Rimonabant to Reduce Alcohol Consumption
Rimonabant to Reduce Alcohol Consumption
This study will examine whether Rimonabant, a drug that blocks cannabinoid-1 (CB1) receptors
 in the brain, affects alcohol consumption. Substances called endocannabinoids, which have
 many of the same effects of marijuana, bind to CB1 receptors. Animal studies show that when
 CB1 receptors are blocked, the animals consume less alcohol.

 Healthy normal volunteers between 21 and 40 years of age who consume between 20 and 40
 alcoholic drinks per week, drink at least 4 days a week, and are not seeking treatment for
 alcoholism may be eligible for this study. Candidates are screened with a medical history,
 including questions about alcohol and drug use, physical examination, blood and urine tests,
 breath alcohol test, and electrocardiogram.

 Participants are asked about their mental health history and use of alcohol, cigarettes and
 illicit drugs, and fill out questionnaires evaluating their emotional state and personality.
 Then, they begin a baseline evaluation in which they call a number at the NIH Clinical Center
 for 21 days to report how much alcohol they drank that day. One week after starting the
 baseline evaluation, they are randomly assigned to take either Rimonabant or placebo (a pill
 with no active ingredient) for 2 weeks. Before starting the drug, they have a urine drug
 screen and measurement of blood alcohol level. After 1 week on the test medication, they
 return to the Clinical Center to monitor drug or placebo side effects, if any, and to have a
 blood alcohol level test, urine drug screen, and blood tests for routine blood chemistries.
 After 2 weeks on the test medication, they come to the Clinical Center at noon for an alcohol
 self-administration test. Before the test, they are given a breath alcohol test and a urine
 drug test. The results of both tests must be negative to continue in the study.

 The alcohol self-administration test is videotaped. A heparin lock is placed in a vein in the
 participant's arm. This small needle remains in the arm for the duration of the study to
 avoid multiple needle sticks for blood draws. Blood is drawn periodically during the test to
 determine routine laboratory values, cotinine level (assessment of smoking status), the
 amount of Rimonabant or placebo in the body, and levels of various hormones. Thirty minutes
 before the test begins and every 30 minutes during the test, participants complete
 questionnaires and rating scales regarding their mood and desire to drink. Five minutes
 before the test be...
Recent studies show that endogenous cannabinoids modulate appetitive behaviors. For example,
 an antagonist of the CB1 cannabinoid receptor, SR141716, decreases food intake in animals as
 well as in humans and decreases alcohol consumption in rodent models of voluntary ethanol
 consumption. In this protocol, individuals consuming between 20 and 40 alcohol drinks per
 week, and who are not seeking alcohol treatment, will be recruited from the community.
 Following a one week baseline evaluation, participants will be randomized according to a
 double-blind design to receive either placebo or SR141716 for two additional weeks prior to
 being admitted to the hospital to participate in an alcohol self-administration experiment.
 The design of this experiment has been previously shown by O'Malley et al. (1) to be an
 effective paradigm to study the effects of medication on alcohol consumption. Following
 baseline psychological and endocrine measures, participants will receive a priming dose of
 ethanol designed to raise the breath alcohol levels (BAL) to 0.03 g/dl and then have the
 opportunity to consume up to eight drinks or to receive $3 dollars for each drink not
 consumed over a two hour period. It is hypothesized that participants receiving SR141716,
 compared to those receiving placebo, will have decreased alcohol consumption. Following the
 study, each participant will be carefully counseled about their alcohol consumption and
 provided referrals for alcohol treatment.
-  INCLUSION CRITERIA

 Male and female healthy participants, between 21 and 45 years of age.

 Weight and Body Mass Index:

 Males: between 60 kg and 90 kg; Body Mass Index between 18 and 28.

 Females: between 45 kg and 80 kg; Body Mass Index between 18 and 28.

 Certified as healthy by a comprehensive clinical assessment (detailed medical history and
 complete physical examination).

 Normal vital signs after 10 minutes in supine position:

 systolic blood pressure between 95 mmHg and 140 mmHg,

 diastolic blood pressure between 50 mmHg and 90 mmHg,

 heart rate between 45 bpm and 90 bpm.

 Normal 12-lead EKG, PR less than 210 ms, QRS less than 120 ms, QTcB(1) less than or equal
 to 430 ms for male and less than or equal to 450 ms for female (incomplete right bundle
 branch block can be accepted).

 Laboratory results should be within the normal range. Laboratory results which are found to
 be marginally outside the normal range (i.e., minor variances in the complete blood count
 (CBC) or electrolytes) will be clinically evaluated for relevance to this protocol. Liver
 functions must be less than two times normal.

 Written informed consent prior to study participation.

 Female participants of childbearing capability must use a double contraceptive method (such
 as oral contraceptives, condom with spermicide or intra-uterine device with spermicide)
 from the start of the study until two months post medication trial.

 Normal dietary habits and willingness to abstain from grapefruit juice consumption during
 the study. (Grapefruit juice inhibits hepatic enzymes which could potentially interfere
 with the metabolism of SR141716.)

 Must agree to abstain from the use of illicit drugs for the duration of the study.

 EXCLUSION CRITERIA:

 Any history or presence of significant cardiovascular, pulmonary, gastro-intestinal,
 hepatic, renal, metabolic, hematological, neurologic (including any history of
 convulsions), systemic, infectious diseases, or psychiatric disorders (i.e., a current
 diagnosis of major depression, panic disorder, eating disorders, or history of
 schizophrenia, bipolar disorder, or obsessive compulsive disorder). Individuals who report
 suicidal ideation or who have a past history of suicide attempts.

 Frequent headaches and/or migraine, recurrent nausea and/or vomiting.

 Symptomatic hypotension whenever the decrease of blood pressure or asymptomatic postural
 hypotension defined by a decrease in systolic blood pressure (SBP) equal to or greater than
 20 mmHg within two minutes when changing from the supine to the standing position.

 Blood donation within three months before administration.

 Presence or history of any allergy or unusual reactions to drugs or anesthetics that would
 suggest the participant could have a problem tolerating SR141716 or placebo.

 A participant who, in the judgment of the Investigator, is likely to be non-compliant, is
 violent when drinking, or is unable to cooperate because of a language problem or poor
 mental development.

 Participant who cannot be contacted in case of emergency.

 Currently taking any prescription medications or over-the-counter medications on a regular
 basis. Participants will be allowed to take an occasional pain medication or an antibiotic,
 if they get sick during their participation in the protocol.

 Excessive consumption of beverages with xanthine bases (greater than 6 cups or
 glasses/day).

 Female participants who have a positive Beta-HCG test (urine and/or plasma) or who are
 lactating.

 Positive reaction to any of the following tests: HBs antigen, anti-HCVantibody, anti-HIV1
 antibodies, anti-HIV2 antibodies. (Hepatitis could interfere with the metabolism of
 SR141716 in the liver. HIV could alter brain function.)

 Positive results of screening for drugs of abuse (amphetamines, barbiturates,
 benzodiazepines, cannabinoids, cocaine, or opiates).

 A DSM-IV diagnosis of illicit drug dependence in the last 6 months.

 Participants who come to the NIAAA Clinic and evidence withdrawal symptoms that result in a
 score of 8 or above on the CIWA Instrument.