Cannabidiol as an adjunctive short-term treatment during Inpatient detoxification in patients with Alcohol dependence: A multicenter Phase III Randomized controlled trial

Cannabidiol as an adjunctive short-term treatment during Inpatient detoxification in patients with Alcohol dependence: A multi-centre Phase III Randomized controlled trial

Introduction:

National mental health survey of India, 2015-2016 data suggests that alcohol is the commonly used substance (4.6% prevalence) across the country apart from tobacco. Several non-pharmacological and pharmacological strategies are available in the management of alcohol dependence1. Disulfiram, acamprosate and naltrexone are the first-line medications approved for use in alcohol dependence. These agents are preferably started after the ‘detoxification phase’ of alcohol withdrawal management is completed. Detoxification is a set of interventions aimed at managing acute intoxication and withdrawal. However, significant proportion of patients tend to drop out from treatment and relapse in the alcohol use. In a recent review of Indian studies which assessed the relapse rates and predictors in alcohol dependence, the relapse rates were found to be as high as 72.6%2. In a recent longitudinal study from South India which assessed the course and outcome of alcohol dependent individuals, only a third of patients remained abstinent at 6 months of follow up3. Poor adherence to prescribed medicines is one of the important factors responsible for higher relapse rates 4. This highlights the importance of understanding relapse, ensuring treatment adherence and the need for development of newer treatment modalities for the disorder. Another recent longitudinal study has suggested the need for safer therapeutic options at grass root level for improvement of adherence and achieving complete abstinence 5.

Benzodiazepines along with thiamine supplementation remain the gold standard treatment for managing alcohol withdrawal/ detoxification irrespective of severity of alcohol dependence. Prescription of benzodiazepines during detoxification has certain disadvantages like psychomotor retardation, balance disorders, respiratory depression, risk of addiction, dementia etc. 6(Billioti de Gage S, 2014) The ideal agents during detoxification should have rapid onset, low risk for alcohol dependence, sedative/anxiolytic properties, anticonvulsant effect, shouldn’t cause liver damage and should be devoid of respiratory depression. Medication like dexmedetomidine, ketamine, alpha adrenergic agonists, barbiturates, carbamazepine, gabapentin, melatonin etc have been tried as adjunctive medication during detoxification along with benzodiazepines. Evidence is still controversial about the efficacy and safety of these treatments. Some positive evidence favours the use of anticonvulsants in reducing withdrawal and duration of hospital stay.7(Qu L, 2024)

Off label drug use defines the use of any drug outside the conditions of product license in terms of dose, patient age, route of administration, indications and contraindications. Cannabidiol (CBD) is a newer medicinal non-psychotropic-phytocannabinoid popular for its neuroprotective properties due to the various receptor level effects. As described it is a phytocannabinoid, one of the 113 identified cannabinoids in Cannabis. It accounts for 40% of the plant extract. It binds to endocannabinoid and (5HT1A/2A/3A, TRPV1-2) other types of receptors present within the body. CBD acts as a negative allosteric modulator of CB1R and CB2R receptors. It is hypothesised to have anti-inflammatory activity, anti-oxidant activity, anxiolytic, antipsychotic, anticonvulsant, sleep inducer, muscle relaxant and neuroprotective properties. These mechanisms of CBD’s are those which will be beneficial in acute alcohol withdrawal. These actions of CBD are different from those of Detla-9 tetra hydrocannabinol, which produces psychotomimetic effects through weak agonist action at CB1R and CB2R.8

In addition, CBD modulates GABA and glutamate signalling in the basal ganglia and dorsomedial prefrontal cortex. It regulates dopamine activity in regions associated with mesolimbic reward pathways (salience) and limbic, fronto-striatal networks (role in reward anticipation, emotion regulation, salience processing and executive functioning). All these pathways play a key role in the development of substance use disorders.9 (Chye Y, 2019)

