Clinical trial NCT01843205
Conditions: Methamphetamine Dependence Methamphetamine Abuse
Sponsor: University of Kentucky
Start date: 2013-04-01; Completion date: 2017-03-01
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Methamphetamine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce methamphetamine use, however, these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. This study proposes to determine the impact of buspirone maintenance on self-administration of methamphetamine. These preliminary data will be used to support further research developing buspirone as a pharmacotherapy for methamphetamine use disorders. The investigators hypothesize that buspirone will attenuate the reinforcing effects of methamphetamine.

Detailed description:

Arms: arm 1: Subjects will be maintained on placebo. arm 2: Subjects will be maintained on buspirone.
Interventions: intervention 1: Methamphetamine intervention 2: Placebo
Intervention descriptions: intervention 1: The pharmacodynamic effects of methamphetamine will be determined during placebo and buspirone maintenance. intervention 2: The pharmacodynamic effects of placebo methamphetamine will be determined during placebo and buspirone maintenance.

Protocol documents:
Prot_SAP_000.pdf: 
Behavioral Effects of Drugs: Inpatient (26) (Methamphetamine and Buspirone) (PI: Craig R. Rush, 
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Cover Page 
Official Title: Buspirone as a Candidate Medication for Methamphetamine Abuse 
NCT01843205 
Approval Date: February 23, 2017 


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1. BACKGROUND 
Methamphetamine (MA) abuse is a significant problem. The number of Americans that 
reported recent MA use nearly doubled from 2008 to 2009 and this number did not change 
significantly between 2009 and 2010. Treatment admissions for MA use more than doubled 
from 1998 to 2007 in the United States. While behavioral therapies effectively reduce MA use, 
many patients are unable to achieve significant periods of abstinence suggesting other 
strategies like pharmacotherapy are needed. An effective medication has not been identified 
for MA dependence despite being a high priority for the National Institute on Drug Abuse 
(NIDA) and extensive efforts by the scientific and treatment communities. MA acts as a 
substrate for monoamine transporters and is taken into the nerve terminal where it promotes 
the release of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into the synapse by 
preventing the accumulation of neurotransmitter in storage vesicles and by carrier-mediated 
exchange. MA abuse has been largely attributed to its ability to increase synaptic DA levels. 
However, targeting DA systems has not identified a broadly effective pharmacotherapy for 
managing MA abuse. Targeting other monoamine systems implicated in the effects of MA is a 
vital and innovative strategy for identifying an effective pharmacotherapy. Buspirone (BUSP) is 
an anxiolytic that lacks the abuse potential and sedation produced by benzodiazepines. BUSP 
is a 5HT1A receptor partial agonist, DA autoreceptor antagonist, and a selective DA D3 receptor 
antagonist. Receptor partial agonists have proven effective for managing nicotine and opioid 
use disorders and may be preferable to full agonists or antagonists because they can stimulate 
receptors when neurotransmitter tone is low (i.e., during abstinence) and block receptors when 
neurotransmitter tone is high (i.e., following a lapse). DA autoreceptors (or presynaptic D2 
receptors) stabilize DA tone; antagonists at these receptors increase DA release. DA D3 
receptors play a critical role in motivation to take drugs. BUSP antagonized amphetamine-
induced locomotion and stereotypy in rodents. BUSP also attenuated the discriminative effects 
of amphetamine in monkeys. While BUSP has not yet been tested as a potential 
pharmacotherapy for MA abuse in a human laboratory experiment or clinical trial to our 
knowledge, the results of these preclinical experiments suggest it may be a viable option.  The 
results of this “proof-of-concept” study will provide critical information regarding the initial 
efficacy of BUSP for MA dependence, which will enhance the probability of success when 
advanced to a clinical trial.  
2. OBJECTIVES 
The primary objective of this study is to determine the influence of BUSP maintenance on the 
reinforcing effects of MA.  We will also include a battery of subject-rated and physiological 
measures to more fully characterize the influence of BUSP maintenance on the effects of MA.  
3. STUDY DESIGN 
A double-blind, placebo-controlled, crossover design will be used in this experiment.  A 
completely within-subject design will be used such that each subject will receive all possible 
dose conditions, including placebo. 
4. STUDY POPULATION 
Up to 100 individuals will be screened to participate in this study.  We intend to enroll twelve (8 
male and 4 female) completers into the study. These individuals must be English-speaking, 
English-reading subjects 18-55 years of age of varying ethnic backgrounds and they will be 
recruited to participate in this seven-week experiment. Enrollment in this study will occur 
between January 1, 2013 and December 31, 2014. Subjects will be required to provide legal 
proof of age.  Subjects must be healthy and without contraindications to MA and BUSP.  


