Effects of Nimodipine on Alcohol Drinking

A Randomized Controlled Study on the Effects of Nimodipine on Alcohol Drinking Among Adults Who Are Heavy Alcohol Drinkers

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Drug: Nimodipine; Drug: Placebo

Detailed Description

Participants with AUD who drink heavily, will participate in a double-blind, placebo-controlled, cross-over design. At baseline, eligible participants will complete an MRI scan at the Yale MR center and MEG/EEG at the VA MIND Center. ADP Lab sessions will be conducted in the CNRU at the Connecticut Mental Health Center.

Nimodipine is rapidly absorbed after oral administration & peak concentrations are achieved within 0.5 to 1.5 hours. However, due to high first-pass metabolism, initial elimination is rapid (equivalent to a half-life of 1-2 hours); consequently, the bioavailability of nimodipine is approximately 13% after oral administration and there is a need for frequent dosing. The terminal elimination half-life of nimodipine is approximately 8 to 9 hours. In order to ensure adequate exposure and CNS bioavailability investigators will follow the administration schedule used in the Krupitsky trial*1. In this study 26 alcohol-dependent patients (who had not consumed alcohol for a month) received treatment with 90 mg dose of nimodipine (in the schedule portrayed below) prior to ketamine administration; results suggest that this dose of nimodipine reduced ketamine-induced psychosis, negative symptoms, euphoria and sedation as well as the perceived similarity of ketamine effects to alcohol. While the Krupitsky trial*1 did not report any adverse events following exposure to this dose investigators will closely monitor blood pressure and adverse events during the treatment period prior to the ADP 1 (vitals monitored at time of each dosing and again 30 minutes, 1 hour, and 2 hours after each dose).

Participants will receive either NIM or PLA in random order, during two sessions, separated by 3-5 washout days (to allow flexibility in scheduling). NIM/PLA will be provided at a dose of 90 mg/every 6 hours, over an 18-hour period (4 doses totaling 360mg), with the last dose administered approx. 1-2 hours prior to the start of the ADP period at 12 pm. MEG/EEG will be obtained 1-2 hours after the 3rd dose of NIM/PLA. During the two ADP sessions, 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 blood alcohol levels.

Participants will have 2 follow-up visits at 1-week and 1-month after the ADP session.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Thomas Liss; Phone Number: 2034447545; Email: thomas.liss@yale.edu
• Study Contact Backup: Name: Nicholas Franco; Phone Number: 2039745759; Email: nicholas.franco@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine (Connecticut Mental Health Center)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. Ability to read English at 6th grade level or higher.
3. Meet DSM-V criteria for at least moderate AUD.
4. 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).

Exclusion Criteria:

1. Individuals who are seeking alcohol treatment or have been in alcohol treatment within the past 6 months.
2. Meet current DSM-V criteria for substance use disorder, except for tobacco use disorder or mild cannabis use disorder.
3. Positive urine drug screens at more than 1 baseline appointment for opiates, cocaine, benzodiazepines, and barbiturates.
4. Psychotic or other severe psychiatric disorders as determined by clinical evaluation.
5. Regular use of psychoactive drugs, except for individuals on a stable dose of an antidepressant for at least 2 months.
6. Medical conditions that would contraindicate the consumption of alcohol or use of nimodipine including untreated or not adequately controlled hypertension or hypotension. Blood pressure at or below 100/65 will be exclusionary.
7. Heart rate of less than 50 bpm.
8. Clinically significant abnormalities in screening laboratories, including aspartate aminotransferase (AST) >3 times upper limit of normal (ULN); alanine aminotransferase (ALT) > 3 times ULN; total bilirubin >1.5 times ULN; serum creatinine >2.0 times ULN.
9. Concurrent use of the following medications: CYP3A4 inhibitors and inducers, other calcium channel blockers, or other blood pressure lowering medications.
10. Neurological trauma or disease, delirium, or hallucinations, or clinically significant or unstable medical conditions, including uncontrolled hypertension or diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic diseases, which in the opinion of the study physician and PI, may put the patient at risk because of participation in the study.
11. Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores of 8 or greater or a history of significant repeated alcohol withdrawals to reduce the likelihood of withdrawal symptomatology if subjects reduce their drinking.
12. Women who are pregnant or nursing.
13. Participants who refuse to use a reliable method of birth control from the time of first medication administration to 7 days after. These include oral contraceptives, contraceptive sponge, patch, double barrier (diaphragm/spermicidal or condom/spermicidal), intrauterine contraceptive system, etonogestrel implant, medroxyprogesterone acetate contraceptive injection, complete abstinence from sexual intercourse, hormonal vaginal contraceptive ring, surgical sterilization, or true abstinence.
14. Subjects who report disliking spirits will be excluded because hard liquor will be provided during the ADP.
15. Subjects who have taken any investigational drug within 4 weeks of the anticipated date of the first study dose.
16. Individuals who report heavy drinking days in the 2 days prior to their intake appointment but have a negative ethyl glucuronide (EtG) test to rule out subjects who are misrepresenting their drinking history.
17. Subjects who have donated blood within the past 6 weeks.
18. Heart rate of less than 50 bpm.
19. Subjects with a history or presence of cirrhosis.
20. MRI contraindications including incompatible implants, other metal in body (e.g. pacemakers, shrapnel, metal implants) or claustrophobia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nimodipine 1st / Placebo 2nd; Participants randomized to the Nimodipine 1st Arm will be administered Nimodipine prior to their 1st ADP session. Then after a washout period, participants will take a matching placebo prior to the 2nd lab session.	Drug: Nimodipine; 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.; Drug: Placebo; 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).
Experimental: Placebo 1st / Nimodipine 2nd; Participants randomized to the Placebo1st Arm will be administered matching placebo prior to their 1st ADP session. Then after a washout period, participants will be administered Nimodipine prior to the 2nd lab session.	Drug: Nimodipine; 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.; Drug: Placebo; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of drinks consumed	Total number of drinks (out of 12) that were consumed during each of the two alcohol drinking paradigm (ADP) session.	ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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.	ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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.	ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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.	ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Systolic Blood Pressure	Mean change in systolic blood pressure in mmHg	Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
Change in Diastolic Blood Pressure	Mean change in diastolic blood pressure in mmHg	Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
Change in Heart Rate	Mean change in heart rate measured in beats per minute	Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)
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.	Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Suchitra Krishnan-Sarin, Yale University School of Medicine, Dept of Psychiatry

