Cocaine Dependence
Conditions
Keywords
cocaine dependence, psychopharmacology, attentional bias, risky decision making, buspirone, methylphenidate
Brief summary
Chronic cocaine use may produce disruption of neurotransmitter functions (including dopamine). This may in turn contribute to measurable dysfunction in important cognitive and behavioral processes. Stimulants that enhance dopamine (DA) function may help in treating cocaine dependence and improving behavioral function -- supporting the notion that these processes are related. An important step is to understand the subjective, physiological, and behavioral effects of potential medications for cocaine dependence. DA-modulating drugs may be targets for pharmacotherapy for substance dependence, and particularly for stimulant drugs like cocaine, which disrupt normal DA function. Buspirone is currently the only available dopamine subtype 3 (DA3) approved for human administration, and is thus a viable investigational compound. This project proposes to evaluate the DA-modulating effects of buspirone on behavioral deficiencies related to DA depletion. Accordingly, the project aims to characterize the effects of buspirone in individuals with cocaine dependence. Employing a daily dosing designs within an acute stimulant challenge (methylphenidate), the experiment will characterize the subjective effects, cardiovascular effects, and behavioral effects (attentional bias to drug cues and risky decision making). The primary hypotheses are that buspirone will attenuate the increases in subjective drug effects (stimulated, like drug) and behavioral effects (increases in attentional bias and risky decision making) that are produced by acute methylphenidate administration.
Detailed description
Chronic cocaine use may produce disruption of monoamine systems (including dopamine). This may in turn contribute to measurable dysfunction in important cognitive and behavioral processes. Pharmacotherapy with stimulants that enhance dopamine (DA) function has shown efficacy in treating cocaine dependence and improving behavioral function -- supporting the notion that these processes are related. In the development of novel pharmacotherapies for cocaine dependence, an important step is a full characterization of the psychopharmacological properties of potential medications for cocaine dependence, including subjective, physiological, and behavioral effects. Selective medications may play a key role in the modulation of DA neurotransmission by enhancing DA receptor activation. The D3 receptor is an autoreceptor that may function to control phasic DA activity and mediate sensitization of DA agonists, thus playing a role in conditioning of drugs of abuse like cocaine. Growing evidence suggests that D3 receptor antagonists may be targets for pharmacotherapy for substance dependence, and particularly for stimulant drugs like cocaine, which disrupt normal DA function. Importantly, administration of D3 antagonists may disrupt reactivity (attention) to drug cues and attenuate cue-induced craving. Buspirone is currently the only available D3 antagonist approved for human administration, and is thus a viable investigational compound. This project proposes to evaluate the potential pharmacotherapeutic action of the D3 antagonist buspirone. The DA-modulating effects of buspirone may help with affective and behavioral deficiencies related to DA depletion. Accordingly, the project aims to characterize the psychopharmacology of buspirone in individuals with cocaine dependence. Employing chronic dosing designs within an acute stimulant challenge (methylphenidate), the experiment will be conducted using well-established psychopharmacological methods in order to characterize the shape and magnitude of chronic pretreatment-mediated change in the methylphenidate dose-response curve. Measures will include subjective effects, cardiovascular effects, and behavioral effects (attentional bias to drug cues and risky decision making). These data will compliment and provide valuable information to clinical trials using these agents to treat cocaine dependence.