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Subjects must also report recent use of stimulants and must meet diagnostic criteria for 
stimulant abuse or dependence using the Structured Clinical Interview for DSM-IV (SCID).  
Subjects must provide a stimulant positive urine during screening to verify stimulant use status. 
Screening procedures for all subjects will include a medical history questionnaire, laboratory 
chemistries (blood chemistry screen, complete blood count, ECG and urinalysis) and a brief 
psychiatric examination. These procedures will be conducted under our lab’s screening 
protocol (03-0509).  Chemistry values and screening outcomes must be deemed normal.  If 
chemistry values or screening outcomes fall outside normal ranges, a study physician must 
deem them clinically insignificant for a subject to be enrolled.  An electrocardiogram must also 
be within normal limits.  Any potential subject with a history of serious physical disease, current 
physical disease, impaired cardiovascular functioning, chronic obstructive pulmonary disease, 
history of seizure or current or past histories of serious psychiatric disorder that in the opinion 
of the study physician would interfere with study participation will be excluded from 
participation.  Subjects with current or past histories of substance abuse or dependence that 
are deemed by the doctor to interfere with study completion will also be excluded from 
participation.  Female subjects must be using an effective form of birth control (e.g., birth 
control pills, surgical sterilization, IUD, cervical cap with a spermicide, condoms or abstinence) 
in order to participate.  A urine pregnancy test will be conducted before the start of each 
experimental session to ensure that female subjects do not continue in the study if pregnant.  
All study subjects will be judged by one of the study physicians, Dr. Lon R. Hays or Dr. Abner 
O. Rayapati to be healthy.  
During the initial screening process, potential subjects will be asked to provide a urine 
specimen that will be screened for the presence of MA, amphetamine, benzodiazepines, 
barbiturates, cocaine, tetrahydrocannabinol (THC) and opiates. In order to participate in an 
experimental session, subjects must provide a urine negative for cocaine, barbiturates, 
benzodiazepines and opiates on each day of their participation.  Subjects will be allowed to 
continue if they test positive for MA or amphetamine, if it is determined that this drug was given 
in a recent session and it is likely that the result is positive due to experimental administration. 
Drs. Hays and Rayapati will be notified of MA- or amphetamine-positive urines on experimental 
session days and sessions will only proceed if subjects pass the sobriety test and have vital 
signs within acceptable limits (see below). Subjects will be maintained on a caffeine free diet 
and will have to abstain from alcohol for the duration of their participation. They will be allowed 
to smoke cigarettes ad libitum except during experimental sessions.  
5. SUBJECT RECRUITMENT METHODS AND PRIVACY 
 Subjects are recruited primarily through formal advertisement (i.e., regular newspaper 
advertisements placed generally in free newspapers), local flyers posted in public areas (e.g., 
bars, restaurants, stores) and by word-of-mouth.  These advertisements are approved under 
our screening protocol (IRB # 03-0509).  Subjects will make initial contact by phone with one of 
our recruiters who have completed the research training and HIPAA compliance web-based 
teaching models.  If the subject self-discloses information that would make him/her potentially 
eligible for the study, they will be invited to come in for a screening appointment.  Screening is 
completed by one of our research assistants at the UK Laboratory of Human Behavioral 
Pharmacology (LHBP).  Study investigators may interact with subjects in this setting and 
appropriate cautions are in place to ensure privacy during the intake process.   
 


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6. INFORMED CONSENT PROCESS 
All potential subjects that are identified using the subject recruitment methods noted above will 
provide informed consent prior to participating in the protocol. Subjects that meet the eligibility 
criteria noted above will come to the LHBP and will undergo a field sobriety test and provide an 
expired air sample that will be tested for the presence of alcohol.  If the subject passes the field 
sobriety test (walk and turn, one-leg balance [timed], finger-to-nose and backwards-counting 
tasks) and the expired air sample is negative, he or she will then be given a copy of the 
approved informed consent document to read and sign. After reading the consent document, 
the PI or one of the Co-Is on this protocol will address any questions the subject may have in 
order to assess the subject’s understanding of the protocol.  After this, the subject will receive 
a copy of the informed consent document and will sign a form indicating that they have 
received a copy of the form they read and signed.   
7. RESEARCH PROCEDURES 
General Procedures. Subjects that meet the inclusion criteria will participate as inpatients at 
the University of Kentucky Clinical Services Core (CSC). Subjects will be discharged upon 
completion of the entire protocol.  
This experiment will require each subject to participate for approximately three weeks. 
Experimental sessions will be conducted as outlined in the table below. We would like to note 
that the order of the maintenance conditions (i.e., starting with BUSP or placebo) will be 
counterbalanced across subjects. Moreover, to avoid testing MA on weekends, subjects may 
be maintained on each condition by up to two more days, so participation may be as long as 
25 days.  
Day 
Experimental Procedures 
1 
Admission and acclimation to the CSC. 
2 
Practice Session. 
3-12 
Placebo maintenance. Placebo administered at 0700, 1500, 2300 hours. 
10-
12 
Experimental Sessions. Reinforcing effects of intranasal MA (0, 10 and 30 mg) 
determined. Effects of each dose will be determined in a single day.  
13-
22 
BUSP maintenance (45 mg/day). BUSP administered at 0700, 1500 and 2300 hours. 
The daily BUSP dose will be titrated up to the target dose (i.e., 5 mg three times daily 
for 1 day, 10 mg three times daily for 2 days, 15 mg daily for remainder of 
maintenance period).  
20-
22 
Experimental Sessions. Details are the same as for Days 9-11. 
23 
Discharge 
During their participation in the research protocol, subjects will not be allowed to leave the 
CSC, nor will visitors be allowed, with the exception that subjects can leave for walks under 
clinical supervision and if approved by physicians. Research subjects will be allowed to make 
local telephone calls. After completing the research protocol, interested subjects will be offered 
a referral to an appropriate drug abuse treatment program. 
All subjects will provide urine and expired air samples before and periodically during study 
participation. The presence of non-nicotine drugs of abuse or alcohol not administered 
experimentally in the research protocol will result in immediate termination from the research 
study. 


