Alcoholism
Conditions
Keywords
alcoholism, ghrelin, craving
Brief summary
Only a few medications are approved for the treatment of alcohol dependence and there exists a substantial need for discovering ways to provide more effective treatments. Accordingly, identifying new potential neuropharmacological targets in the treatment of alcohol dependence represents a high priority in public health. Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin was first isolated from the stomach, but a central hypothalamic production of ghrelin has also been demonstrated. Ghrelin plays a key role in the regulation of appetite. Consistent with the common neurobiological substrates for control of food and alcohol consumption, preclinical investigations suggest that ghrelin plays a role in the neurobiology of alcohol dependence, thus representing a new potential neuropharmacology target. In keeping with the preclinical studies, human investigations showed that alcohol consumption affects blood ghrelin levels and that blood ghrelin levels significantly and positively correlate with craving measurements in alcohol-dependent individuals. The effects of exogenous ghrelin injected intravenous (i.v.) in alcohol-dependent individuals, however, have never been investigated. The current project proposes a randomized double-blind placebo-controlled 3-group between-subject laboratory study aimed at investigating the effects of exogenous ghrelin i.v. on non-treatment seeking alcohol-dependent subjects in terms of urges to drink, attention to cues and related psychophysiological measures. This project has the goals to: i) conduct an alcohol laboratory study testing the role of ghrelin i.v., therefore demonstrating the feasibility of such a study and the safety of ghrelin i.v. when administered to alcohol-dependent individuals; and ii) explore the effects of ghrelin i.v. on alcohol craving assessed under controlled conditions, such as a cue-reactivity (CR) experiment. This study will address whether alcohol craving is affected when ghrelin levels are modified acutely via a ghrelin i.v. injection. Given the crucial need to expand our understanding of the underlying neurobiology of alcoholism, this study potentially will lead to identify new targets for the development of pharmacological treatments that may improve interventions for alcohol dependent individuals.
Interventions
DRUGGhrelin
A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
DRUGSaline solution
Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
Sponsors
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Understanding that this is not a treatment study. * Breath alcohol concentration (BAC) equal to 0.00 when the participants sign the informed consent document. * Age between 18 and 70 years old (inclusive). * Female participants must be postmenopausal for at least one year, surgically sterile, or practicing an effective method of birth control before entry and throughout the study; have a negative urine pregnancy test at screening and cue-reactivity (CR) visits. * Diagnosis of Alcohol dependence using Module E of the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders - Text Revised (DSM-IV-TR). * Participants must meet criteria for heavy drinking, defined as averaging ≥4 drinks/day for women and ≥5 drinks/day for men during a consecutive 30-day period within the 90 days prior to baseline evaluation * Good health as confirmed by medical history, physical examination, electrocardiogram (ECG), laboratory tests and vital signs. * Participant must be willing to receive an I.V. line.