Interventions
DRUGBuspirone
\[week 1: Buspirone 30 mg twice a day (9am and 6pm) on Monday through Sunday\] \[weeks 2-3: Buspirone 45 mg twice a day (9am and 6pm) on Monday through Sunday\]
DRUGPlacebo for Buspirone
\[week 1: Placebo for Buspirone twice a day (9am and 6pm) on Monday through Sunday\] \[weeks 2-3: Placebo for Buspirone twice a day (9am and 6pm) on Monday through Sunday\]
DRUGMethylphenidate
Methylphenidate serves as an acute stimulant challenge. \[week 1: no Methylphenidate or Methylphenidate placebo\] \[week 2: 0mg Methylphenidate (placebo for Methylphenidate) on Monday at 10am; Methylphenidate once a day (10am) on Wednesday and Friday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] \[week 3: Methylphenidate once a day (10am) on Monday and Wednesday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\]
DRUGPlacebo for Methylphenidate
\[week 1: no Methylphenidate or Methylphenidate placebo\] \[week 2: 0mg Methylphenidate (placebo for Methylphenidate) on Monday at 10am; Methylphenidate once a day (10am) on Wednesday and Friday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] \[week 3: Methylphenidate once a day (10am) on Monday and Wednesday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\]
Sponsors
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* cocaine dependent subjects, non-treatment seeking * meet current DSM-IV criteria for cocaine dependence disorder * report using cocaine within the past 30 days * at least 1 positive urine toxicology screen for the cocaine metabolite benzoylecgonine (BE) \[300 ng/mL, during the initial (2-4 day) screening period * acceptable health on the basis of interview, medical history, and physical exam * able to understand the consent form and provide written informed consent.
Exclusion criteria
* currently dependent on any psychoactive substance other than cocaine or nicotine * current DSM-IV diagnosed major psychiatric disorder (e.g., psychosis, bipolar, major depressive disorder) * any medical condition that would contraindicate administration of medications * taking medications known to have significant drug interactions study medications * probation / parole requiring reports of drug use to court officers * pregnant or nursing for female patients * cannot read, write, or speak English.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Attentional Bias as Assessed by Score on the Stroop Task | 1 time a day on Wednesday and Friday of week 2; 1 time a day on Monday and Wednesday of week 3 | The mean score over all 4 time points is reported in this outcome measure (i.e., a summary score is reported). Each subject contributed 1 data point for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 20 data points per dose level per arm. The Stroop task assesses attentional biases to cocaine-related (drug-related) and rewarding (non-drug related) stimuli vs. neutral stimuli. Participants are instructed to respond to words shown in different colors on the screen, by pressing as quickly and accurately as possible on one of three colored buttons. Attentional bias is measured as the difference in reaction times on cocaine vs. neutral words. The reported score is a difference score in milliseconds (cocaine minus neutral), in which positive means slower to respond to cocaine and thus greater attentional bias, and negative means no attentional bias to cocaine words. |
| Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 1 time a day on Wednesday and Friday of week 2; 1 time a day on Monday and Wednesday of week 3 | The mean score over all 4 time points is reported in this outcome measure (i.e., a summary score is reported). Each subject contributed 1 data point for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 20 data points per dose level per arm. The risky decision making task provides subjects with three choice options on each of 100 repeated trials. Options are low, moderate, and high risk, based on variance and probability in gain/loss amounts. The low risk option is more adaptive over many trials. The outcome measure is a risk index (ranging from 0.33 to 100) that factors in tolerance for variability and amount of gains and losses across the three options. 100 is highest risk. 0.33 is lowest risk. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The DEQ is a visual analog scale questionnaire that assesses the extent to which subjects experience four subjective states: Feel Drug, Feel High, Like Drug, and Want More. The Feel High subscale is reported, and this subscale is scored on a visual analogue scale (scroll bar on computer screen) ranging from 0-100. 100 represents the highest score for that subjective state, and the higher the score, the worse the outcome. |
| Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The VAS presents 100-mm horizontal lines labeled with an adjective: stimulated, high, anxious, elated, hungry, and nauseated. The elated subscale is reported, and this sub scale is anchored by not at all (0) on the left and extremely (100) on the right, with a score range of 0-100. The higher the score, the worse the outcome. |