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This experiment will consist of 6 experimental sessions conducted according to the timeline in 
Table 1, above. After admission, subjects will be allowed to acclimate to the CSC for two days 
before beginning the study. During this time, subjects will receive instructions concerning the 
details of the daily research procedures and general rules of the psychiatry inpatient research 
unit and complete a "practice" session to familiarize them with the experimental routine and 
tasks. 
Each day after the practice session, subjects will be awakened at 0700 hours and will receive 
maintenance medication (see Table 2, below). Medications will not be administered if a 
subject’s heart rate is ≥100 bpm, systolic pressure is ≥150 mmHg or diastolic pressure is ≥100 
mmHg. Maintenance medication will be administered again at 1500 and 2300 h, as long as the 
aforementioned physiological dosing criteria are met. The UKU side effects scale will be 
completed daily to monitor for the emergence of side effects.  
On experimental session days, after receiving maintenance medication, subjects will then be 
allowed to eat a standard, fat-free breakfast (cereal with skimmed milk, 2 pieces of toast with 
jam or jelly and 8 ounces of fruit juice). Tables 3, below, outlines the activities of experimental 
sessions. Experimental sessions will begin at 0900 hours and will last approximately 5.5 hours. 
Medications will not be administered if a subject’s heart rate is ≥100 bpm, systolic pressure is 
≥150 mmHg or diastolic pressure is ≥100 mmHg or if clinically significant and/or prolonged 
ECG abnormalities are detected.  
Subjects will be excluded from further research participation if at any time during the 
experimental sessions MA increases heart rate above 130 bpm, systolic pressure above 180 
mmHg, diastolic pressure above 120 mmHg or if clinically significant and/or prolonged ECG 
abnormalities are noted. Subjects will remain seated for the duration of the experimental 
session. No experimental activities will be scheduled for the remainder of the day after an 
experimental session, but subjects will receive their appropriate maintenance medication at 
1500 and 2300. Subjects will be free to engage in recreational activities (e.g., watch television, 
read, listen to music, arts and crafts, play video or board games). Research subjects will be 
required to be in bed with the lights out by 2300 hours. 
 
Time 
Table 2-Daily Activities for Maintenance Days 
0700 Patient awakened. Vital signs recorded. Medication administered if vitals are within 
range. Subject eats breakfast. 
1200  Lunch is served. 
1300  Nursing staff completes UKU. 
1500 Vital signs recorded. Medication administered if vitals are within range. 
1800 Dinner is served. 
2300 Vital signs recorded. Medication administered if vitals are within range. Lights out. 
Time 
Table 3-Daily Activities for Experimental Days 
0700 Patient awakened. Vital signs recorded. Medication administered if vitals are within 
range and no indication of sedation or withdrawal. Subject eats breakfast. 
0900 Vital signs recorded. Computerized tasks completed. ECG monitoring begins. 
0930 Vital signs recorded. 0 [placebo], 10 or 30 mg intranasal METH administered if vitals 
are within range. Measures completed 0, 15, 30, 45, 60, 90 and 120 minutes after 
drug administration. 
1130 Session ends.  Lunch is served. Nursing staff completes UKU. 


