Alcohol Use Disorder
Conditions
Brief summary
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.
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.
Interventions
DRUGNimodipine
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.
DRUGPlacebo
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).
Sponsors
Yale University
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double blind, only statistician and pharmacist will not be masked.
Intervention model description
Participants will receive NIM or PLA in random order, during two sessions, separated by a washout period.
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of drinks consumed | ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later) | Total number of drinks (out of 12) that were consumed during each of the two alcohol drinking paradigm (ADP) session. |
| Alcohol Craving using Yale Craving Scale | ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later) | 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. |
| Stimulation Effect | ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later) | 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. |
| Sedation Effect | ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure | Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later) | Mean change in systolic blood pressure in mmHg |
| Change in Diastolic Blood Pressure | Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later) | Mean change in diastolic blood pressure in mmHg |
| Change in Heart Rate | Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later) | Mean change in heart rate measured in beats per minute |
Countries
United States
Contacts
CONTACTThomas Liss
CONTACTNicholas Franco
PRINCIPAL_INVESTIGATORSuchitra Krishnan-Sarin
Yale University School of Medicine, Dept of Psychiatry
Outcome results
None listed