| Heart Rate | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Heart rate is the measure of heart beats per minute. |
| Subjective Effects as Assessed by the Addiction Research Center Inventory (ARCI) | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The ARCI short form will be used. It is a 49-item true / false questionnaire that has been empirically-derived to assess five different factors, including euphoria, sedation, and dysphoria. The PCAG scale has proven to be a sensitive measure of subjective effects in many studies administering stimulant drugs. |
| Diastolic Blood Pressure | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Diastolic blood pressure is the blood pressure when the heart muscle is between beats. |
| Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | baseline | Subjects are required to respond selectively to a series of stimuli (e.g., numbers) presented briefly for 500 ms with a 500 ms intertrial interval (ITI). Increases in false alarm rates are interpreted as failures in response inhibition. Five digit numbers are presented on a computer screen every 500 ms sec. Subjects are instructed to respond when the first number of a set was repeated. A hit response is scored when a subject correctly responds. Distracters consist of five-digit numbers that are completely different from the first, and numbers in which four of the five digits match the original, with the non-matching number occurring randomly across the five digit places. A response to the number with 4 of 5 digits correct is scored as a false alarm. The a-prime value reflects the ability of the participant to discriminate between signal (Go stimulus) and noise (No-Go stimulus) and ranges from 0.5 (chance level) to 1 (perfect discrimination). |
| Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | baseline | The task is a rapid-presentation, probablistic gain/loss design. Reversal learning is assessed by means of a simple computerized card game. The paradigm utilizes a visual discrimination task where subjects have to learn to respond to outcome contingencies between two stimuli (high probability gain/low probability loss vs. low probability gain/high probability loss). At an unsignaled time point halfway into testing, the contingencies are reversed; the losing card becomes the winning card and the winning card becomes the losing one. Visual feedback regarding win or loss ($0.20) is provided after each trial and the cumulative total gained/lost is also shown. Using trial-and-error feedback, subjects have to discover which of the two patterns is correct and are instructed to win as much money as possible. The duration of the task is approximately 10 minutes, consisting of 80 trials. |
| Systolic Blood Pressure | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Systolic blood pressure is the amount of pressure in the arteries during contraction of the heart muscle. |
| Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3 | The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The POMS is a self-rating measure of current mood, consisting of six subscales demonstrated to be sensitive to a range of acute drug effects, including amphetamine, cocaine, and caffeine. The six subscales are: depression, vigor, confusion, tension, anxiety, and fatigue. A 37-item short form of the POMS was used, which correlates highly with the full scale. The vigor subscale is reported, and the vigor subscale score ranges from 0 to 28, with 28 representing the highest score for that mood state. The higher the value, the worse the outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Buspirone Plus Methylphenidate \[week 1: Buspirone 30 mg twice a day (9am and 6pm) on Monday through Sunday; no Methylphenidate or Methylphenidate placebo\] \[week 2: Buspirone 45 mg twice a day (9am and 6pm) on Monday through Sunday; 0mg Methylphenidate (placebo) on Monday at 10am; Methylphenidate once a day (10am) on Wednesday and Friday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] \[week 3: Buspirone 45 mg twice a day (9am and 6pm) on Monday through Sunday; Methylphenidate once a day (10am) on Monday and Wednesday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] | 20 |
| Placebo for Buspirone Plus Methylphenidate \[week 1: Placebo for Buspirone twice a day (9am and 6pm) on Monday through Sunday; no Methylphenidate or Methylphenidate placebo\] \[week 2: Placebo for Buspirone twice a day (9am and 6pm) on Monday through Sunday; 0mg Methylphenidate (placebo for Methylphenidate) on Monday at 10am; Methylphenidate once a day (10am) on Wednesday and Friday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] \[week 3: Placebo for Buspirone twice a day (9am and 6pm) on Monday through Sunday; Methylphenidate once a day (10am) on Monday and Wednesday, and on each of these 2 days the Methylphenidate dose will be different (15 mg, 30mg, 60 mg, or 0mg)\] | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Placebo for Buspirone Plus Methylphenidate | Total | Buspirone Plus Methylphenidate |
|---|---|---|---|