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All drugs will be administered under double-blind conditions and under medical supervision. 
Test doses of MA will be 0, 10 and 30 mg, administered in random order. These doses were 
chosen based on prior work and have safely been administered to human subjects (Lile et al., 
2011; Marks et al., In Preparation; Pike et al., In Preparation). The maintenance conditions will 
be placebo and a maximum of 45 mg BUSP/day. Doses will be administered 3 times/day (i.e., 
the maximum individual BUSP dose is 15 mg) at 0700, 1500 and 2300. Subjects will be 
maintained on these doses for at least four days before beginning experimental sessions. The 
dose of BUSP was selected based on results of previous clinical trial research, which have 
shown that higher doses can be safely administered to active stimulant users (Moeller et al, 
2001). Placebo powder and capsules will contain only lactose or cornstarch, but will be visually 
identical to the powder and capsules that contain active drug.  
Apparatus. Behavioral testing will be conducted at the CSC. Subjects will be tested using an 
individual Macintosh laptop computer that automates behavioral tasks.  
Progressive-Ratio Procedure. During each afternoon self-administration session, subjects will 
be given 10 opportunities to work on a computer to earn all, or some, of the powder that was 
administered during the preceding sampling session.  Prior to each of the 10 opportunities to 
earn a drug, subjects will be asked if they want to work for a portion (i.e., 1/10th) of the drug 
administered during the sampling session. Subjects will respond by clicking on one of two 
buttons on the computer screen labeled YES or NO. If the subject responds YES, they will 
then be required to click the computer mouse a predetermined number of times to earn a 
portion of the sampled dose. To earn the first portion, subjects will have to click the mouse 400 
times.  The number of clicks required to earn each additional capsule increases by 100 (i.e., 
500, 600, 700, 800, 900, 1000, 1100, 1200 and 1300 responses).  To receive a full dose, 
subjects will have to click the mouse a total of 8500 times.  If the subject responds NO at any 
time when they are asked if they want to work for one of the capsules, the task is terminated. 
While completing each component of the progressive-ratio schedule, subjects are also able to 
terminate the task by clicking on a button labeled STOP.   The dependent measure on this task 
is the break point (i.e., the last ratio completed). 
Subject-Rated Questionnaires. A battery of subject-rated questionnaires will also be used to 
assess drug effects. These measures have previously been shown to be sensitive to the 
effects of stimulants (Rush et al., 2009). These experimental measures will be taken on all 
experimental session days. The measures described below will be recorded as described in 
the tables above. The subjective-effects measures are included in Appendix A. 
Vital Signs. Heart rate, blood pressure, oral temperature and heart rhythmicity (via ECG) will 
be recorded using a Dinamap digital monitor (Critikon, Pro 1000, Tampa, FL). These measures 
will be completed at as described in the tables above. Telemetry-certified nurses will interpret 
the results of the ECG with instructions to contact Dr. Hays or Rayapati regarding 
abnormalities.  
1230 Vital signs recorded. Computerized tasks completed (including progressive-ratio 
task). ECG monitoring begins. 
1330 Vital signs recorded. Portion of intranasal dose earned is administered if vitals are 
within range. Measures completed 0, 15, 30, 45, 60, 90 and 120 minutes after drug 
administration 
1530 Session ends. Remainder of daily activities identical to those listed in Table 2. 


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Subject-Rated Questionnaires. A battery of subject-rated questionnaires will also be used to 
assess drug effects. These measures have previously been shown to be sensitive to the 
effects of stimulants (Rush et al., 2009). These experimental measures will be taken on all 
experimental session days. The measures described below will be recorded as described in 
the tables above. The subjective-effects measures are included in Appendix A. 
Vital Signs. Heart rate, blood pressure, oral temperature and heart rhythmicity (via ECG) will 
be recorded using a Dinamap digital monitor (Critikon, Pro 1000, Tampa, FL). These measures 
will be completed at as described in the tables above. Telemetry-certified nurses will interpret 
the results of the ECG with instructions to contact Dr. Hays or Rayapati regarding 
abnormalities.  
Drug Dose and Administration. All drugs will be administered under double-blind conditions 
and under medical supervision. Doses of MA will be prepared by weighing out the appropriate 
amount of powdered drug (NIDA, Rockville, MD). The MA will be mixed with lactose 
monohydrate powder, N.F. to make a total of 100 mg powder. Doses of MA will be prepared 
individually for each subject. These MA doses are behaviorally active and well tolerated under 
controlled conditions (e.g., Lile et al., 2011; Marks et al., In Preparation; Pike et al. In 
Preparation). For afternoon doses, drug will be labeled from 1-10, indicating the portion of drug 
earned on the progressive-ratio procedure. Subjects will only be administered the dose they 
earned (i.e., if they earned 3/10ths of the morning drug dose, they will be given the dose 
labeled 3). Intranasal MA administrations within an experimental session will be separated by 
at least 2 hours.  
Maintenance Dosing. BUSP (0 and 45 mg/day) will be prepared by over-encapsulating 
commercially available doses in a size 0 capsule. All capsules will then be filled with lactose 
monohydrate powder, N.F. Placebo capsules will be identical, but will contain only lactose. 
BUSP will be administered thrice daily (i.e., 0700, 1500 and 2300 hours). The BUSP dose was 
selected based upon clinical dosing recommendations for anxiety (i.e. 15-60 mg/day in 2-3 
divided doses). Subjects will be maintained on BUSP for at least 7 days, with at least 4 days at 
the target dose, before experimental sessions, which is sufficient to reach steady-state blood 
levels (Sakr and Andheria, 2001). The daily dose is clinically effective and well-tolerated when 
administered acutely or chronically (Evans and Levin, 2002; McRae-Clark et al., 2009; Moeller 
et al., 2001; Rush and Griffiths, 1997; Sakr and Andheria, 2001). The daily BUSP dose will be 
titrated upward until the target dose is achieved (i.e., 15 mg/day for 1 day [5 mg thrice daily]; 
30 mg/day for 2 days [10 mg thrice daily]; and 45 mg/day for 4 days [15 mg thrice daily]). 
Subjects that are unable to tolerate BUSP, alone or in combination with MA, will be discharged 
from the study. Subjects that are dismissed will be replaced so that 12 subjects complete the 
study to ensure adequate statistical power to detect changes in the reinforcing effects of MA as 
a function of BUSP. Subjects will be blind to the maintenance drug administered.  
Data Analysis. Data will be analyzed as raw scores. Statistical significance refers to p ≤ 0.05. 
Progressive-ratio data (i.e., break point and number of MA doses earned) will be analyzed with 
two-factor repeated measure ANOVA to test the primary hypotheses.  Factors for these 
analyses will be MA (0, 10 and 30 mg), and BUSP (0 and 45 mg/day). A significant attenuation 
(i.e., rightward shift in the dose-response) of the effects of MA will be inferred if the main effect 
of BUSP or the interaction of MA and BUSP attains statistical significance in the ANOVA. If the 
MA-BUSP interaction attains statistical significance, the mean square error term will be used to 
conduct Tukey’s HSD post-hoc test to make appropriate pair-wise comparisons between 
means. Peak effect and area-under-the-time-action curve (AUC) data for the subjective-effects 


