METHAMPHETAMINE SELF-ADMINISTRATION IN HUMANS DURING D-AMPHETAMINE MAINTENANCE

Abstract

Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of d-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted d-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested two d-amphetamine maintenance conditions in counter-balanced order (0 and 40 mg/day). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled one of four doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug-effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 13 items of the drug-effects questionnaires, 10 of which were attenuated by d-amphetamine maintenance (e.g., increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by d-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during d-amphetamine maintenance and no adverse events occurred. Although d-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that d-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.

INTRODUCTION

Methamphetamine use disorders are a significant problem in the United States. In 2012, 440,000 individuals over 12 years of age reported using methamphetamine in the last month and 535,000 individuals reported being dependent on stimulants including methamphetamine. In 2012, over 12 million individuals reported using methamphetamine in their lifetime (1, 2, 3). In 2011, over 100,000 individuals over 12 years of age being admitted to substance abuse treatment reported methamphetamine as their primary substance of abuse (4). Despite the number of methamphetamine users, there is no universally effective pharmacological treatment for methamphetamine abuse.

Agonist replacement is commonly used for other substance use disorders, including methadone for opioid dependence and nicotine replacement for promoting smoking cessation. Dopamine agonists have also shown promise when tested for treating cocaine dependence (reviewed in: 5–7). Few studies have tested agonist replacement for methamphetamine. The results of a recent safety and tolerability study showed that 45 mg/day d-amphetamine significantly reduced subject-rated drug-effects of methamphetamine (0, 2.5, 5, 10, 20 mg) in stimulant-dependent individuals compared to placebo, however this study did not assess self-administration of methamphetamine (8). Previous research has shown that self-administration may have better predictive validity for outcomes observed in clinical trials (reviewed in: 9, 10). Thus, human laboratory self-administration studies may be ideally suited to determine the potential efficacy of medications for methamphetamine use disorders.

The aim of the present study was to further evaluate d-amphetamine as a potential pharmacotherapy for methamphetamine use disorders by examining the reinforcing, subject-rated, and physiological effects of methamphetamine during maintenance on d-amphetamine and placebo. We hypothesized that methamphetamine would be self-administered by participants more than placebo and that d-amphetamine maintenance would reduce methamphetamine self-administration relative to placebo maintenance. We also hypothesized that d-amphetamine would reduce the subject-rated drug-effects of methamphetamine compared to placebo and that d-amphetamine-methamphetamine combinations would be well tolerated.

METHODS

Study Population, Inclusion/Exclusion Criteria, and Screening

Eight non-treatment seeking adult participants with recent histories of stimulant use who met criteria for stimulant dependence as determined by a computerized version of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders – IV (SCID) completed this within-subjects, placebo-controlled study. Four additional participants were enrolled, but left the protocol for reasons unrelated to the study procedures. Data from these individuals were excluded from the analyses. The Institutional Review Board of the University of Kentucky Medical Center approved this study and the participants gave their written informed consent prior to participating. Participants were informed that during the study they would be given medications that may be placebo or a stimulant, such as d-amphetamine or methamphetamine. Participants were informed that the purpose of the study was to see how drugs affect mood and behavior and if they like the drugs and would be willing to take them again. Participants were not informed of the specific drugs they received, possible outcomes, or performance expectations. Participants were paid for their participation.

Prior to enrollment in the experimental protocol, all participants underwent a comprehensive physical and mental health screening as described previously (11). Participants had to meet the following inclusion criteria: self-reported stimulant use, confirmation of recent stimulant use by a stimulant positive urine sample, and fulfillment of the diagnostic criteria for stimulant abuse or dependence on a computerized version of the SCID that was reviewed by a psychologist or psychiatrist. Potential participants with histories of serious physical disease or current physical disease, impaired cardiovascular functioning, chronic obstructive pulmonary disease, seizure, head trauma or central nervous system tumors, or current or past histories of serious psychiatric disorder (i.e., Axis I of DSM-IV) other than substance abuse or dependence, were excluded from participation. All participants were physically and psychologically healthy, as determined by the medical staff, with no contraindications to stimulants.