| Age, Continuous | 44.15 years STANDARD_DEVIATION 7.23 | 42.925 years STANDARD_DEVIATION 7.525 | 41.7 years STANDARD_DEVIATION 7.82 |
| Attentional Bias as assessed by score on the Stroop task | 28.67933 milliseconds STANDARD_DEVIATION 69.99501 | 20.53846 milliseconds STANDARD_DEVIATION 70.12276 | 12.39759 milliseconds STANDARD_DEVIATION 70.25051 |
| Diastolic blood pressure | 75.34091 mmHg STANDARD_DEVIATION 8.234265 | 74.932485 mmHg STANDARD_DEVIATION 8.2695775 | 74.52406 mmHg STANDARD_DEVIATION 8.30489 |
| Heart rate | 64.44886 beats per minute STANDARD_DEVIATION 11.28527 | 64.938335 beats per minute STANDARD_DEVIATION 11.254135 | 65.42781 beats per minute STANDARD_DEVIATION 11.223 |
| Region of Enrollment United States | 20 participants | 40 participants | 20 participants |
| Risky decision making as assessed by score on the risky decision making task | 8.945935 units on a scale STANDARD_DEVIATION 5.512101 | 9.362085 units on a scale STANDARD_DEVIATION 6.44012 | 9.778235 units on a scale STANDARD_DEVIATION 7.368139 |
| Sex: Female, Male Female | 16 Participants | 34 Participants | 18 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
| Subjective Effects as assessed by Score on Feel High Subscale of the Drug Effects Questionnaire | 8.128655 units on a scale STANDARD_DEVIATION 17.20622 | 11.7246525 units on a scale STANDARD_DEVIATION 21.259135 | 15.32065 units on a scale STANDARD_DEVIATION 25.31205 |
| Subjective Effects as assessed by score on the Vigor Subscale of the Profile of Mood States (POMS) | 5.080925 units on a scale STANDARD_DEVIATION 5.594259 | 5.535086 units on a scale STANDARD_DEVIATION 5.950416 | 5.989247 units on a scale STANDARD_DEVIATION 6.306573 |
| Subjective Effects as assessed by the elated subscale of the visual analogue scale (VAS) | 20.4593 units on a scale STANDARD_DEVIATION 26.25991 | 21.23234 units on a scale STANDARD_DEVIATION 26.24241 | 22.00538 units on a scale STANDARD_DEVIATION 26.22491 |
| Systolic blood pressure | 113.2727 mmHg STANDARD_DEVIATION 11.94963 | 115.377 mmHg STANDARD_DEVIATION 13.040245 | 117.4813 mmHg STANDARD_DEVIATION 14.13086 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Attentional Bias as Assessed by Score on the Stroop Task
The mean score over all 4 time points is reported in this outcome measure (i.e., a summary score is reported). Each subject contributed 1 data point for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 20 data points per dose level per arm. The Stroop task assesses attentional biases to cocaine-related (drug-related) and rewarding (non-drug related) stimuli vs. neutral stimuli. Participants are instructed to respond to words shown in different colors on the screen, by pressing as quickly and accurately as possible on one of three colored buttons. Attentional bias is measured as the difference in reaction times on cocaine vs. neutral words. The reported score is a difference score in milliseconds (cocaine minus neutral), in which positive means slower to respond to cocaine and thus greater attentional bias, and negative means no attentional bias to cocaine words.
Time frame: 1 time a day on Wednesday and Friday of week 2; 1 time a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 15 mg methylphenidate | -13.90333 milliseconds | Standard Deviation 62.76434 |
| Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 30 mg methylphenidate | -9.361269 milliseconds | Standard Deviation 30.66139 |
| Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 60 mg methylphenidate | 15.59167 milliseconds | Standard Deviation 142.0095 |
| Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 0 mg methylphenidate | 4.688844 milliseconds | Standard Deviation 30.59728 |
| Placebo for Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 0 mg methylphenidate | 41.22625 milliseconds | Standard Deviation 74.82985 |
| Placebo for Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 15 mg methylphenidate | 27.118 milliseconds | Standard Deviation 58.84988 |
| Placebo for Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 60 mg methylphenidate | 23.28063 milliseconds | Standard Deviation 42.25839 |
| Placebo for Buspirone Plus Methylphenidate | Attentional Bias as Assessed by Score on the Stroop Task | 30 mg methylphenidate | 15.35407 milliseconds | Standard Deviation 66.51272 |
Primary
Risky Decision Making as Assessed by Score on the Risky Decision Making Task
The mean score over all 4 time points is reported in this outcome measure (i.e., a summary score is reported). Each subject contributed 1 data point for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 20 data points per dose level per arm. The risky decision making task provides subjects with three choice options on each of 100 repeated trials. Options are low, moderate, and high risk, based on variance and probability in gain/loss amounts. The low risk option is more adaptive over many trials. The outcome measure is a risk index (ranging from 0.33 to 100) that factors in tolerance for variability and amount of gains and losses across the three options. 100 is highest risk. 0.33 is lowest risk.