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measures and physiological indices obtained during the sampling phase will be analyzed in the 
same fashion as data from the progressive-ratio procedure in order to test the secondary 
hypotheses. Subjective-effects and physiological data from the self-administration phase will 
not be analyzed statistically because participants will likely ingest varying amounts of MA 
making these data difficult to interpret.   
8. RESOURCES 
This study will take place at the CSC.  Study sessions will only be conducted on weekdays. All 
drug administration will take place at the UK CSC in a room equipped with all the necessary 
physiologic and computer equipment for the study. Dr. Hays is an adult psychiatrist who has 
worked extensively with individuals with substance use disorders in both the clinical and 
research setting and he is the responsible medical investigator for this study. Dr. Rayapati is a 
psychiatrist who has worked extensively with individuals with substance use disorders in both 
the clinical and research setting and he is the back up medical investigator for this study.  They 
will be available to attend to medical problems as well as any psychological or psychiatric 
issues that may arise. Drs. Rush, Stoops and Lile will provide scientific oversight for the study 
and have safely completed numerous human behavioral pharmacology studies.  Overall, the 
study team and resources described above are well equipped to protect subjects and 
successfully implement, carry out and complete this study protocol. 
9. POTENTIAL RISKS 
The subject-rated drug-effect questionnaires and physiological measures employed in these 
studies are benign.  The risks to the study subjects are those related to the ingestion of the 
drugs under study.  All of the drugs to be administered in the proposed research are 
commercially available.  The relative safety as well as the contraindications and possible side 
effects of these compounds are well known and documented.  However, the administration of 
any drug involves some risks simply because individuals differ in their reactions to drugs.  The 
main risk is that subjects will experience side effects that may be unpleasant. 
Side-effects of MA include nausea, abdominal pain, loss of appetite, dry mouth, weight loss, 
changes in mood, headache, tremor, difficulty sleeping, nervousness, restlessness, increases 
in temperature, changes in heart rate or blood pressure (including irregular heart rate and 
blood pressure), palpitations, anxiety, dizziness, hallucinations, forgetfulness, sleepiness and 
performance impairment.  The severity and likelihood of these side effects usually varies with 
dosage and chronic administration.  More serious side effects could include allergic reaction, 
chest pain, heart attack or other heart related problems, changes in blood platelet levels, 
stroke, psychotic episodes, seizures, Tourette’s Syndrome and sudden unexplained death. 
These side effects may be more frequent and larger in magnitude when testing the BUSP-MA 
combinations.  
Common side effects of BUSP include dizziness, nausea, headache, nervousness, 
lightheadedness, excitement and insomnia. Less common side effects include unsteady gait, 
diarrhea, weakness, hostility, skin rash and tremors.  
The doses to be administered in the present experiment were chosen to minimize, if not 
eliminate, the chance of these side effects occurring since these side effects are related to 
dose. Thus, it is unlikely that subjects will experience side effects during the experimental 
protocol. All sessions proposed in this application will be conducted at the CSC and under 
medical supervision.  Side effects of the drugs are temporary, usually dissipating in less than 
24 hours. The principal investigator on this project, Dr. Rush, has had extensive experience 
over more than 20 years administering therapeutic and supratherapeutic doses of stimulant 