Participants ranged in age from 24 to 52 years (mean 42 years) and in weight from 66 to 104 kg (mean 87 kg). All participants were male. Five participants were black and three were white (one Hispanic). All participants reported using illicit stimulants 2–16 days (mean 11 days) in the month and 1–4 days (mean 3 days) in the week prior to screening. All participants reported smoking tobacco cigarettes daily (range 3–30 cigarettes per day, mean 13 cigarettes). Participants also reported use of a range of substances including alcohol, caffeine, marijuana, opiates, hallucinogens, and sedatives. Five participants reported drinking alcohol (range 6–64 standard drinks, mean 15 drinks) in the week prior to screening and five participants reported consuming caffeine (range 7–451 mg per day, mean 91 mg). All participants reported using marijuana 1–30 days (mean 17) and two participants reported using opiates 4 and 10 days in the month prior to screening. No other illicit drug use was reported in the month prior to screening.

Study Procedures

Participants resided at the University of Kentucky Medical Center Clinical Services Core (CSC) for approximately 28 days and completed one practice and eight experimental sessions.

Practice Session

Participants completed a practice session prior to beginning maintenance medication to familiarize them with the behavioral tasks, progressive ratio, and timeline of experimental sessions, as described below. No medications were administered during the practice session.

Drug Maintenance Days

Drug maintenance began on the day immediately after the practice session and continued throughout the protocol. Placebo or sustained-release d-amphetamine was administered at 7:00 AM and 7:00 PM. After approximately 7 days of maintenance participants completed four experimental sessions as described in the next section and began maintenance on the subsequent condition the following day. The order of drug maintenance conditions was counterbalanced across participants. The total daily dose for each condition was 0 or 40 mg sustained-release d-amphetamine. To enhance participant safety, participants received 5 mg twice daily on the first day of d-amphetamine maintenance, 10 mg twice daily on the second and third days, and 20 mg twice daily for the remaining days.

Experimental Sessions

When possible, sessions were conducted on consecutive days. However, experimental sessions were not conducted on weekends, when medical coverage at the CSC was limited, so the appropriate maintenance dose was given on intervening weekend days and testing resumed Monday if necessary.

Participants received the appropriate maintenance dose at 7:00 AM on the morning of all experimental sessions. Experimental sessions started at 8:30 AM and lasted 8 hours. At 9:30 AM, participants sampled the intranasal methamphetamine dose that they had the opportunity to work for later in the session. In the afternoon, participants completed the progressive ratio and received the portion of the dose they earned on that task. The portion of the dose that the participants earned was administered at 2:30 PM. Participants had vitals recorded and completed subject-rated drug-effects questionnaires pre-methamphetamine administration and 0, 15, 30, 45, 60, 90, and 120 minutes following methamphetamine administration.

Following the sampling dose, participants completed a battery of cognitive tasks, including the visual probe task (12), cued go/no-go task (13), and Balloon Analog Risk Task (14). The results of the cognitive assessments will be reported separately.

Urine and breath samples were collected before each session to confirm drug and alcohol abstinence, respectively. Participants occasionally tested positive for methamphetamine and amphetamine, which was likely attributable to the administration of the experimental medications.

All participants who reported smoking were allowed to smoke 1 cigarette the morning of experimental sessions, but were not allowed to smoke during sessions. All participants were required to keep their smoking behavior consistent throughout the experiment in order to keep nicotine exposure constant within subjects.

Modified Progressive-Ratio Procedure

During the self-administration portion of each experimental session participants had 10 opportunities to work to earn a portion of the drug sampled that morning. Participants were presented with the progressive-ratio task on a computer screen and they were instructed to use the computer mouse to click on a button to work to earn a portion of the drug, each completed ratio earned 1/10^th of the sampled dose. Participants were instructed that they could choose to work to earn all, a portion of, or none of the sampled dose. To complete the first ratio, participants were required to click 400 times and each additional ratio increased by 100 (i.e. 500, 600, 700, 800, 900, 1000, 1100, 1200, and 1300). The participant was allowed to terminate the task at any time if they clicked a button labeled stop. The portion of the dose earned was (e.g., 50% if subjects completed 5 ratios) was administered after completion of this task. The primary outcome variable was number of ratios completed.

