Ignite Creation Date:
2024-05-05 @ 12:07 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00247689
Status:
TERMINATED
Last Update Posted:
2019-12-12
First Post:
2005-10-31
Brief Title:
Methylphenidate Studies for Drug Abuse Vulnerability Molecular Genentics
Sponsor:
National Institute on Drug Abuse NIDA
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Methylphenidate Studies for Drug Abuse Vulnerability Molecular Genentics
Status:
TERMINATED
Status Verified Date:
2015-02-27
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Research has shown that several human genes have been associated with vulnerability to substance abuse and dependence However little is known about how people with these genetic tendencies react to drugs in controlled settings
Methylphenidate also known as Ritalin is commonly prescribed for a number of conditions including attention deficit disorder Because methylphenidate is widely used in studies of brain chemistry and behavior and has relatively low risks associated with it use researchers are interested in seeing how it affects the thinking processes of people with apparent genetic vulnerability to drug abuse
Objectives
- To evaluate whether individuals with apparent genetic vulnerability to drug abuse react differently to methylphenidate than people who do not have this vulnerability
Eligibility
- Individuals at least 18 years of age or older who have participated in the NIDA protocol Allelic Linkage in Substance Abuse
Design
Participants will be asked to avoid using a number of over-the-counter medications including antihistamines cough medicines and nasal decongestants for 24 hours before the study day Participants will also be asked to avoid consuming caffeinated beverages nicotine or tobacco products or alcohol on the morning of the day of the study and will provide a urine sample at the start of the study to be tested for chemicals that may interfere with the study
Because of the nature of the study drug participants will not be allowed to drive to the clinical center on the day of the study Return transportation will be arranged
At the start of the study participants will take two tablets each 1 hour apart and will not be told whether the tablets are the study drug or a placebo
Participants will give regular answers to questions about mood and thinking processes on a computer for approximately 5 hours Blood samples will be taken during this part of the study
Research has shown that several human genes have been associated with vulnerability to substance abuse and dependence However little is known about how people with these genetic tendencies react to drugs in controlled settings
Methylphenidate also known as Ritalin is commonly prescribed for a number of conditions including attention deficit disorder Because methylphenidate is widely used in studies of brain chemistry and behavior and has relatively low risks associated with it use researchers are interested in seeing how it affects the thinking processes of people with apparent genetic vulnerability to drug abuse
Objectives
- To evaluate whether individuals with apparent genetic vulnerability to drug abuse react differently to methylphenidate than people who do not have this vulnerability
Eligibility
- Individuals at least 18 years of age or older who have participated in the NIDA protocol Allelic Linkage in Substance Abuse
Design
Participants will be asked to avoid using a number of over-the-counter medications including antihistamines cough medicines and nasal decongestants for 24 hours before the study day Participants will also be asked to avoid consuming caffeinated beverages nicotine or tobacco products or alcohol on the morning of the day of the study and will provide a urine sample at the start of the study to be tested for chemicals that may interfere with the study
Because of the nature of the study drug participants will not be allowed to drive to the clinical center on the day of the study Return transportation will be arranged
At the start of the study participants will take two tablets each 1 hour apart and will not be told whether the tablets are the study drug or a placebo
Participants will give regular answers to questions about mood and thinking processes on a computer for approximately 5 hours Blood samples will be taken during this part of the study
Detailed Description:
Scientific Goals We and others have now identified several human chromosomal regions that contain genetic markers that have been associated with vulnerability to substance abusedependence in several different human populations Uhl et al 2002 However little is known about the biological or behavioral mechanisms by which specific molecular genetic characteristics enhance risks for drug disorders This protocol will test hypotheses that genetically-mediated individual differences in acute responses to abused substances contribute to the mechanisms through which specific human allelic variants influence individual differences in vulnerability to drug abusedependence This protocol will characterize individual differences in responses to oral methylphenidate 30 mg also known as Ritalin We have chosen this agent due to a its wide clinical use b its moderate to low risks which are largely well-understood as a result of this widespread use and c its prior usefulness to us and others as a probe for reward system activities in for example patients with dopaminergic brain lesions Persico et al 1998 We have chosen this dose due to a our prior success with this dose even in a brain lesioned clinical population Persico et al 1998 b our preliminary work with candidate gene studies in individuals administered oral doses of up to 60-70 mg GRU et al in preparation c consultations with other workers in the field who advise use of this dose and who have used doses of 05 mgkg intravenously in prior work with few reported adverse events Volkow et al 2003