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drugs to subjects in both inpatient and outpatient settings and has never observed a serious, 
unexpected adverse effect.  Dr. Rush will train all staff on this project. 
To avoid potential drug interactions, subjects taking any prescribed medication chronically, 
except birth control, will be excluded.  The medical personnel on this protocol will determine if 
it is safe for a potential subject to discontinue taking their medication during their participation. 
There is some theoretical risk that subjects might choose to seek out illicit sources of drugs 
they received experimentally and liked.  However, this risk is minimal since all drugs are 
administered under blind conditions and in a setting that is not conducive to the development 
of dependence. 
10. SAFETY PRECAUTIONS 
Subjects are carefully screened (history and physical exam, routine labs such as CBC, 
complete metabolic panel and urinalysis, ECG and psychiatric assessment) to exclude those 
with potential increased risk of adverse effects, such as personal or family histories of heart 
disease, histories of seizure or head injury associated with more than a brief loss of 
consciousness, hypertension, psychosis, etc.  During sessions subjects remain under careful 
medical observation and are monitored continuously by on-site medical staff. Vital signs will be 
collected throughout the dosing period. Staff is familiar with the acceptable physiological 
parameters for these studies and this information is posted in every experimental session 
room. In addition, Dr. Rush has substantial experience administering medications to human 
subjects under a variety of dosing conditions.  Lastly, female subjects are also given 
pregnancy tests prior to each session to ensure that we do not administer active medications 
to a pregnant woman.  
Legal risks including loss of confidentiality: All intake documentation that contains 
personal information is handled separately from the actual data collected during the study.  All 
information of a personal nature (intake assessments, medical test results) is kept locked 
either on password-protected computers or in secure filing cabinets all behind locked doors 
and accessible only to key personnel involved in the research.  A Certificate of Confidentiality 
will be obtained from NIDA.   
11. BENEFIT vs. RISK 
The degree of risk to which individual study subjects are exposed as a consequence of their 
research participation is slight.  In contrast, the potential and probable benefits to be derived by 
society in general and by patients as a group appear to be considerable.  The major benefits of 
these studies are clinical and scientific ones related to the knowledge gained about putative 
medications for MA use disorders.  The data from this project will contribute to a better 
understanding of drug abuse and will ultimately contribute to the development of improved 
prevention, control and treatment procedures.   Individual study subjects are expected to 
benefit personally from the medical and psychiatric evaluations and from referrals for medical 
and psychiatric treatment that are provided whenever appropriate.  Overall, the risk/benefit 
ratio appears favorable and the conduct of this research seems well justified. 
12. AVAILABLE ALTERNATIVE TREATMENTS  
There are no available alternative treatments as this is not a treatment study.  If subjects 
express the desire for treatment they will be given referrals for treatment and not be allowed to 
participate in this study. 
13. RESEARCH MATERIALS, RECORDS AND PRIVACY 
Urine and blood samples will be collected at screening prior to a subject’s participation in the 
experimental protocol under another IRB approved protocol (Number 03-0509).  These urine 


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samples will be tested for the presence of a full range of drugs of abuse.  Blood samples will 
be used for the laboratory chemistries.  Females will also be given a pregnancy test at the time 
of screening (via the urine sample).  Urine drug and pregnancy tests will be conducted prior to 
the conduct of each experimental session.  Other data obtained from the subjects will involve 
subjective effects based on questionnaires, various computer-based tasks and non-intrusive 
staff observations and ratings. The consent form states that subject’s confidentiality will be 
protected.   
14. CONFIDENTIALITY 
Identifying information will be stored in a separate, locked area from all other de-identified data 
and codes linking the two will be kept under lock and key or on password protected computers.  
Incidental materials containing subject identifiers will be shredded or incinerated.  Identification 
and access of identified data/specimens will be available only to study investigators when it is 
detrimental to subject safety or the conduct of the research protocol.  For example, if a subject 
has an adverse event, we will want to obtain a quantitative drug screen to identify whether 
there may have been illicit drug use while in the study versus a true adverse event related to 
the study procedures.  In the future, data/specimens may be shared with non-UK affiliations in 
a HIPAA compliant manner.    
15. PAYMENT 
Subjects will be paid $40 for each day they reside on the CSC and will receive a $40 
completion allowance for these days if they complete the entire experiment. The amount 
earned by the subject will be disbursed to them upon completion of the study.  Payments will 
be disbursed in amounts up to $500 dollars and will be given once per week following 
discharge until the subject is paid in full. When subjects return on a weekly basis to receive 
their payments, we will survey them regarding their drug use since being discharged from the 
study.  A subject can earn a maximum of $2000 for participating in this study. 
16. COSTS TO SUBJECTS 
There will be no cost to the subject for participating.  Costs for the screening procedures (i.e., 
medical history questionnaire, physical examination including laboratory chemistries (blood 
chemistry screen, complete blood count, urinalysis) and a psychiatric examination will be paid 
by the Laboratory of Human Behavioral Pharmacology. 
17. DATA AND SAFETY MONITORING 
Data Monitoring Plan 
Data will be collected using a computerized data collection and management system wherever 
possible. This system automates the collection of data, which ensures the accuracy and 
completeness of data collection. The data are stored in a unique file on the hard drive of the 
computer and are printed after all the tasks are completed. In all instances, the data files do 
not contain the name of the subject, but instead, each subject is identified by a unique four-
digit number. A computer file linking the unique number with the subject’s name will be kept on 
a stand-alone, password-protected computer. All data requiring hand entry (e.g., 
cardiovascular measures) will be entered by two separate staff members and comparison 
macros will be run to ensure accuracy. Data files for experimental tasks and physiological 
measures from each experimental session will be manipulated and combined into a single 
electronic spreadsheet for each subject by one of the investigators. Data for all subjects will 
then be combined into a single electronic spreadsheet and separated by experimental 
measure for statistical analysis using Statview (SAS Institute Inc., Cary, NC). 


