Methylphenidate Studies for Drug Abuse Vulnerability Molecular Genentics

Scientific Goals. We and others have now identified several human chromosomal regions that
contain genetic markers that have been associated with vulnerability to substance
abuse/dependence 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 abuse/dependence. 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 0.5 mg/kg
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 and/or
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 abuse/dependence
compared to matched controls with few of these genomic characteristics. Confidence will be
greatest for those associations that are consistent among both Caucasian/European 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 deficit/hyperactivity 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, (i.e. 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 1,000) 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
low/moderate 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.

- INCLUSION CRITERIA:

Self-reported White/Caucasian or Black/African American individual who have participated in
the protocol #148 (90-DA-N448) in order to obtain the molecular genetic variables needed in
the current study. We will contact only those individuals (substance abusers, non-substance
abusing controls, and family members if the proband does not qualify) who have participated
in study #148 (90-DA-N448) at times when their consent included written agreement to be
contacted at a later date and are enrolled at the NIDA Intramural Research Program.

EXCLUSION CRITERIA:

1. Do NOT have a history of

1. Seizures,

2. Head injury resulting in unconsciousness and/or requiring hospitalization

3. Cardiovascular abnormalities (i.e. murmur)

4. Uncontrolled or untreated hypertension

-Diastolic >95 mmHg and/or Systolic > 145 mmHg

5. Clinically significant anxiety, depression, and/or panic disorder

6. Coronary artery disease.

History of known coronary artery disease,

- History of a prior myocardial infarction or stroke.

- An 12 lead EKG will be done during screening (no more than three months
prior to enrollment), reviewed by an M.D, and may be sent to an outside
cardiologist for manual reading.

- EKG abnormalities which will EXCLUDE a subject will include the following:
QTc interval > 450 ms or changes suggesting acute ischemia, second or third
degree heart block, left bundle branch block, atrial fibrillation, signs of
left ventricular hypertrophy or other clinically important arrhythmias.

7. Dependence on methylphenidate or a psychostimulant

8. History of an adverse reaction to cocaine, methylphenidate, amphetamine, other
psychostimulant, herb and/or over the counter medication

9. Urine sample positive for a psychostimulant on the day of the study. (An observed
urine specimen will be tested on the day of the study)

10. Clinically significant abnormal renal and/or liver function

- Renal (lab cut off ): BUN > 35mg/dl; Cr > 2.0 mg/dl

- Liver (lab cut off): AST > 200 U/L; ALT >200 U/L; Alk P > 200 U/L; GGT> 400
U/L

11. Diagnosed with a movement disorder

12. Diagnosed with glaucoma

13. Currently taking any of the following: monoamine oxidase inhibitors (within 2
weeks of protocol participation), insulin, and/or a psychostimulant

14. A major medical diagnosis (i.e. .stroke, rheumatoid arthritis on therapy,
diabetes)

2. Competent to give informed consent. Competency of research participation at the NIDA
will be determined by a Shipley Institute of Living Scales estimated IQ score of 80 or
greater and an SCL-90-R Global Severity Index T-score of 70 or less. Cognitive
impairment will be defined using the Shipley Institute of Living Scale or WRAT
(equivalent to WAIS-R IQ < 79). With individuals having SCL-90-R scores greater than
70 referred for evaluation to a Counselor or Physician before admission to the study
can be complete. The counselor or physician using his/her clinical judgment will make
1 of 2 determinations: a) The applicant may continue with the screening process; b)
The applicant is disqualified from participation in the study and an appropriate
referral is made if indicated.

3. To evaluate the understanding of the study, its risk and benefits, and how to
withdrawal from the study at anytime will be determined by a Consent Quiz score of 80
percent or greater (answering 8 of 10 questions correctly) in NIDA participants