Publications and helpful links

General Publications

• Tadel F, Baillet S, Mosher JC, Pantazis D, Leahy RM. Brainstorm: a user-friendly application for MEG/EEG analysis. Comput Intell Neurosci. 2011;2011:879716. doi: 10.1155/2011/879716. Epub 2011 Apr 13.
• Donoghue T, Haller M, Peterson EJ, Varma P, Sebastian P, Gao R, Noto T, Lara AH, Wallis JD, Knight RT, Shestyuk A, Voytek B. Parameterizing neural power spectra into periodic and aperiodic components. Nat Neurosci. 2020 Dec;23(12):1655-1665. doi: 10.1038/s41593-020-00744-x. Epub 2020 Nov 23.
• Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH. Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists. Neuropsychopharmacology. 2001 Dec;25(6):936-47. doi: 10.1016/S0893-133X(01)00346-3.
• Freeman WJ, Holmes MD, Burke BC, Vanhatalo S. Spatial spectra of scalp EEG and EMG from awake humans. Clin Neurophysiol. 2003 Jun;114(6):1053-68. doi: 10.1016/s1388-2457(03)00045-2.
• Freeman WJ, Rogers LJ, Holmes MD, Silbergeld DL. Spatial spectral analysis of human electrocorticograms including the alpha and gamma bands. J Neurosci Methods. 2000 Feb 15;95(2):111-21. doi: 10.1016/s0165-0270(99)00160-0.
• Chowdhury RA, Zerouali Y, Hedrich T, Heers M, Kobayashi E, Lina JM, Grova C. MEG-EEG Information Fusion and Electromagnetic Source Imaging: From Theory to Clinical Application in Epilepsy. Brain Topogr. 2015 Nov;28(6):785-812. doi: 10.1007/s10548-015-0437-3. Epub 2015 May 28.
• Chowdhury RA, Pellegrino G, Aydin U, Lina JM, Dubeau F, Kobayashi E, Grova C. Reproducibility of EEG-MEG fusion source analysis of interictal spikes: Relevance in presurgical evaluation of epilepsy. Hum Brain Mapp. 2018 Feb;39(2):880-901. doi: 10.1002/hbm.23889. Epub 2017 Nov 21.
• Cortes-Briones J, Skosnik PD, Mathalon D, Cahill J, Pittman B, Williams A, Sewell RA, Ranganathan M, Roach B, Ford J, D'Souza DC. Delta9-THC Disrupts Gamma (gamma)-Band Neural Oscillations in Humans. Neuropsychopharmacology. 2015 Aug;40(9):2124-34. doi: 10.1038/npp.2015.53. Epub 2015 Apr 24.
• De Clercq W, Vergult A, Vanrumste B, Van Paesschen W, Van Huffel S. Canonical correlation analysis applied to remove muscle artifacts from the electroencephalogram. IEEE Trans Biomed Eng. 2006 Dec;53(12 Pt 1):2583-7. doi: 10.1109/TBME.2006.879459.
• De Vos M, Ries S, Vanderperren K, Vanrumste B, Alario FX, Van Huffel S, Burle B. Removal of muscle artifacts from EEG recordings of spoken language production. Neuroinformatics. 2010 Jun;8(2):135-50. doi: 10.1007/s12021-010-9071-0.
• Gao R, Penzes P. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med. 2015;15(2):146-67. doi: 10.2174/1566524015666150303003028.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): June 30, 2032
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: March 25, 2026
• First Submitted That Met QC Criteria: June 25, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nicotinic Acids; Dihydropyridines; Nimodipine
• Other Study ID Numbers: 2000038566_a; 2P50AA012870-21 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No