Time frame: 1 time a day on Wednesday and Friday of week 2; 1 time a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 15mg Methylphenidate | 9.126667 units on a scale | Standard Deviation 5.094545 |
| Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 30mg Methylphenidate | 10.77167 units on a scale | Standard Deviation 6.58645 |
| Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 60mg Methylphenidate | 8.946263 units on a scale | Standard Deviation 6.947867 |
| Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 0mg Methylphenidate | 11.415 units on a scale | Standard Deviation 6.147164 |
| Placebo for Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 0mg Methylphenidate | 8.715333 units on a scale | Standard Deviation 6.34345 |
| Placebo for Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 15mg Methylphenidate | 10.07396 units on a scale | Standard Deviation 5.44448 |
| Placebo for Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 60mg Methylphenidate | 7.889825 units on a scale | Standard Deviation 5.277534 |
| Placebo for Buspirone Plus Methylphenidate | Risky Decision Making as Assessed by Score on the Risky Decision Making Task | 30mg Methylphenidate | 9.699333 units on a scale | Standard Deviation 6.334753 |
Secondary
Diastolic Blood Pressure
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Diastolic blood pressure is the blood pressure when the heart muscle is between beats.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 15mg Methylphenidate | 74.72727 mmHg | Standard Deviation 8.177168 |
| Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 30mg Methylphenidate | 74.56684 mmHg | Standard Deviation 8.160986 |
| Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 60mg Methylphenidate | 73 mmHg | Standard Deviation 9.153999 |
| Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 0mg Methylphenidate | 72.92513 mmHg | Standard Deviation 9.052699 |
| Placebo for Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 0mg Methylphenidate | 76.88636 mmHg | Standard Deviation 7.938955 |
| Placebo for Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 15mg Methylphenidate | 76.71591 mmHg | Standard Deviation 6.985616 |
| Placebo for Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 60mg Methylphenidate | 75.5625 mmHg | Standard Deviation 7.56583 |
| Placebo for Buspirone Plus Methylphenidate | Diastolic Blood Pressure | 30mg Methylphenidate | 78.53409 mmHg | Standard Deviation 8.962077 |
Secondary
Heart Rate
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Heart rate is the measure of heart beats per minute.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Heart Rate | 60mg Methylphenidate | 66.36364 beats per minute | Standard Deviation 10.55586 |
| Buspirone Plus Methylphenidate | Heart Rate | 15mg Methylphenidate | 66.84492 beats per minute | Standard Deviation 13.48406 |
| Buspirone Plus Methylphenidate | Heart Rate | 30mg Methylphenidate | 66.43316 beats per minute | Standard Deviation 13.03261 |
| Buspirone Plus Methylphenidate | Heart Rate | 0mg Methylphenidate | 63.21925 beats per minute | Standard Deviation 9.372807 |
| Placebo for Buspirone Plus Methylphenidate | Heart Rate | 0mg Methylphenidate | 69.60795 beats per minute | Standard Deviation 12.09863 |
| Placebo for Buspirone Plus Methylphenidate | Heart Rate | 60mg Methylphenidate | 69.13068 beats per minute | Standard Deviation 13.71256 |
| Placebo for Buspirone Plus Methylphenidate | Heart Rate | 30mg Methylphenidate | 68.26136 beats per minute | Standard Deviation 12.89296 |
| Placebo for Buspirone Plus Methylphenidate | Heart Rate | 15mg Methylphenidate | 67.75568 beats per minute | Standard Deviation 14.40208 |
Secondary
Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT)
Subjects are required to respond selectively to a series of stimuli (e.g., numbers) presented briefly for 500 ms with a 500 ms intertrial interval (ITI). Increases in false alarm rates are interpreted as failures in response inhibition. Five digit numbers are presented on a computer screen every 500 ms sec. Subjects are instructed to respond when the first number of a set was repeated. A hit response is scored when a subject correctly responds. Distracters consist of five-digit numbers that are completely different from the first, and numbers in which four of the five digits match the original, with the non-matching number occurring randomly across the five digit places. A response to the number with 4 of 5 digits correct is scored as a false alarm. The a-prime value reflects the ability of the participant to discriminate between signal (Go stimulus) and noise (No-Go stimulus) and ranges from 0.5 (chance level) to 1 (perfect discrimination).