Though a number of reviews were conducted over the use of cannabidiol in childhood disorders, cognitive disorders, anxiety disorders, mood disorders, schizophrenia and psychotic disorders, substance use disorders, only in few psychiatric disorders like opioid use disorder, schizophrenia and autism spectrum disorder Phase-II trials with cannabidiol (CBD) were carried out.10-12 With respect to substance use disorders, though evidence is small, but it supports the use of CBD in cannabis use disorder, opioid and tobacco use disorder. In case of alcohol use disorder, the evidence is insufficient. The use of CBD is restricted to improving sleep in alcohol use disorder patients previously.13 As per a review, an exploratory study on 120 cannabis and alcohol-using adults assigned showed that the CBD group had fewer drinks per drinking day, fewer alcohol use days, and fewer days of alcohol and cannabis co-use compared with the other groups.14 A recent feasibility study among 44 participants with alcohol use disorder comparing three conditions: full-spectrum CBD (n = 13), broad-spectrum CBD (n = 15, bsCBD), or placebo (n = 16) for 8 weeks found that safety profiles fsCBD and bsCBD were similar, and fsCBD was associated with a greater reduction in craving and AUD symptoms relative to other groups.15

Hence, we intend to carry out a randomised controlled trial (RCT) with cannabidiol in in-patients with alcohol dependence during the detoxification phase.

Rationale:

So far, many non-pharmacological and pharmacological strategies have been employed in the management of alcohol use disorder. Despite a plethora of treatment options, lack of treatment adherence and high degree of relapse post-discharge remain the major challenges in the management of these disorders. Treatment received during the detoxification phase is important as it influences the overall outcome of these patients. Another advantage of this is the ensured treatment adherence of the patient. Cannabidiol was approved by DCGI in April 2023 for treatment of seizures associated with Gestaut syndrome, Dravet syndrome or tuberous sclerosis complex. Off-label use of the drug suggests use of an approved drug for one indication for a different indication, at different dosage, for use in patients beyond approved age group and in different route of administration etc. As mentioned in the review cannabidiol has been tried off-label in a number of psychiatric conditions. The rationale behind these trials was hypothesized to be the neuroprotective effect of the cannabidiol without having psychotropic properties. Preliminary evidence showed that cannabidiol is beneficial in the management of cannabis use disorder. But evidence regarding its use in alcohol use disorder is still sparse. The results of the available studies about use of cannabidiol in alcohol use disorder have shown inconsistent results.

Hypothesis

Adjunctive CBD during detoxification is effective in improving the outcomes (withdrawal severity, duration of hospital stay, craving and abstinence) of inpatients with alcohol dependence compared to placebo

Aims and Objectives:

To assess the efficacy and safety of adjunctive CBD during inpatient detoxification on the withdrawal severity, duration of hospital stay, craving and abstinence compared to withdrawal severity in patients with alcohol dependence.

Primary objective:

To assess the effect of adjunctive CBD during inpatient detoxification on the severity of withdrawal symptoms, duration of hospital stay compared to placebo in patients with alcohol dependence till week 6 of the study

Secondary objectives:

To compare the craving and changes in the Alcohol consumption pattern (in terms of duration of abstinence and amount of daily alcohol consumption) between individuals with Alcohol dependence receiving adjunctive CBD vis-à-vis placebo (TAU) from discharge till week 6 of the study

·        To assess the safety of 300 mg of cannabidiol as an add-on to treatment as usual in patients with alcohol dependence during inpatient alcohol detoxification till week 6 of the study

·        To compare cumulative dose of benzodiazepine required between individuals with Alcohol dependence receiving adjunctive CBD vis-à-vis those who received placebo during 10 days of in-patient detoxification

Methodology:

***Study design, setting and duration:***This multicentre, Double blind Randomised control trial with 2 arms, parallel design (Interventional) will be carried out, in the In-patient setting of Department of Psychiatry, at AIIMS Bibinagar, and other centres are AIIMS Mangalagiri, AIIMS Raipur, AIIMS Guwahati. Intervention will be given for 10 days during the detoxification phase. The trial duration will be 6 weeks. Study duration will be 3 years.

Sample size: Apparently there are no previous RCT’s seeing the effect of Cannabidiol during alcohol detoxification. Assuming a small effect size of 0.21, 15,16 two groups, an alpha error probability of 0.05, and a statistical power of 0.80, sample size of 178 per centre has been calculated (total 714). By adding a dropout rate of 18% to 714 participants, as estimated by Gpower with the above-mentioned input parameters, the final estimated total sample is 844.

