Cannabidiol as an Adjunct Treatment for Alcohol Withdrawal and Craving

Johns Hopkins University

Status and phase: Begins enrollment in 2 months; Phase 3; Phase 2

Conditions: Alcohol Use Disorder (AUD); Craving; Withdrawal From Addictive Substance; Detoxification

Treatments: Drug: Placebo; Drug: Cannabidiol (CBD)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07148843

IRB00519608

Details and patient eligibility

About

Cannabidiol (CBD), one of the most prevalent cannabinoids in cannabis (marijuana) has been shown to reduce alcohol withdrawal symptoms in laboratory animals. In people without alcohol use disorder (AUD), CBD has been show to be effective in reducing anxiety, sleep problems, and seizures; all of these are common symptoms of alcohol withdrawal. This randomized placebo-controlled clinical trial will evaluate the potential of CBD to improve alcohol withdrawal symptoms and reduce craving during acute abstinence among individuals with moderate-to-severe AUD. Adult participants with moderate-to-severe AUD will be admitted to an inpatient research unit at the Johns Hopkins Hospital for a 5-day, 4-night stay that includes alcohol abstinence with management of their alcohol withdrawal. In addition to standard care, participants will receive CBD or placebo (no CBD), complete assessments of withdrawal, sleep quality and provide breath and blood samples.

Full description

Alcohol withdrawal during acute abstinence represents a major health threat to millions of individuals struggling with alcohol use disorder (AUD): it has been associated with complications in patients admitted for medically supervised withdrawal including seizures and delirium tremens (the latter of which can be fatal if not managed appropriately) and can interfere with treatment efforts. Benzodiazepines, such as lorazepam (Ativan) represent the first-line treatments for control of alcohol withdrawal, yet higher doses of benzodiazepines required to manage more complicated withdrawal cases increase risk of respiratory depression and delirium. Furthermore, a growing frequency of benzodiazepine shortages (at least 20 shortages within the previous ten years lasting a median of 244 days) necessitates a need for alternative and adjunctive medications. Preclinical animal trials involving cannabidiol (CBD), one of the most prevalent cannabinoids in cannabis (marijuana) have shown its use is associated with statistically significant reductions in withdrawal symptoms and there is evidence in non-AUD populations that CBD is effective in reducing anxiety, insomnia, and seizures, which are all symptoms of alcohol withdrawal. The capacity for CBD to enhance the effect of the inhibitory neurotransmitter GABA in a manner akin to benzodiazepines has also been demonstrated. Collectively this information suggests that CBD could alleviate signs and symptoms of alcohol withdrawal, and subsequently reduce the need for adjunctive benzodiazepines.

This randomized placebo-controlled clinical trial will enroll adults with moderate-to-severe AUD who will be admitted to an inpatient research unit at the Johns Hopkins Hospital for management of their alcohol withdrawal. Enrolled participants with a history of alcohol withdrawal symptoms will be randomized to receive an oral formulation of either placebo or one of two CBD doses (10 mg/kg or 20 mg/kg). These doses have been well-studied and tolerated in prior studies and clinical trials for other disorders. Alcohol withdrawal symptoms, as defined by Diagnostic and Statistical Manual (DSM-5) criteria, will be assessed by nursing administration of the Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) and participant completion of the Alcohol Withdrawal Symptom Checklist (AWSC). The CIWA-Ar scale will be used to guide the administration of symptom-triggered lorazepam (trade name Ativan) for all participants. As insomnia is a DSM-5 criterion for alcohol withdrawal, sleep quality will be assessed by completion of the Consensus Sleep Diary (CSD) and wrist actigraphy. Last, since cravings correlate closely with withdrawal symptoms and CBD has been observed to reduce craving for other substances, we will explore CBD's impact on alcohol craving by having participants complete the Alcohol Urge Questionnaire throughout the study. In short, the goals of this study will be to (1) determine the effect of CBD on physiologic and subjective symptoms of alcohol withdrawal, (2) determine the capacity of CBD to improve insomnia and disordered sleep during withdrawal, and (3) determine if CBD can attenuate alcohol cravings during acute abstinence.

