A total of 12 subjects completed the entire study. A 13th participant completed one part of the study (modafinil portion), and his data were included in the final analyses, so outcomes are presented as N=12 or N=13.
Participants were recruited using advertisements and paid $700 in cash for the inpatient stay and an additional $50 in gift certificates if they completed the entire study. Subjects did not receive the entire payment at once, but received 50% when they were discharged and 50% when they returned for a 2-week follow-up. All participants met DSM-IV-TR criteria for methamphetamine-dependence (as determined using the MINI neuropsychiatric interview) and did not meet criteria for dependence on other drugs, other than nicotine or marijuana. Additional inclusion criteria included being between 18-45 years of age, having a history of using methamphetamine by the smoked or IV route of administration, and being otherwise healthy, as confirmed by a physical examination and safety laboratories. Exclusion criteria included having a history of seizure disorder or head trauma, having a history of prior adverse event associated with methamphetamine abuse (e.g., loss of consciousness), or the presence of any axis I psychiatric disorder other than those noted above. Current serious medical conditions, such as symptomatic HIV disease, heart disease, or neurologic disease, were also exclusionary.
2.2 Study Design
This double-blind, placebo-controlled, within-subjects study was conducted in the UCLA General Clinical Research Center (GCRC). The institutional review board at UCLA approved the study. All participants give informed consent after having the potential risks fully explained to them.
On the day following admission, blood for hematology studies was collected in anticoagulant-containing Vacutainer tubes for analysis of complete blood count, chemistry, liver function tests, renal function tests, and Hepatitis B and C. In females, a urine-based pregnancy test measured human chorionic gonodotropin.
The study schema is provided in . On Day 1, subjects were randomized to modafinil or placebo in the morning then 3 and 6 h later received infusions of methamphetamine (0 and 30 mg, IV), and cardiovascular and subjective effects were assessed. On Day 3, participants completed IV self-administration sessions during which they made 10 choices for low doses of methamphetamine (3 mg, IV) or saline or a money alternative. Days 4-7 were used as a washout period and on Day 8 participants were assigned to the alternate study medication (placebo or modafinil) and the same testing procedures were repeated through Day 10. Subjects remained in the GCRC for the duration of the study (i.e., all 10 days).
A physician was present during all methamphetamine infusion sessions and carefully monitored participant's heart rate (HR), blood pressure (BP), and ECG wave form. Stopping rules were in place to halt dosing if cardiovascular indices exceeded preset values. These included 1) systolic BP > 185 mm Hg, 2) diastolic BP > 100 mm Hg, 3) heart rate > 130 bpm, 4) behavioral manifestation of methamphetamine toxicity (e.g., agitation, psychosis, inability to comply with study procedures), and/or 5) an uncorrected QT of 470 msec or a rate-corrected QTc of 500 msec on ECG reading.
2.3 Cardiovascular and Subjective Measures
Cardiovascular data (automated heart rate (HR) and blood pressure (BP)) were collected 15 min before, and at several time points (5, 10, 15, 20, 30, 45, 60, 90, and 120 min) following the methamphetamine (0 and 30 mg, IV) infusions.
Subjective effects data were collected at the same time points using visual analog scales (VAS). For VAS scales, subjects reported the degree to which they feel ‘Any Drug Effect’, ‘High’, ‘Good effects’, ‘Bad effects’, ‘Like methamphetamine’, ‘Want methamphetamine’, ‘Desire methamphetamine’, ‘Crave methamphetamine’, ‘Depressed’, ‘Anxious’, ‘Stimulated’, and ‘Likely to Use’ on a continuous scale digitized between 0 and 100 and reported as change from baseline (described below).
Participants also completed the Monetary Value questionnaire 15 min after each infusion. The two questions include ‘How much would you pay (in dollars) for what was just administered to you?’, and ‘How much do you normally pay (in dollars) for a gram of methamphetamine on the street?’
The Addiction Research Center Inventory (ARCI) short form (Martin et al., 1971
) was administered 15 min prior to and 60 min following each injection of methamphetamine or saline. The ARCI consists of 49 statements in a true/false format. Scores were calculated for the morphine-benzedrine group (MBG; a measure of euphoria; generally used to assess abuse liability), the pentobarbital, chlorpromazine, alcohol group (PCAG; a measure of sedation), the lysergic acid diethylamide group (LSD; a measure of dysphoria), and stimulant-sensitive scales, including the benzedrine group (BG) and amphetamine (A) scales.
2.4 Sample Sessions and IV Self-Administration
During the sample sessions, on Days 1 and 8, participants received methamphetamine 0 mg (saline) and 30 mg under double-blind conditions at either 11:30 a.m. or 2:30 p.m. A 120 min time period between infusions was selected on the basis of our previous data, which indicates that peak subjective and cardiovascular responses have passed by this time (Newton et al., 2005b
). Concerns about potential “carryover effects” from one infusion period to another were also mitigated by using a subtraction from baseline to determine actual effects (see Data Analysis). Participants were made aware that the 30 mg dose reflected the maximum effects the participants could anticipate feeling if they selected all 10 infusions during choice sessions to be held on Days 3 and 10.
Sample infusions were coded as either “red” or “green”. Participants were instructed to write down any positive or negative subjective effects produced by the infusion, and encouraged to reference these notes prior to and during subsequent choice sessions. Participants and investigators were blinded as to the coding of methamphetamine or saline as the red or green infusion. This coding was counterbalanced among participants, but kept constant throughout the duration of the study for each individual.