Inclusion Criteria:

·        Patients hospitalized for alcohol dependence as per ICD-11 criteria

·        Either gender

·        Aged 18-65 years old

Exclusion Criteria:

·        Any unstable medical condition at entry, such as acute confusion, chronic or acute hepatic or renal impairment or cirrhosis or any acute psychiatric disorder

·        Elevated liver enzymes (more than 3 times) and/or elevated bilirubin

·        Previously using or need medication which metabolise through CYP 2C19 or CYP3A4 or UGT enzymes and having strong inhibitor/inducer properties

·        Concomitant use of other medications, including leflunomide, lomitapide, mipomersen, pexidartinib, teriflunomide, and valproate, is known to cause liver damage

·        Those with history of cardiac arrhythmias, myocardial infarction and stroke

·        Other current substance dependence as per ICD-11 criteria (like opiates, cannabis, cocaine, amphetamines, sedatives) except for tobacco use disorder

·        Pregnancy and lactating females

Procedure:

CONSORT flow diagram- figure 1

 ·        Sampling strategy: All patients with alcohol dependence will be screened for eligibility and those who fulfil the inclusion criteria will be enrolled for the purpose of the study

·        Sampling technique: Convenience sampling will be done to recruit the cases after written informed consent. Socio demographic and clinical profile details to be collected

·        Randomization and Allocation concealment

Randomization: Randomization into 2 groups will be done using variable block Randomization using computer generated random numbers at each participating centre

Allocation concealment: Using sealed opaque envelopes. Allocation will be done by a person not involved in the delivery of intervention or rating, they will reveal the group which the patient belongs to investigators just before recruitment. Investigator or raters will not have access to these envelopes.

·         Blinding

Double blind Randomised control trial with 2 arms, parallel design (Interventional)

Patient blinding:

Patients will be blinded to the treatment received. For those randomized to intervention arm the cannabidiol solution will be provided whereas placebo for the control arm.

Investigator blinding:

Investigator blinding will be followed and the person who is treating or rating the patient will be unaware of the intervention status of the patient.

Cannabidiol and it’s administration

Patients who are allotted to study group will be given oral cannabidiol upto a maximum of 300mg in divided doses, on the first day they will be started with 75mg BD and on day 2 dose will be hiked to 150 mg BD based on tolerability and then continued till day 10 along with treatment as usual (TAU) during the detoxification part of treatment. The required dose is calculated based on tolerability and previous literature.12 Patients will be monitored for the side effects during the course of administration till 6 weeks post discharge.

Placebo and it’s administration

Patients who are randomized to placebo group will be administered placebo syrup in divided doses. The placebo syrups are kept in identical looking bottles to that of CBD and physical appearance and taste of the placebo will be similar to that of cannabidiol syrup.

Tools used:

Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)16

Alcohol use disorders identification test (AUDIT)17.

Time line follow back (TLFB)18

Patient-Rated Inventory of Side Effects - Modified (PRISE-M)19

Penn Alcohol Craving Scale (PACS) 20

Follow-up details

1.      In-person evaluation will be carried out on daily basis from day 1 to day 10 and day 14 for withdrawal severity, craving and assessment of side effects on PRISE-M

2.      Duration of hospital stay will be noted on the day of discharge

3.      In-person evaluation of severity assessment will be done using AUDIT questionnaire at baseline (day 1 of admission) and day 42 (6 weeks)

4.      Telephonic assessment of withdrawal, craving, alcohol consumption, side effects assessments will be done weekly after discharge on day 21, day 28, day 35

5.      Physical evaluation of withdrawal, craving, alcohol consumption, side effects at day 42 (week 6) of the study

Outcome measures and their evaluation

During the course of admission assessment of outcome measures will be done in person during in-patient stay and follow up, as and when required telephonically details about other outcome measures will be evaluated.

Primary Outcome Measures:

1. Reduction of alcohol withdrawal severity and duration of hospital stay, alcohol craving till week 6 of the study

2. Changes in the alcohol consumption pattern in terms of self-declared abstinence and Alcohol amount reduction in case of relapse till week 6 of the study

Secondary Outcome Measures:

1.      To assess the safety of 300 mg Cannabidiol till week 6 of the study

The study investigators will be responsible for continuous close safety monitoring of all study participants, and for alerting the IEC/CTRC if concerns arise.