We will study individuals who are selected based on their genotypes We will test the hypothesis that individuals who display combinations of the abuse-associated andor resistance-associated allelic variants at different genomic loci that we and others have reproducibly associated with substance abuse Uhl et al 2002 will differ in their acute responses to methylphenidate administration We will also perform exploratory analyses of these data We will study the genotypes of individuals who display high- or low-level responses to oral methylphenidate administration Both the hypothesis-testing and exploratory aspects of this study will allow us to identify which addiction-associated human gene variants can alter subjective and physiologic responses to administration of methylphenidate
Method We will study previous participants in study 148 90-DA-N448 who have already consented to recontact from NIDA personnel We will select individuals who are eligible for study participation based on their genotypes at markers whose alleles differ between drug abusers those who report significant lifetime use and dependence on at least one illegal substance and controls individuals free from significant lifetime use of any addictive substances as well as allelic variants in genes expressed in reward circuits Patients will receive psychiatric and medical screening Eligible volunteering participants will have a one-day study session in which they receive oral placebo and oral methylphenidate 30 mg in single-blinded fashion This design was chosen to allow study participation by a larger fraction of eligible participants than those likely to consent to inpatient stays and longer designs Subjective methylphenidate effects plasma levels of methylphenidate and heart rate will be assessed periodically before and for 4 hours after the drug is administered Methylphenidate was chosen as a probe because 1 its mechanism of action directly involves central monoaminergic reward pathways including dopamine and norepinephrine transporter inhibition 2 there is such broad clinical experience with the drug that significant side effects are well known to be of low frequency in broad populations 3 there are individual differences in methylphenidate subjective responses documented in several sorts of studies including the studies of Parkinsonian patients and controls previously reported from our group
Hypothesis We advance a two-tailed hypothesis that subjective liking VAS responses to methylphenidate will be different in those individuals with multiple candidate genetic characteristics that are related to enhanced vulnerability to substance abusedependence compared to matched controls with few of these genomic characteristics Confidence will be greatest for those associations that are consistent among both CaucasianEuropean American and African American participants an internal replication built into this design
Benefits The results will have important implications for possible mechanisms by which genetic vulnerability to substance abuse particularly psychostimulants is expressed in humans The findings will also bear on genetic predictors of the response to methylphenidate which may be important for attention deficit hyperactivity disorder narcolepsy and other clinical disorders in which drugs of this class are used therapeutically
Risks Methylphenidate is also known as Ritalin and is commonly prescribed for a number of clinical conditions including attention deficithyperactivity syndrome The drug has been used for many individuals with few serious complications Individuals who use this drug for long periods of time may show nervousness and sleep changes Skin rashes appetite suppression nausea dizziness heart palpitations pulse and heart rhythm changes headache abnormal movements sleepiness chest pain abdominal pain liver function changes blood cell changes and changes in thinking have also been rarely reported in individuals who use this drug chronically A review of patients taking a treatment dose of methylphenidate for ADHD revealed serious cardiovascular adverse events in patients with underlying serious heart problems or defects and reports of stroke and heart attack in adults with certain risk factors ie untreated high blood pressure and a history of coronary artery disease Another review of patients taking a treatment dose of methylphenidate for ADHD revealed a slight increased risk about 1 per 1000 for drug-related psychiatric adverse events such as hearing voices becoming suspicious for no reason or becoming manic even in patients who did not have previous psychiatric problems Additional modest to minimal risks to participants include the risks of venous catheterization and blood withdrawal including pain bruising and bleeding and the risks of confidentiality We will minimize each of these more than minimal risks by appropriate exclusionary criteria medical screening use of lowmoderate drug doses evaluation prior to discharge availability of taxi for return home aseptic methods small total amounts of blood drawn standard minimal risk recording procedures coded locked data and Confidentiality Certification of this work