Time frame: Monday of week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8569118 a-prime | Standard Deviation 0.0773489 |
| Placebo for Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8695347 a-prime | Standard Deviation 0.0723827 |
Secondary
Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT)
Subjects are required to respond selectively to a series of stimuli (e.g., numbers) presented briefly for 500 ms with a 500 ms intertrial interval (ITI). Increases in false alarm rates are interpreted as failures in response inhibition. Five digit numbers are presented on a computer screen every 500 ms sec. Subjects are instructed to respond when the first number of a set was repeated. A hit response is scored when a subject correctly responds. Distracters consist of five-digit numbers that are completely different from the first, and numbers in which four of the five digits match the original, with the non-matching number occurring randomly across the five digit places. A response to the number with 4 of 5 digits correct is scored as a false alarm. The a-prime value reflects the ability of the participant to discriminate between signal (Go stimulus) and noise (No-Go stimulus) and ranges from 0.5 (chance level) to 1 (perfect discrimination).
Time frame: Thursday of week 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8673529 a-prime | Standard Deviation 0.0764632 |
| Placebo for Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8551562 a-prime | Standard Deviation 0.0849648 |
Secondary
Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT)
Subjects are required to respond selectively to a series of stimuli (e.g., numbers) presented briefly for 500 ms with a 500 ms intertrial interval (ITI). Increases in false alarm rates are interpreted as failures in response inhibition. Five digit numbers are presented on a computer screen every 500 ms sec. Subjects are instructed to respond when the first number of a set was repeated. A hit response is scored when a subject correctly responds. Distracters consist of five-digit numbers that are completely different from the first, and numbers in which four of the five digits match the original, with the non-matching number occurring randomly across the five digit places. A response to the number with 4 of 5 digits correct is scored as a false alarm. The a-prime value reflects the ability of the participant to discriminate between signal (Go stimulus) and noise (No-Go stimulus) and ranges from 0.5 (chance level) to 1 (perfect discrimination).
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8327941 a-prime | Standard Deviation 0.1418202 |
| Placebo for Buspirone Plus Methylphenidate | Rapid Response Inhibition as Assessed by the Immediate Memory Task (IMT) | 0.8498438 a-prime | Standard Deviation 0.0854399 |
Secondary
Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task
The task is a rapid-presentation, probablistic gain/loss design. Reversal learning is assessed by means of a simple computerized card game. The paradigm utilizes a visual discrimination task where subjects have to learn to respond to outcome contingencies between two stimuli (high probability gain/low probability loss vs. low probability gain/high probability loss). At an unsignaled time point halfway into testing, the contingencies are reversed; the losing card becomes the winning card and the winning card becomes the losing one. Visual feedback regarding win or loss ($0.20) is provided after each trial and the cumulative total gained/lost is also shown. Using trial-and-error feedback, subjects have to discover which of the two patterns is correct and are instructed to win as much money as possible. The duration of the task is approximately 10 minutes, consisting of 80 trials.
