AlcoholismNCT00816439
Imaging Cannabinoid CB1 Receptors in Alcohol Dependence
An observational study of Alcoholism, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
The cannabinoid type 1 (CB1) receptor is a protein found in the brain that is involved with the effects of marijuana; it may also play a role in the effects of alcohol dependence and withdrawal. Read more about this study
- Who is it for?
- Ages 18 to 65 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Alcoholism
- How many people
- 101 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Dec 2008to 28 Aug 2014
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- ALCOHOL DEPENDENT SUBJECTS:
- All subjects must be male, 18-65 years of age and be able to give written informed consent.
- All subjects must be healthy based on history and physical examination.
- 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.
- 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:
Show all 15Show fewer
- All subjects must be male, 18-65 years of age and be able to give written informed consent.
- This comparison group must be healthy based on history and physical examination.
- About half of the healthy subjects will currently smoke cigarettes and about half will not.
- About half of the healthy subjects will be carriers of the C allele of the rs2023239 SNP and half will not.
- CANNABIS USERS:
- All subjects must be male, 18-65 years of age and be able to give written informed consent.
- All subjects must be healthy based on history and physical examination.
- 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.
- A positive urine cannabinoid test within 90 days of admission.
Who cannot join
- ALCOHOL DEPENDENT PATIENTS:
- Any serious medical condition as judged by the investigator in consultation with the attending physician in the NIAAA program.
- 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.
Show all 38Show fewer
- 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:
- Any current Axis I diagnosis; and any lifetime diagnosis of drug abuse or dependence.
- Clinically significant laboratory abnormalities.
- 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.
- Psychotropic medication use (including benzodiazepines and illicit drugs) during the 28 days (42 day for fluoxetine) prior to the PET scan.
- Serious medical problems.
- Positive test for HIV.
- 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.
- Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.
- History of fetal alcohol syndrome or other neurodevelopmental disorder.
- History of seizures, other than in childhood and related to fever.
- Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.
- Positive urine drug screen.
- Inability to lie flat on camera bed for about 2.5 h
- History or presence of any clinically significant illness, as determined by history, physical examination, and/or laboratory tests.
- 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).
- Current physical dependence on any substance other than cannabis, nicotine, or caffeine;
- Positive test for HIV.
- 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.
- Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.
- History of fetal alcohol syndrome or other neurodevelopmental disorder.
- History of seizures, other than in childhood and related to fever.
- Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.
- Inability to lie flat on camera bed for about 2.5 h.
- 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.
- Currently interested in or participating in drug abuse treatment, or participated in drug abuse treatment within 60 days preceding study enrollment.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
The cannabinoid type 1 (CB1) receptor is a protein found in the brain that is involved with the effects of marijuana; it may also play a role in the effects of alcohol dependence and withdrawal. Earlier animal studies have shown that although long-term alcohol use decreases the number of CB1 receptors in the brain, the number returns to normal after alcohol use stops. This study will use positron emission tomography (PET) and magnetic resonance imaging (MRI) scans to trace a radioactive chemical called [11C]MePPEP, which can locate and measure the number of CB1 receptors in the brain. Researchers will study the CB1 receptors in the brains of people with alcohol dependence, and compare the results to the CB1 receptors in the brains of people without alcohol dependence. The results of this study will be used to further research into appropriate treatment procedures for alcohol dependence.
This study will include 30 men with alcohol dependence and 50 men without alcohol dependence. All of the men must be between 18 and 65 years of age. Participants in both groups must not have any medical conditions that will prevent them from undergoing PET or MRI scans.
Read more
For the PET scan, participants will be injected with a small amount of [11C]MePPEP and will then be brought to the PET scanner. The scan will take between 3 and 4 hours, but participants will be allowed to take breaks over the course of the scan. The MRI scan will not require any injections and will take approximately 1 hour to complete.
Participants without alcohol dependence will make three visits to the National Institutes of Health Clinical Center. Blood and urine samples will be taken during one visit, and participants will arrange to have an MRI scan on one visit and a PET scan on the other visit, in whichever order they prefer.
Participants with alcohol dependence will undergo two PET scans: the first will be performed between 3 and 7 days after the participant last consumed alcohol, and the second will be performed approximately 2 to 4 weeks after the first scan (with no alcohol consumption permitted in the interval). Participants will alcohol dependence will also undergo an MRI scan and will provide blood and urine samples.
Read the detailed description
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.
- Conditions
- Alcoholism
- Keywords
- Positron Emission Tomography, Brain Imaging, Alcoholism
- Medical subject headings
- Alcoholism
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jan 2009 (estimated)
- Study start29 Dec 2008
- Study completion28 Aug 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for AlcoholismStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Time perspective
- Prospective
- Enrolment
- 101 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
- Investigators
- Robert B Innis, M.D., Principal investigator, National Institute of Mental Health (NIMH)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00816439
- Sponsor's protocol ID
- 090040
- Other IDs
- 09-M-0040
- Status last verified
- 28 Aug 2014
- First submitted
- 31 Dec 2008
- Last updated
- 5 Jul 2018
- Results posted
- No
Publications
Basavarajappa BS, Hungund BL. Role of the endocannabinoid system in the development of tolerance to alcohol. Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24. doi: 10.1093/alcalc/agh111. Epub 2004 Nov 18.