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In this protocol the primary outcome measure will be the influence of BUSP maintenance on 
the reinforcing effects of MA. The alpha level will be set at 5%. 
As noted above, wherever possible, data are collected using an automated computer system, 
which increases the accuracy and completeness of data collection and ensures the validity and 
integrity of the data. The initial data manipulation described above will be conducted twice and 
compared. The quality of manipulated data and data analyses will be monitored by random 
inspection by the PI and/or Co-Investigators. 
Safety Monitoring Plan 
Potential subjects will provide information regarding their drug use history and undergo an 
extensive physical and psychiatric health screening to determine their eligibility and safety of 
their participation. Any potential subject with a history of clinically significant physical disease, 
current physical disease (e.g., impaired cardiovascular functioning, histories of seizure, head 
trauma or CNS tumors) or current or past histories of psychiatric disorder that in the opinion of 
the study physician would interfere with study participation, other than substance abuse or 
dependence, will be excluded from research participation. Females must be using an effective 
form of birth control in order to participate and must not be pregnant. Methods for monitoring 
adverse events (AEs) will include observations by the medical and research staff, spontaneous 
report by the subjects and, regular measurement of cardiovascular function. Subjects will not 
receive study drug if they have any signs or symptoms that may contraindicate its 
administration (e.g., HR and BP outside of predetermined range, development of serious side 
effects). 
All AEs occurring during the course of the study will be collected, documented and reported to 
the PI. The occurrence of AEs will be assessed for the duration of participation. Each week a 
study investigator will review the AE forms from the previous week for events that were 
reported as new or continuing. The study investigators will follow all AEs to the point of a 
satisfactory resolution. Subjects may be withdrawn from the study if the medically responsible 
investigator determines it is the best decision in order to protect the safety of the subject. All 
AEs will be assessed to determine if they meet criteria for a serious adverse event (SAE). 
Serious Adverse Events, as defined by the FDA, will be systematically evaluated for the 
duration of participation and during the follow-up visits at 2 and 4 weeks following study 
completion. Any SAE, whether or not related to the study drug, will be reported to the IRB, 
CSC, NIDA and the FDA. The initial SAE report will be followed by submission of a completed 
SAE report to all three institutions. 
In the event that a subject either withdraws from the study or the investigator decides to 
discontinue a subject due to an SAE, the subject will have appropriate follow-up medical 
monitoring. Monitoring will continue until the problem requiring hospitalization has resolved or 
stabilized with no further change expected, is clearly unrelated to the study drugs or results in 
death. Outcome of SAEs will be periodically reported to the IRB, CSC, NIDA and the FDA. A 
summary of the SAEs that occurred during the previous year will be included in the annual 
progress report to NIDA, the IRB, CSC and FDA. 
18. SUBJECT COMPLAINTS 
Subjects may at any time ask study personnel questions about the study procedures or make 
complaints. All staff will be aware to notify Drs. Rush, Stoops, Lile, Hays or Rayapati about any 
subject concern or complaint as it arises.  Subjects will be allowed the opportunity to discuss 
any concerns or questions with an investigator promptly, in person and in confidence. It should 
be noted, however, that subjects will be told that some concerns and complaints will not be 