Choice sessions were held twice per day on Days 3 and 10. On these days, one session was held at 11:30 a.m. and involved choices for methamphetamine or saline, and the other session was held at 2:30 p.m. and involved choices for the alternate condition (saline or methamphetamine). On Days 3 and 10, participants made a series of choices between money options of increasing value or 1/10 of the red or green infusion from the day before (i.e. 3 mg methamphetamine or saline). The ten monetary options included $0.05, $0.05, $0.05, $0.05, $1, $4, $7, $10, $14, and $16 (presented in that ascending sequence). The dollar choices made available ($0.05 - $16) were selected on the basis of our prior work (De La Garza et al., 2008a
) and others (Walsh, 2000
). All choices were separated by 15 min. The research assistant did not approach the participant every 15 min, rather the participant was told at the beginning of the experiment that they would have to make a choice on a computer tablet every 15 min. If the participant chose money, the cash was immediately placed into an envelope within the participants view. If the participant chose an infusion, he/she actuated the patient-controlled analgesia (PCA) pump him/herself. The PCA pump had a 13 min lockout following a 2 min infusion, thus preventing repeated dosing prior to the completion of the 13 min lockout.
Self-administration sessions were held on Days 3 and 10. On these days, methamphetamine infusions (0 or 3 mg, IV) were administered over 2 min using a PCA pump activated by the participant. One button push, equivalent to a fixed ratio 1 schedule, was sufficient to activate the pump. The 3 mg dosage for methamphetamine was selected as a safe increment that could be self-administered repeatedly, and has been used with success by our laboratory (De La Garza et al., 2008a
). Given this information, the dosages and timing of drug administration were deemed appropriate for this study.
For safety purposes, participants were monitored for 4 additional hours after the last infusion on each of the infusion days (1, 3, 8 and 10).
A NIDA contractor provided sterile methamphetamine solution for human use and a saline solution of equal volume and appearance was used as the control. Modafinil was obtained from Cephalon, and re-packaged by the UCLA Research Pharmacy to de-identify the tablets. An IND was obtained from the FDA for the use of modafinil and methamphetamine in this study.
The dose of modafinil (200 mg) was selected on the basis of several published reports showing efficacy for blocking cocaine's effects (Hart et al., 2007
) and for enhancing cognition (Turner et al., 2003
), and is a dose that has been shown to be well-tolerated in several distinct patient populations. Peak plasma concentrations of modafinil are obtained 2–3 h after oral administration with an elimination half-life of 10–12 h (Wong et al., 1998
). The half-life of methamphetamine is ~11–12 h. On Days 1 and 8, methamphetamine (0 and 30 mg, IV) was administered over 2-min using an infusion pump activated by a physician. A single bolus of 30 mg methamphetamine was used in the sample session since it has been associated with significant increases in positive subjective effects as well as increases in blood pressure and heart rate (Newton et al., 2005a
; De La Garza et al., 2008b
), though these changes are not accompanied by adverse events greater than observed after saline administration. The participants were made aware that the 30 mg dose reflected the maximum effects the participants could anticipate feeling if they selected all 10 infusions during choice sessions to be held on Days 3 and 10.
Self-administration sessions were held on Days 3 and 10. On these days, methamphetamine infusions (0 or 3 mg, IV) were administered over 2-min using a PCA pump activated by the participant.
2.6 Data Analyses
Data were analyzed using StatView 5.0 (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were compiled for demographic variables and analyzed using appropriate parametric or non-parametric tests. For all measures, statistical significance was set at p<0.05. All data are presented as mean ± standard error.
Sample size was calculated on the basis of the work of Hart and colleagues (2007)
. Given those findings, a sample of 10 would allow detection of medium to large effects (approximately d = .70) when comparing groups, with power = .80 and one-tailed alpha = .05. Use of one-tailed tests of significance is appropriate for pilot studies in which the major goal is to determine if there is a signal indicating therapeutic efficacy. On the basis of this information, the sample of N=12-13 reported here appears adequate to detect significant effects.
2.7 Across-study measures
The total number of adverse events (AEs) was summed from Days 1-3 and Days 8-10 separately and analyzed using an ANOVA as a function of modafinil dose (0 or 200 mg). Other aspects of AE data reporting (type, severity and duration) were not analyzed since the overall number of AEs was low and not different between treatment conditions.
For across-study measures, all data except time were analyzed as between-subjects factors. Time (in days) was analyzed as a within-subjects factor.
2.8 Post-randomization measures
Heart rate, systolic blood pressure, diastolic blood pressure, and VAS data were analyzed using repeated measures ANOVA as a function of modafinil dose (0 or 200mg) and Time (in min). Time-courses reflect within-session change from baseline (value at a given time-point minus the value at T=−15 min). These data were also analyzed with respect to peak effects (occurring at any time point) using a one-way ANOVA as a function of modafinil dose (0 or 200 mg).
For total infusions self-administered, a one-way ANOVA was used to assess differences as a function of modafinil dose (0 and 200 mg) and methamphetamine dose (0 and 3 mg). This analytic approach was based upon one described previously (Walsh et al., 2001), and as previously published by our research group (De La Garza et al., 2008a
For post-randomization measures, all data except Time were analyzed as between-subjects factors. Time (in min) was analyzed as a within-subjects factor.