 2 (NCT03248167) Date of registration: 2017‐08‐09. See study record for protocols, statistical analysis plans, and data sharing provisions.
Michael P. Bogenschutz and Esther Blessing: Co‐primary authors.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S3
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.