Behavioral Effects of Drugs: Inpatient (26) (Methamphetamine and Buspirone) (PI: Craig R. Rush, 
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12 
kept private such as an adverse event, protocol deviation or threat to the safety of subjects or 
integrity of the research study.  In these cases, all information will be made available to the 
Principal Investigator in order to determine any further course of action. Drs. Hays and 
Rayapati will also communicate with the nursing or laboratory staff on at least a weekly basis 
in order to discuss any concerns regarding particular subjects or with respect to the conduct of 
the study. 
19. RESEARCH INVOLVING NON-ENGLISH SPEAKING SUBJECTS OR SUBJECTS 
FROM A FOREIGN CULTURE  Not Applicable.   
20. HIV/AIDS RESEARCH POLICY  Not applicable. 
21. PI SPONSORED FDA-Regulated Research  
Dr. Rush currently holds an IND for intranasal MA (#104,829).  This application will be modified 
to combining intranasal MA with oral BUSP. Dr. Rush has held INDs for behavioral 
pharmacology research with a number of drugs for over twelve years and is well aware of the 
necessary reporting requirements and other responsibilities associate with IND sponsorship.  
As required by the FDA, Dr. Rush will submit annual reports on the progress of the IND and 
will also report serious adverse events in accordance with published guidelines.  Dr. Rush has 
trained all study staff on their responsibilities regarding the IND.   


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APPENDIX A 
 
Subject-Rated Drug-Effect Questionnaires Descriptions 


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 Adjectives Rating Scale (ARS) 
 
Individual questions are presented sequentially, one at a time. Subjects rate their 
response to each question on a 5-point scale (0 = Not at all, 1 = A little, 2 = Moderately, 3 
= Quite a bit, 4 = Extremely). 
 
(1) How "ACTIVE" do you feel right now? (2) How "AGITATED" do you feel right now? (3) How 
"CLUMSY" do you feel right now? (4) How "ALERT" do you feel right now" (5) How "DIZZY" do 
you feel right now? (6) How "CONFUSED" do you feel right now? (7) How "ENERGETIC" do 
you feel right now? (8) Are you in a "GOOD MOOD" right now? (9) How "DAZED" do you feel 
right now? (10) How "EXCITED" do you feel right now? (11) How "SLEEPY" do you feel right 
now? (12) How "DEPRESSED" do you feel right now? (13) How "EUPHORIC" do you feel right 
now? (14) Are you experiencing an "IRREGULAR HEARTBEAT" right now? (15) Do you feel 
as if you would have "DIFFICULTY WALKING" right now? (16) How "TALKATIVE" do you feel 
right now? (17) Are your "MUSCLES TWITCHING" right now? (18) How "DROWSY" do you 
feel right now? (19) How "NAUSEOUS" do you feel right now? (20) How "DRUNK" do you feel 
right now? (21) How "NERVOUS" do you feel right now? (22) How "FATIGUED" do you feel 
right now? (23) Is your "HEART RACING" right now? (24) How "IRRITABLE" do you feel right 
now? (25) How "RESTLESS" do you feel right now? (26) How "LAZY" do you feel right now? 
(27) How "SHAKY" do you feel right now? (28) How "RELAXED" do you feel right now? (29) 
How "TIRED" do you feel right now? (30) How "SLUGGISH" do you feel right now? (31) How 
"SWEATY" are you right now? (32) How "SPACED OUT" do you feel right now? 
 
 
Drug Effect-Questionnaire (DEQ)-VAS 
 
Individual questions are presented sequentially, one at a time. Subjects rate their 
response to each question by marking a 100-unit line anchored with “Not at All” on the 
left side and “Extremely” on the right side.  
 
(1) 
Is 
the drug producing "ANY EFFECT" right now? (2) Is the drug producing any "BAD EFFECTS" 
right now? (3) Is the drug producing any "GOOD EFFECTS" right now? (4) Is the drug making 
you feel "HIGH" right now? (5) Are you experiencing a "RUSH" from the drug right now"? (6) 
How much do you "LIKE" the drug right now? (7) Is the drug making you feel “STIMULATED” 
right now? (8) Is the drug "IMPAIRING YOUR PERFORMANCE" right now? (9) Is the drug 
"IMPROVING YOUR PERFORMANCE" right now? (10) Based on how the drug effect feels 
right now, would you be willing to "TAKE THIS DRUG AGAIN"? (11) Based on how the drug 
effect feels right now, would you be willing to "PAY FOR THIS DRUG"? (12) Is the drug 
making you feel "ACTIVE, ALERT OR ENERGETIC" right now? (13) Is the drug making you 
feel "EUPHORIC" right now? (14) Is the drug making you experience an "IRREGULAR OR 
RACING HEARTBEAT" right now? (15) Is the drug making you "TALKATIVE OR FRIENDLY" 
right now? (16) Is the drug making you feel "NAUSEATED, QUEAZY OR SICK TO YOUR 
STOMACH" right now?  (17) Is the drug making you feel "SHAKY OR JITTERY" right now? 
(18) Is the drug making you feel “NERVOUS OR ANXIOUS” right now? (19) Is the drug 


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making you feel "RESTLESS" right now? (20) Is the drug making you feel "SLUGGISH, 
FATIGUED OR LAZY" right now?