About this trial

This is a randomized placebo-controlled trial (RCT). Participants will be non-treatment seeking adults, 21-50 years of age, with Alcohol Use Disorders. All will participate in two alcohol drinking paradigm (ADP) sessions separated by at least 3 days at The Clinical Neuroscience Research Unit (CNRU). Participants will stay overnight and receive nimodipine (90 mg/dose) or placebo every six hours during an 18-hour period prior to each ADP. MEG and/or EEG data will be collected before the first dose and after the third dose of nimodipine (NIM) or placebo (PLA). Adverse events will be closely monitored during this period. During the ADP participants will receive a priming dose of alcohol followed by a one-hour monitoring period. This will be followed by three one-hour self-administration periods; during each hour they will be able to choose between four drinks or monetary equivalents of these drinks (total of 12 drinks over three hours). ADP outcomes will include number of drinks consumed, alcohol craving, mood changes and alcohol effects, physiological measures (heart rate, blood pressure), as well as breath alcohol levels. Investigators anticipate having to recruit up to 40 participants to achieve 20 completers.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Ages 21-50 (The lower limit is to avoid offering alcohol to individuals below the drinking age of 21. The upper age is determined by experience recruiting for our prior studies).

Ability to read English at 6th grade level or higher.

Meet DSM-V criteria for at least moderate AUD.

Average weekly alcohol consumption of 30-70 standard drinks for men and 20-65 drinks for women. The lower limits are consistent with the lower sex-specific cut-offs defining high-risk drinking based on World Health Organization Risk Levels (WHO, 2000); the upper limits are designed to avoid recruiting participants whose drinking is likely to exceed the number of drinks available in the alcohol drinking paradigm (ADP).

Disqualifiers

Individuals who are seeking alcohol treatment or have been in alcohol treatment within the past 6 months.

Meet current DSM-V criteria for substance use disorder, except for tobacco use disorder or mild cannabis use disorder.

Positive urine drug screens at more than 1 baseline appointment for opiates, cocaine, benzodiazepines, and barbiturates.

Psychotic or other severe psychiatric disorders as determined by clinical evaluation.

Trial design

Design model

Crossover

Treatments tested in this trial

Nimodipine
Drug
Nimodipine 90mg/dose or matching placebo will be administered every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm). In total, participants will receive a total of 4 doses totaling to 360mg.
Placebo
Drug
Matching placebo will be administered on the same schedule as Nimodipine, every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm).

Treatment groups

40 Participants

are divided into 2 treatment groups

Group A: Nimodipine 1st / Placebo 2ndExperimental treatment 2 interventions

Group B: Placebo 1st / Nimodipine 2ndExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Number of drinks consumed

Total number of drinks (out of 12) that were consumed during each of the two alcohol drinking paradigm (ADP) session.

Time frame

ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)

2

Alcohol Craving using Yale Craving Scale

Stimulation effect collected using the Biphasic Alcohol Effect Scale. Brief Biphasic Alcohol Effects Scale-Stimulation subscale, measuring stimulation effects of alcohol on an 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher stimulation.

Time frame

ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)

3

Stimulation Effect

Stimulation effect collected using the Biphasic Alcohol Effect Scale. Brief Biphasic Alcohol Effects Scale-Stimulation subscale, measuring stimulation effects of alcohol on an 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher stimulation.

Time frame

ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)

4

Sedation Effect

Stimulation effect collected using the Biphasic Alcohol Effect Scale. Brief Biphasic Alcohol Effects Scale-Sedation subscale, measuring sedation effects of alcohol on Day 7, 6 items, 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher sedation.

Time frame

ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)

Secondary outcomes

1

Change in Systolic Blood Pressure

Mean change in systolic blood pressure in mmHg

Time frame

Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)

2

Change in Diastolic Blood Pressure

Mean change in diastolic blood pressure in mmHg

Time frame

Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)

3

Change in Heart Rate

Mean change in heart rate measured in beats per minute

Time frame

Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)

Other outcomes

1

Changes in brain circuit hyperexcitation - Preprocessing and source analysis

Magnetoencephalography/Electroencephalography (MEG/EEG) data will be preprocessed following a standard pipeline\[13\] including bandpass filtering (0.1-100 Hz), notch filtering (60Hz), and removal of artifacts with independent component analysis (ICA)\[14-16\]. For each subject, an MRI will be segmented using the FreeSurfer software suite and imported into the MEG/EEG data analysis toolbox for Matlab Brainstorm\[17\]. Data will be segmented into two-second epochs, and the time series will be obtained using maximum entropy on the mean (MEM)\[10,11\] on individual head models. Reconstructed sources of subjects will be projected on the FSAverage atlas with FreeSurfer using a spherical representation of the cortex. The Destrieux Atlas will be used to parcellate the cortex into regions of interest (ROIs) to be used to extract the time series of each ROI (ventromedial, medial and orbitofrontal). MEG/EEG to be done before the 1st and after the 3rd dose of nimodipine at each lab session.

Time frame

Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)

2

Changes in brain circuit hyperexcitation - Power Spectral Density (PSD) Exponent Estimation

Magnetoencephalography/Electroencephalography (MEG/EEG) will be collected before the first dose and after the third dose of nimodipine at each of the 2 lab session days. The Python implementation of the specparam algorithm (https://github.com/fooof-tools)\[2\] will be used to estimate the exponent χ of the PSD power law (1⁄f\^χ with χ\>0 )\[19,4,5\]. For each subject, prefrontal cortex region of interest (ROI), and signal epoch, PSD will be calculated with Welch's method and fitted with the specparam algorithm in the 20-50Hz frequency range, as the exponent in this range has the strongest correlations with excitatory/inhibitory (E/I) ratio\[2\]. The resulting exponents and intercepts will be averaged across epochs, to obtain a single exponent and intercept estimate per ROI per subject.

Time frame

Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)

Effects of Nimodipine on Alcohol Drinking

About this trial

Eligibility criteria

Qualifiers

Disqualifiers

Trial design

Treatments tested in this trial

Treatment groups

Trial outcomes

Primary outcomes

Secondary outcomes

Other outcomes

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