PubMed 15550443Brown AK, George DT, Fujita M, Liow JS, Ichise M, Hibbeln J, Ghose S, Sangare J, Hommer D, Innis RB. PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. Alcohol Clin Exp Res. 2007 Jan;31(1):28-32. doi: 10.1111/j.1530-0277.2006.00261.x.
PubMed 17207098Cippitelli A, Bilbao A, Hansson AC, del Arco I, Sommer W, Heilig M, Massi M, Bermudez-Silva FJ, Navarro M, Ciccocioppo R, de Fonseca FR; European TARGALC Consortium. Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci. 2005 Apr;21(8):2243-51. doi: 10.1111/j.1460-9568.2005.04056.x.
PubMed 15869521Hirvonen J, Zanotti-Fregonara P, Gorelick DA, Lyoo CH, Rallis-Frutos D, Morse C, Zoghbi SS, Pike VW, Volkow ND, Huestis MA, Innis RB. Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography. Biol Psychiatry. 2018 Nov 15;84(10):715-721. doi: 10.1016/j.biopsych.2018.07.009. Epub 2018 Jul 21.
PubMed 30121138
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Imaging Cannabinoid CB1 Receptors in Alcohol Dependence
- ClinicalTrials.gov ID
- NCT00816439
- Acronym / sponsor ID
- 090040
- Conditions
- Alcoholism
- Keywords
- Positron Emission Tomography, Brain Imaging, Alcoholism
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 101 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- 29 Dec 2008
- Study completion
- 28 Aug 2014
- First posted
- 1 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The cannabinoid type 1 (CB1) receptor is a protein found in the brain that is involved with the effects of marijuana; it may also play a role in the effects of alcohol dependence and withdrawal. Earlier animal studies have shown that although long-term alcohol use decreases the number of CB1 receptors in the brain, the number returns to normal after alcohol use stops. This study will use positron emission tomography (PET) and magnetic resonance imaging (MRI) scans to trace a radioactive chemical called [11C]MePPEP, which can locate and measure the number of CB1 receptors in the brain. Researchers will study the CB1 receptors in the brains of people with alcohol dependence, and compare the results to the CB1 receptors in the brains of people without alcohol dependence. The results of this study will be used to further research into appropriate treatment procedures for alcohol dependence.
This study will include 30 men with alcohol dependence and 50 men without alcohol dependence. All of the men must be between 18 and 65 years of age. Participants in both groups must not have any medical conditions that will prevent them from undergoing PET or MRI scans.
For the PET scan, participants will be injected with a small amount of [11C]MePPEP and will then be brought to the PET scanner. The scan will take between 3 and 4 hours, but participants will be allowed to take breaks over the course of the scan. The MRI scan will not require any injections and will take approximately 1 hour to complete.
Participants without alcohol dependence will make three visits to the National Institutes of Health Clinical Center. Blood and urine samples will be taken during one visit, and participants will arrange to have an MRI scan on one visit and a PET scan on the other visit, in whichever order they prefer.
Participants with alcohol dependence will undergo two PET scans: the first will be performed between 3 and 7 days after the participant last consumed alcohol, and the second will be performed approximately 2 to 4 weeks after the first scan (with no alcohol consumption permitted in the interval). Participants will alcohol dependence will also undergo an MRI scan and will provide blood and urine samples.
Detailed description
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.
Study design
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- All subjects must be male, 18-65 years of age and be able to give written informed consent.
- All subjects must be healthy based on history and physical examination.
- 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.
- About half of the patients with alcohol dependence will be carriers of the C allele of the rs2023239 SNP and half will not.
- All subjects must be male, 18-65 years of age and be able to give written informed consent.
Key exclusion criteria (38 listed)
- Any serious medical condition as judged by the investigator in consultation with the attending physician in the NIAAA program.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jul 2018.
- Background: PubMed 15550443Basavarajappa BS, Hungund BL. Role of the endocannabinoid system in the development of tolerance to alcohol. Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24. doi: 10.1093/alcalc/agh111. Epub 2004 Nov 18.
- Background: PubMed 17207098Brown AK, George DT, Fujita M, Liow JS, Ichise M, Hibbeln J, Ghose S, Sangare J, Hommer D, Innis RB. PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. Alcohol Clin Exp Res. 2007 Jan;31(1):28-32. doi: 10.1111/j.1530-0277.2006.00261.x.
- Background: PubMed 15869521Cippitelli A, Bilbao A, Hansson AC, del Arco I, Sommer W, Heilig M, Massi M, Bermudez-Silva FJ, Navarro M, Ciccocioppo R, de Fonseca FR; European TARGALC Consortium. Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci. 2005 Apr;21(8):2243-51. doi: 10.1111/j.1460-9568.2005.04056.x.
- Derived from this study: PubMed 30121138Hirvonen J, Zanotti-Fregonara P, Gorelick DA, Lyoo CH, Rallis-Frutos D, Morse C, Zoghbi SS, Pike VW, Volkow ND, Huestis MA, Innis RB. Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography. Biol Psychiatry. 2018 Nov 15;84(10):715-721. doi: 10.1016/j.biopsych.2018.07.009. Epub 2018 Jul 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert B Innis, M.D. principal investigator
National Institute of Mental Health (NIMH)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Alcoholism, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00816439, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2018.