We will study individuals who are selected based on their genotypes We will test the hypothesis that individuals who display combinations of the abuse-associated andor resistance-associated allelic variants at different genomic loci that we and others have reproducibly associated with substance abuse Uhl et al 2002 will differ in their acute responses to methylphenidate administration We will also perform exploratory analyses of these data We will study the genotypes of individuals who display high- or low-level responses to oral methylphenidate administration Both the hypothesis-testing and exploratory aspects of this study will allow us to identify which addiction-associated human gene variants can alter subjective and physiologic responses to administration of methylphenidate
Method We will study previous participants in study 148 90-DA-N448 who have already consented to recontact from NIDA personnel We will select individuals who are eligible for study participation based on their genotypes at markers whose alleles differ between drug abusers those who report significant lifetime use and dependence on at least one illegal substance and controls individuals free from significant lifetime use of any addictive substances as well as allelic variants in genes expressed in reward circuits Patients will receive psychiatric and medical screening Eligible volunteering participants will have a one-day study session in which they receive oral placebo and oral methylphenidate 30 mg in single-blinded fashion This design was chosen to allow study participation by a larger fraction of eligible participants than those likely to consent to inpatient stays and longer designs Subjective methylphenidate effects plasma levels of methylphenidate and heart rate will be assessed periodically before and for 4 hours after the drug is administered Methylphenidate was chosen as a probe because 1 its mechanism of action directly involves central monoaminergic reward pathways including dopamine and norepinephrine transporter inhibition 2 there is such broad clinical experience with the drug that significant side effects are well known to be of low frequency in broad populations 3 there are individual differences in methylphenidate subjective responses documented in several sorts of studies including the studies of Parkinsonian patients and controls previously reported from our group
Hypothesis We advance a two-tailed hypothesis that subjective liking VAS responses to methylphenidate will be different in those individuals with multiple candidate genetic characteristics that are related to enhanced vulnerability to substance abusedependence compared to matched controls with few of these genomic characteristics Confidence will be greatest for those associations that are consistent among both CaucasianEuropean American and African American participants an internal replication built into this design
Benefits The results will have important implications for possible mechanisms by which genetic vulnerability to substance abuse particularly psychostimulants is expressed in humans The findings will also bear on genetic predictors of the response to methylphenidate which may be important for attention deficit hyperactivity disorder narcolepsy and other clinical disorders in which drugs of this class are used therapeutically
Risks Methylphenidate is also known as Ritalin and is commonly prescribed for a number of clinical conditions including attention deficithyperactivity syndrome The drug has been used for many individuals with few serious complications Individuals who use this drug for long periods of time may show nervousness and sleep changes Skin rashes appetite suppression nausea dizziness heart palpitations pulse and heart rhythm changes headache abnormal movements sleepiness chest pain abdominal pain liver function changes blood cell changes and changes in thinking have also been rarely reported in individuals who use this drug chronically A review of patients taking a treatment dose of methylphenidate for ADHD revealed serious cardiovascular adverse events in patients with underlying serious heart problems or defects and reports of stroke and heart attack in adults with certain risk factors ie untreated high blood pressure and a history of coronary artery disease Another review of patients taking a treatment dose of methylphenidate for ADHD revealed a slight increased risk about 1 per 1000 for drug-related psychiatric adverse events such as hearing voices becoming suspicious for no reason or becoming manic even in patients who did not have previous psychiatric problems Additional modest to minimal risks to participants include the risks of venous catheterization and blood withdrawal including pain bruising and bleeding and the risks of confidentiality We will minimize each of these more than minimal risks by appropriate exclusionary criteria medical screening use of lowmoderate drug doses evaluation prior to discharge availability of taxi for return home aseptic methods small total amounts of blood drawn standard minimal risk recording procedures coded locked data and Confidentiality Certification of this work
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-DA-N381 | None | None | None |