Exclusion criteria
* Individuals expressing interest in treatment for alcoholism. * Females who are of child bearing potential and not practicing effective birth control. * Current (last 12 months) diagnosis of dependence on any psychoactive substance other than alcohol and nicotine (according to the DSM-IV-TR) * DSM-IV-TR Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or other psychoses; an active illness within the past 6 months that meet the DSM-IV-TR criteria for a diagnosis of Major Depressive Disorder or Anxiety Disorder; in the investigators' opinion, moderate to severe risk of suicide (e.g. active plan, or attempt in last 6 months). * History of hospitalization for alcohol intoxication delirium, alcohol withdrawal delirium or seizure. * Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) ≥ 10, at any assessment. * Positive urine drug screen at baseline for any illegal substance other than marijuana (a urine drug screen may be repeated once during the screening period). * Subjects who have received any behavioral and/or pharmacological treatment for alcoholism within the past 30 days. * Current use of psychotropic medications that cannot be discontinued. * Clinically significant medical abnormalities \[e.g., alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>300% the upper limit of normal\]. * Significant medical conditions, such as cancer, liver cirrhosis, heart chronic failure, chronic kidney failure, chronic intestinal diseases (e.g., Crohn's disease), chronic neurological disorders (e.g., tardive dyskinesia, epilepsy, Parkinson's disease), diabetes, obesity \[Body Mass Index(BMI) ≥ 30 kg/m2\]. * Participants with a history of hypotension clinically significant (e.g.: history of fainting and/or syncopal attacks). * No history of adverse reactions or hypersensitivity to ghrelin i.v. nor history of adverse reactions to needle puncture.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alcohol Visual Analogue Scale (A-VAS) | approximately 30 minutes after drug administration | Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of urge to drink \[as measured by the Alcohol Visual Analogue Scale (A-VAS)\]. The A-VAS was rated on 11-point anchored Likert-type scales, where 0 is the minimum score (no craving) and 11 is the maximum score (highest craving intensity). The change in the A-VAS score (deltaA-VAS) was used to indicate decrease (-d) or increase (+d) in craving intensity. |
| Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability. | participants will be followed after the cue-reactivity experiment, an expected average of 7 days | Whether ghrelin intravenous (i.v.), as compared to saline i.v., does not significantly increase Adverse Events (AEs). |
| Salivation | approximately 30 minutes after drug administration | Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of psychophysiological responses, namely salivation changes. |
Countries
United States
Participant flow
Recruitment details
Individuals were recruited via advertisements in local public transportation and mass-media
Participants by arm
| Arm | Count |
|---|---|
| Ghrelin (1 Microg/kg) A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment. | 13 |
| Ghrelin (3 Microg/kg) A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment. | 14 |
| Saline Solution Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment. | 18 |
| Total | 45 |
Baseline characteristics
| Characteristic | Ghrelin (1 Microg/kg) | Saline Solution | Ghrelin (3 Microg/kg) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 18 Participants | 14 Participants | 45 Participants |
| Age, Continuous | 42.8 years STANDARD_DEVIATION 9.8 | 46.6 years STANDARD_DEVIATION 9 | 43.9 years STANDARD_DEVIATION 8.6 | 44.7 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment United States | 13 participants | 18 participants | 14 participants | 45 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 9 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 13 | 12 / 14 | 15 / 18 |
| serious Total, serious adverse events | 0 / 13 | 0 / 14 | 0 / 18 |
Outcome results
Primary
Alcohol Visual Analogue Scale (A-VAS)
Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of urge to drink \[as measured by the Alcohol Visual Analogue Scale (A-VAS)\]. The A-VAS was rated on 11-point anchored Likert-type scales, where 0 is the minimum score (no craving) and 11 is the maximum score (highest craving intensity). The change in the A-VAS score (deltaA-VAS) was used to indicate decrease (-d) or increase (+d) in craving intensity.
Time frame: approximately 30 minutes after drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ghrelin (1 Microg/kg) | Alcohol Visual Analogue Scale (A-VAS) | 1.95 units on a scale | Standard Deviation 2.19 |
| Ghrelin (3 Microg/kg) | Alcohol Visual Analogue Scale (A-VAS) | 2.66 units on a scale | Standard Deviation 2.19 |
| Saline Solution | Alcohol Visual Analogue Scale (A-VAS) | 4.29 units on a scale | Standard Deviation 2.17 |
Primary
Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability.
Whether ghrelin intravenous (i.v.), as compared to saline i.v., does not significantly increase Adverse Events (AEs).
Time frame: participants will be followed after the cue-reactivity experiment, an expected average of 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ghrelin (1 Microg/kg) | Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability. | 11 participants |
| Ghrelin (3 Microg/kg) | Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability. | 12 participants |
| Saline Solution | Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability. | 15 participants |
Primary
Salivation
Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of psychophysiological responses, namely salivation changes.
Time frame: approximately 30 minutes after drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ghrelin (1 Microg/kg) | Salivation | 1.8 gram | Standard Deviation 1.4 |
| Ghrelin (3 Microg/kg) | Salivation | 1.9 gram | Standard Deviation 1.4 |
| Saline Solution | Salivation | 3.2 gram | Standard Deviation 1.4 |