Time frame: Monday of week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 10.88235 number of perseverative errors | Standard Deviation 8.305739 |
| Placebo for Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 14.69598 number of perseverative errors | Standard Deviation 16.61123 |
Secondary
Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task
The task is a rapid-presentation, probablistic gain/loss design. Reversal learning is assessed by means of a simple computerized card game. The paradigm utilizes a visual discrimination task where subjects have to learn to respond to outcome contingencies between two stimuli (high probability gain/low probability loss vs. low probability gain/high probability loss). At an unsignaled time point halfway into testing, the contingencies are reversed; the losing card becomes the winning card and the winning card becomes the losing one. Visual feedback regarding win or loss ($0.20) is provided after each trial and the cumulative total gained/lost is also shown. Using trial-and-error feedback, subjects have to discover which of the two patterns is correct and are instructed to win as much money as possible. The duration of the task is approximately 10 minutes, consisting of 80 trials.
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 14.41176 number of perseverative errors | Standard Deviation 8.155204 |
| Placebo for Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 10.625 number of perseverative errors | Standard Deviation 8.023923 |
Secondary
Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task
The task is a rapid-presentation, probablistic gain/loss design. Reversal learning is assessed by means of a simple computerized card game. The paradigm utilizes a visual discrimination task where subjects have to learn to respond to outcome contingencies between two stimuli (high probability gain/low probability loss vs. low probability gain/high probability loss). At an unsignaled time point halfway into testing, the contingencies are reversed; the losing card becomes the winning card and the winning card becomes the losing one. Visual feedback regarding win or loss ($0.20) is provided after each trial and the cumulative total gained/lost is also shown. Using trial-and-error feedback, subjects have to discover which of the two patterns is correct and are instructed to win as much money as possible. The duration of the task is approximately 10 minutes, consisting of 80 trials.
Time frame: Thursday of week 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 11.78154 number of perseverative errors | Standard Deviation 12.04489 |
| Placebo for Buspirone Plus Methylphenidate | Reversal Learning as Assessed by Number of Perseverative Errors on the Reversal Learning Task | 14.13049 number of perseverative errors | Standard Deviation 15.27429 |
Secondary
Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ)
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The DEQ is a visual analog scale questionnaire that assesses the extent to which subjects experience four subjective states: Feel Drug, Feel High, Like Drug, and Want More. The Feel High subscale is reported, and this subscale is scored on a visual analogue scale (scroll bar on computer screen) ranging from 0-100. 100 represents the highest score for that subjective state, and the higher the score, the worse the outcome.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 15mg Methylphenidate | 9.322581 units on a scale | Standard Deviation 17.49543 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 30mg Methylphenidate | 12.71351 units on a scale | Standard Deviation 22.32222 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 60mg Methylphenidate | 5.886486 units on a scale | Standard Deviation 15.6564 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 0mg Methylphenidate | 10.39785 units on a scale | Standard Deviation 17.27747 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 0mg Methylphenidate | 4.508671 units on a scale | Standard Deviation 13.15631 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 15mg Methylphenidate | 9.178161 units on a scale | Standard Deviation 17.58439 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 60mg Methylphenidate | 9.846591 units on a scale | Standard Deviation 20.80863 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Feel High Subscale of the Drug Effects Questionnaire (DEQ) | 30mg Methylphenidate | 10.78857 units on a scale | Standard Deviation 17.63701 |
Secondary
Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS)
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The POMS is a self-rating measure of current mood, consisting of six subscales demonstrated to be sensitive to a range of acute drug effects, including amphetamine, cocaine, and caffeine. The six subscales are: depression, vigor, confusion, tension, anxiety, and fatigue. A 37-item short form of the POMS was used, which correlates highly with the full scale. The vigor subscale is reported, and the vigor subscale score ranges from 0 to 28, with 28 representing the highest score for that mood state. The higher the value, the worse the outcome.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 15mg Methylphenidate | 4.609626 units on a scale | Standard Deviation 5.775599 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 30mg Methylphenidate | 9.924324 units on a scale | Standard Deviation 6.630357 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 60mg Methylphenidate | 4.745946 units on a scale | Standard Deviation 5.702335 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 0mg Methylphenidate | 6.16129 units on a scale | Standard Deviation 6.520306 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 0mg Methylphenidate | 5.735632 units on a scale | Standard Deviation 5.360873 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 15mg Methylphenidate | 3.770115 units on a scale | Standard Deviation 4.558423 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 60mg Methylphenidate | 5.874286 units on a scale | Standard Deviation 5.866932 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by Score on the Vigor Subscale of the Profile of Mood States (POMS) | 30mg Methylphenidate | 6.268571 units on a scale | Standard Deviation 5.721696 |
Secondary
Subjective Effects as Assessed by the Addiction Research Center Inventory (ARCI)
The ARCI short form will be used. It is a 49-item true / false questionnaire that has been empirically-derived to assess five different factors, including euphoria, sedation, and dysphoria. The PCAG scale has proven to be a sensitive measure of subjective effects in many studies administering stimulant drugs.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
Population: ARCI data were not collected.