Results from this study can help inform the possible use of CBD as a novel adjunct treatment for alcohol withdrawal and cravings that may reduce benzodiazepine need for alcohol withdrawal treatment. If CBD is shown to be effective, this line of work also points to the potential of the endogenous cannabinoid system playing a mechanistic role in alcohol's withdrawal symptoms. Finally, this study could provide further insights into the efficacy of CBD as a sleep agent for participants with alcohol withdrawal and lay the groundwork for subsequent studies exploring CBD's use in the treatment of alcohol withdrawal in an outpatient setting.

Enrollment: 105 estimated patients

Sex: All

Ages: 21 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

• Meets DSM-5 criteria Moderate or Severe Alcohol Use Disorder
• Age 21-65
• Report at least one prior episode of alcohol withdrawal symptoms at least one day in duration that caused significant impairment in functioning (i.e., unable to attend work or engage in typical activities) AND/OR required medications to manage symptoms.
• Drinking at least 8 drinks a day over the two weeks prior to screening.
• Negative human chorionic gonadotropin (hCG) on qualitative urine pregnancy screen
• Shipley vocabulary score > 18, corresponding to 5th grade reading level.
• Demonstrated understanding of informed consent and ability to consent to participation in the study.

Exclusion Criteria

• Current or past alcohol-related medical complications including but not limited to cirrhosis of the liver, esophageal varices, pancreatitis, severe gastritis, hemoptysis, hematochezia, or melena.

• Use of gabapentin, benzodiazepines, or other sedative-hypnotic medications within the week prior to admission

• Regular use (e.g., more than twice a week) of cannabis or CBD products.

• Regular use of benzodiazepines (e.g., twice a week or more) within the last three months

• Meet DSM-5 criteria for moderate-to-severe substance use disorder (SUD), including Cannabis Use Disorder (except for alcohol and tobacco)

• Urine drug screen indicating the presence of substances other than cannabis at screening.

• Unstable and/or compromising medical or psychiatric conditions that would interfere with participant safety as determined by study physician.

• Current pregnancy

• BMI <17

• History of anorexia nervosa or bulimia in the past 2 years

• History of seizures or seizure disorder outside of alcohol-withdrawal related seizures

• Systolic blood pressure (SBP) > 180, Diastolic Blood Pressure (DBP) > 120 or pulse > 120 during screening or upon admission

• Any of the following laboratory values during screening or upon admission:

  • AST > 165 U/L (normal range 19-55)
  • ALT > 216 U/L (normal range 19-72)
  • Alkaline phosphatase > 378 U/L (normal range 38-126)
  • Total bilirubin >2.5 mg/dl (normal values=0.3-1.0 mg/dL)
  • Non-fasting glucose > 250 mg/ml (normal range 65-179)
  • Hematocrit < 38 % (normal range 41-53)
  • Hemoglobin < 12 g/dl (normal range 13.5-17.5) or any other laboratory value significantly outside the normal range

• Use of a prescription medication (except for birth control prescriptions) within 14 days of study entry, which, in the opinion of the investigator or sponsor, will interfere with the study result or the safety of the subject. This includes any medication in which CYP2C9, CYP2C19, CYP1A2, CYP2B10, or CYP3A4 enzymes are major metabolizers.

• ECG with corrected QT interval (QTC) >/= 500 ms and/or presence of clinically significant abnormality

• Participation in other clinical trials within the past 60 days

• Court-mandated participation in alcohol treatment or pending incarceration

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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105 participants in 3 patient groups, including a placebo group

10 mg/kg CBD

Active Comparator group

Description:

low dose CBD

Treatment:

Drug: Cannabidiol (CBD)

20 mg/kg CBD

Active Comparator group

Description:

high dose CBD

Treatment:

Drug: Cannabidiol (CBD)

placebo

Placebo Comparator group

Description:

Placebo (no CBD)

Treatment:

Drug: Placebo