Imaging Cannabinoid CB1 Receptors in Alcohol Dependence

Alcohol dependence (alcoholism) is a chronic medical illness with a relapsing course and a
major public health problem. Alcoholism is clinically characterized by periods of
uncontrolled alcohol consumption and withdrawal, during which counter-adaptive mechanisms
such as stress and dysphoria are recruited. Neurobiological research into the pathophysiology
of the illness suggest that both the primary rewarding effects of ethanol as well as
neuroadaptive changes that occur during chronic alcohol exposure involve persistent changes
in various brain neurotransmission systems, such as the dopamine, glutamate, and gamma-amino
butyric acid (GABA) systems. Recent views of the illness also emphasize the long-lasting
recruitment of the brain stress system. Unfortunately, despite this progress, available
pharmacological agents for the treatment of alcoholism are too few and not sufficiently
efficacious.

The brain endocannabinoid (EC) system is a recently discovered brain neurotransmission
system, which involves endogenous cannabinoid agents (ECs) that act upon specific receptors
(CB1 and CB2). CB1 receptor is abundant in the human brain and acts as an inhibitory
modulator of classical neurotransmitters. ECs and CB1 receptors appear to modulate the brain
reward system, and animal studies have demonstrated an important role of CB1 receptor
stimulation in alcohol- and drug-related behaviors. During chronic alcohol exposure, EC
levels in the brain are elevated and CB1 receptor levels are consequently reduced; this
appears to be reversible following withdrawal. Animal studies suggest that CB1 receptor
blockade in the abstinent phase may reduce alcohol craving and relapse. To what extent ECs
and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is
currently unknown. The lack of suitable methods to reliably quantify CB1 receptors in the
living human brain has to date hindered the progress in this field.

In this protocol, we outline studies aiming at elucidating the role of CB1 receptors in
alcohol and cannabis dependence by using positron emission tomography (PET) and the recently
developed radiotracer for CB1 receptors, [(18)F]FMPEP-d2. The aim of this project is to
explore CB1 receptor abnormalities at various stages of alcohol and cannabis dependence in
humans. For the studies in alcohol dependence, the primary hypothesis is that CB1 receptors
are downregulated during chronic alcohol exposure and upregulated during extended abstinence.
For the studies in cannabis users, our primary hypothesis is that CB1 receptors are
downregulated during chronic cannabis use and upregulated during extended abstinence. Insight
into the role of CB1 receptor function in human alcoholism and in chronic cannabis use may
help guide future development of pharmacotherapies.

- INCLUSION CRITERIA:

ALCOHOL DEPENDENT SUBJECTS:

1. All subjects must be male, 18-65 years of age and be able to give written informed
consent.

2. All subjects must be healthy based on history and physical examination.

3. Subjects must fulfill DSM-IV criteria (American Psychiatric Association 1987) for
alcohol dependence. In addition, they must have an alcohol consumption of 35 or more
standard drinks per week, as measured by timeline follow-back during the 28-day period
preceding admission, as well as during the 7-day period immediately preceding it.

4. About half of the patients with alcohol dependence will be carriers of the C allele of
the rs2023239 SNP and half will not.

HEALTHY SUBJECTS:

1. All subjects must be male, 18-65 years of age and be able to give written informed
consent.

2. This comparison group must be healthy based on history and physical examination.

3. About half of the healthy subjects will currently smoke cigarettes and about half will
not.

4. About half of the healthy subjects will be carriers of the C allele of the rs2023239
SNP and half will not.

CANNABIS USERS:

1. All subjects must be male, 18-65 years of age and be able to give written informed
consent.

2. All subjects must be healthy based on history and physical examination.

3. Self-reported cannabis use of at least one year with a typical pattern of use of at
least 5 days per week for the six months prior to unit admission.

4. A positive urine cannabinoid test within 90 days of admission.

EXCLUSION CRITERIA:

ALCOHOL DEPENDENT PATIENTS:

1. Any serious medical condition as judged by the investigator in consultation with the
attending physician in the NIAAA program.

2. Clinically significant coagulopathies or laboratory abnormalities other than those
related to alcohol dependence.

Past or present diagnosis of schizophrenia, bipolar illness or any other psychotic
disorder; any current disorder that has required psychoactive medication (other than
oxazepam) within the preceding 28-day period (42 days for fluoxetine). 3. Oxazepam is a
relatively short acting benzodiazepine and is used clinically during alcohol withdrawal.
Any present substance abuse other than alcohol.

4. Positive test for HIV.

5. Metallic foreign bodies that would be affected by the MRI scanner magnet, or fear of
enclosed spaces likely to make the subject unable to undergo an MRI scan.

6. Head trauma resulting in a period of unconsciousness lasting longer than 1 hour.

7. History of fetal alcohol syndrome or other neurodevelopmental disorder.

8. History of seizures, other than in childhood and related to fever.

9. Recent exposure to radiation (i.e., PET from other research) which when combined with
this study would be above the allowable limits.

10. Positive urine drug screen.

11. Inability to lie flat on camera bed for about 2.5 h

HEALTHY SUBJECTS:

1. Any current Axis I diagnosis; and any lifetime diagnosis of drug abuse or dependence.

2. Clinically significant laboratory abnormalities.

3. Recent heavy use of alcohol. That is, subjects must have an alcohol audit score of
less than or equal to 9. In addition, subjects must agree not to consume any alcohol
in the three days prior to the PET scan.

4. Psychotropic medication use (including benzodiazepines and illicit drugs) during the
28 days (42 day for fluoxetine) prior to the PET scan.

5. Serious medical problems.

6. Positive test for HIV.

7. Metallic foreign bodies that would be affected by the MRI magnet, or fear of enclosed
spaces likely to make the subject unable to undergo an MRI scan.

8. Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.

9. History of fetal alcohol syndrome or other neurodevelopmental disorder.

10. History of seizures, other than in childhood and related to fever.

11. Recent exposure to radiation (i.e., PET from other research) which when combined with
this study would be above the allowable limits.

12. Positive urine drug screen.

13. Inability to lie flat on camera bed for about 2.5 h

EXCLUSION CRITERIA: CANNABIS USERS:

1. History or presence of any clinically significant illness, as determined by history,
physical examination, and/or laboratory tests.

2. Past or present diagnosis of schizophrenia, bipolar illness or any other psychotic
disorder; any current disorder that has required psychoactive medication within the
preceding 28-day period (42 days for fluoxetine).

3. Current physical dependence on any substance other than cannabis, nicotine, or
caffeine;

4. Positive test for HIV.

5. Metallic foreign bodies that would be affected by the MRI scanner magnet, or fear of
enclosed spaces likely to make the subject unable to undergo an MRI scan.

6. Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.

7. History of fetal alcohol syndrome or other neurodevelopmental disorder.

8. History of seizures, other than in childhood and related to fever.

9. Recent exposure to radiation (i.e., PET from other research) which when combined with
this study would be above the allowable limits.

10. Inability to lie flat on camera bed for about 2.5 h.

11. Regular use of alcohol (greater than or equal to 6 standard drinks per day) four or
more times per week in the month prior to study entry.

12. Currently interested in or participating in drug abuse treatment, or participated in
drug abuse treatment within 60 days preceding study enrollment.