Secondary
Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS)
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. The VAS presents 100-mm horizontal lines labeled with an adjective: stimulated, high, anxious, elated, hungry, and nauseated. The elated subscale is reported, and this sub scale is anchored by not at all (0) on the left and extremely (100) on the right, with a score range of 0-100. The higher the score, the worse the outcome.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 15mg Methylphenidate | 11.48128 units on a scale | Standard Deviation 21.53051 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 30mg Methylphenidate | 28.72973 units on a scale | Standard Deviation 29.45967 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 60mg Methylphenidate | 14.54595 units on a scale | Standard Deviation 24.1708 |
| Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 0mg Methylphenidate | 21.95676 units on a scale | Standard Deviation 25.58082 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 0mg Methylphenidate | 14.89017 units on a scale | Standard Deviation 25.46919 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 15mg Methylphenidate | 19.53448 units on a scale | Standard Deviation 23.74495 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 60mg Methylphenidate | 21.81143 units on a scale | Standard Deviation 27.00221 |
| Placebo for Buspirone Plus Methylphenidate | Subjective Effects as Assessed by the Elated Subscale of the Visual Analogue Scale (VAS) | 30mg Methylphenidate | 21.42045 units on a scale | Standard Deviation 25.17651 |
Secondary
Systolic Blood Pressure
The mean score over all 44 time points is reported in this outcome measure (i.e., the summary score is reported). Each subject contributed 11 data points for each dose level of Methylphenidate (15mg, 30mg, 60mg, or 0mg), resulting in a total of 220 data points per dose level per arm. Systolic blood pressure is the amount of pressure in the arteries during contraction of the heart muscle.
Time frame: 11 times a day on Wednesday and Friday of week 2; 11 times a day on Monday and Wednesday of week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buspirone Plus Methylphenidate | Systolic Blood Pressure | 15mg Methylphenidate | 118.0856 mmHg | Standard Deviation 11.56065 |
| Buspirone Plus Methylphenidate | Systolic Blood Pressure | 60mg Methylphenidate | 114.3904 mmHg | Standard Deviation 12.69334 |
| Buspirone Plus Methylphenidate | Systolic Blood Pressure | 30mg Methylphenidate | 114.8396 mmHg | Standard Deviation 10.86901 |
| Buspirone Plus Methylphenidate | Systolic Blood Pressure | 0mg Methylphenidate | 114.7914 mmHg | Standard Deviation 12.56828 |
| Placebo for Buspirone Plus Methylphenidate | Systolic Blood Pressure | 30mg Methylphenidate | 120.4545 mmHg | Standard Deviation 12.3153 |
| Placebo for Buspirone Plus Methylphenidate | Systolic Blood Pressure | 15mg Methylphenidate | 115.9205 mmHg | Standard Deviation 9.891666 |
| Placebo for Buspirone Plus Methylphenidate | Systolic Blood Pressure | 0mg Methylphenidate | 115.6932 mmHg | Standard Deviation 10.68976 |
| Placebo for Buspirone Plus Methylphenidate | Systolic Blood Pressure | 60mg Methylphenidate | 113.6932 mmHg | Standard Deviation 10.50046 |