Following parameters will be monitored as a part of safety measures:

(a)    data with regard to completion/discontinuation of study, adverse events

(b)   Cannabidiol related AEs

(c)    Reports of serious adverse events (SAEs)

2.      Reduction in the cumulative dose of benzodiazepine required during admission

Anticipated adverse events:

RCT’s conducted using cannabidiol in various psychiatric disorders didn’t find any serious adverse effects. Most of the side effects were mild and limited to headache, dizziness, asthenia, malaise. Patients will be monitored for liver damage during the trial due to CBD as some patients may develop dose dependent hepatotoxicity (usually seen at doses more than 300mg). Baseline liver functions will be assessed and anyone with preexisting hepatic impairment will be excluded as mentioned in selection criteria. Patients will be monitored for LFT at baseline, on 7th day and 14th day. Those with elevated LFT will be withdrawn from the study (Elevated liver enzymes (more than 2 times) and/or elevated bilirubin). Any other adverse effect other than those reported will also be documented and reported to IEC.

Data safety monitoring board (DSMB) will be constituted for this study which is independent of the study team members. The team will look into the safety of the intervention proposed with interim analysis report or more frequently based on adverse effects.

Interim analyses:

Interim analysis will be done during the study period and it will be done after completion of first follow up of 300 participants. (1/3rd of total sample size) In case of more SAE’s the board will decide upon the frequency of follow-ups.

Statistical analysis:

Analysis will be done as per the intent to treat protocol (ITT) and handling of the missing data will be done by Maximum Likelihood Estimation. Statistical calculations will be performed using IBM SPSS statistics version 20.0 (SPSS Inc, Chicago, Illinois, USA). For data analysis, we will use Kolmogorov-Smirnov test for determining normality distribution of quantitative variables. For Variables (like CIWA-Ar, OCDS) two time point analysis, paired t-test will be done for within group analysis, and for between group analysis, unpaired t test will be done. For three time point analysis, repeated measures ANOVA will be used. Variables (Abstinence rates, Drop-out rates)-Chi-squared test will be used. Statistical significance will be assessed at a 2-sided p less than .05 level

Data management

Data will be collected in case record proformas (CRPs) prepared for the purpose of the study by PI or Co-PI, each patient will be given unique code at the time of recruitment. One investigator will be responsible for monitoring data intake and managing discrepancies and electronic data entry. These validation checks will be done intermittently and randomly for patients CRP’s. Scoring on scales will be done by one designated investigator for all patients, cross checked by other investigator. After completing the intake, data from CRPs is entered into Microsoft excel. Data will be verified for any errors and cross-checked followed by creation of clean data set. Only staff responsible for the study will have access to the data.

Data Entry in the CRP will be in English language. The authorized person only can cross the found Errors with a single line but not obliterated and the correction inserted should be signed with date. The PI/Investigator will ensure the accuracy, completeness, legibility and timeliness of the data entered in the CRF. The laboratory results will be transcribed into the CRP however, the original laboratory data will be kept in a separate file. CRFs will be kept safely in the department of psychiatry of each centre under the supervision of PI.

Data Storage: Data will be stored in secure server or cloud-based platform. Only authorized persons will have access to data.

Data Monitoring: We will follow regular data monitoring procedures to identify and resolve any data discrepancies or missing data through periodic data quality checks

Data Archiving: The study documents will be archived for three years. The Investigator or head of the medical institution will notify the ICMR of any change in the arrangements for archiving, e.g., relocation or transfer of ownership. The study documents will not to be destroyed without ICMR approval

Expected Outcome:

1. Among patients who are on cannabidiol during detoxification phase of alcohol use disorder management there will be reduction of alcohol craving and withdrawal severity compared to treatment as usual (TAU)

Among patients who receive cannabidiol during detoxification phase of alcohol use disorder management there will be reduction in hospital stay duration

Among patients who receive cannabidiol during detoxification phase there will be a higher rate of Self-declared abstinence at week 6 compared to TAU

Among patients who are on cannabidiol during detoxification phase there will be a greater alcohol reduction in case of relapse at week 6.

Ethical Issues:

The study will be conducted after getting Institutional Ethics Committee approval and Clinical Trials Registry India Registration. Written Informed Consent to be obtained from the participants. Confidentiality about patient identity will be maintained. Participants will be informed about the right to withdraw from the study at any time point Participation/non-participation will not have any bearing on the treatment. No extra cost will be imposed on the patient. Additional cost for cannabidiol solution will be borne by the funding agency (ICMR)