Subject-Rated Drug-Effect Questionnaires

Two subject-rated drug-effect questionnaires were administered using an Apple microcomputer with a mouse attached in a fixed order: the Adjective Rating Scale (15) and the Drug Effect Questionnaire (16).

Physiological Measures

Heart rate, blood pressure, temperature, and heart rhythmicity (via ECG) were measured at regular intervals throughout session. If systolic blood pressure, diastolic blood pressure, or heart rate exceeded 180, 120, or 130, respectively, or if clinically significant electrocardiographic changes occurred at any point after the administration of methamphetamine participation was discontinued. No participant was excluded from participation for exceeding these parameters. Sampling or self-administered doses were held if heart rate was 100 bpm or higher, systolic pressure was 150 mmHg or higher or diastolic pressure was 100 mmHg or higher. Only one self-administered dose was held due to heart rate exceeding 100 bpm.

Drug Administration

All medications were administered in a double blind fashion. Maintenance medications were prepared by over-encapsulating a commercially available 5 mg d-amphetamine spansule and loose filling the capsule with lactose monohydrate powder, N.F. Placebo capsules were prepared in the same way as the d-amphetamine, except only contained lactose monohydrate powder, N.F. Methamphetamine doses were prepared by weighing out the appropriate dose (0, 10, 20 or 30 mg, administered in random order) of methamphetamine, which was then mixed with lactose monohydrate powder, N.F. to make a total of 60 mg of powder. Participants sampled the entire dose in the morning the session and had the opportunity to work for the sampled dose in the afternoon self-administration portion of the session.

Statistical Methods

For all statistical analyses, effects with p ≤ 0.05 were considered significant. Data from the progressive-ratio task were analyzed using a two-factor repeated-measures analysis of variance (ANOVA). The factors were Methamphetamine (i.e., 0, 10, 20, and 30 mg) and d-Amphetamine (i.e., 0 or 40 mg/day). F statistics were used to interpret the ANOVA outcomes. During self-administration sessions, participants determined the amount of drug that they ingested. Thus, varying amounts of drug was administered to participants during the self-administration session. Due to participants ingesting varying amounts of drug in self-administration sessions, only data from subject-rated drug-effects questionnaires and physiological indices from sampling doses were analyzed statistically as peak effect (i.e., the maximum response observed after dosing) in a fashion identical to that for progressive-ratio data.

RESULTS

Methamphetamine Self-Administration During d-Amphetamine Maintenance

ANOVA revealed only a significant main effect of methamphetamine on number of ratios completed (F_3,21 = 32.1). Methamphetamine increased the number of ratios completed regardless of the maintenance condition (Figure 1; Tables 1 and 2).

Figure 1.

Methamphetamine ratios completed on the Progressive Ratio Task (Top Left). Systolic Blood Pressure (Top Right). Subject ratings of Like Drug (Bottom Left) and Willing to Take Again (Bottom Right) from responses on a 100 mm visual analog scale on the Drug-Effect Questionnaire. Data from Systolic Blood Pressure and the Drug-Effect Questionnaire are expressed as peak effect from the sampling session. For all panels circles represent placebo maintenance and squares represent 40 mg/day d-amphetamine and brackets show 1 SEM. All data points represent mean values for 8 participants.

Table 1.

Summary statistics for measures with a statistically significant outcome in the ANOVA. A bold value indicates a significant F statistic (p<0.05).

Measure	F statistics			Cohen’s f
	d-Amphetamine (df1,21)	Methamphetamine (df3,21)	Methamphetamine x d-Amphetamine (df3,21)	d-Amphetamine	Methamphetamine	Methamphetamine x d-Amphetamine
Self-Administration (# Ratios Completed)	1.82	32.06	0.41	0.16	2.36	0.24
Adjective-Rating Scale
Stimulated	3.09	8.89	1.06	0.64	1.34	0.38
Drug-Effect Questionnaire
Active, Alert, Energetic	1.58	5.31	0.69	0.24	1.35	0.31
Any Effect	7.43	10.53	0.49	0.57	1.83	0.27
Good Effect	10.39	9.85	0.63	0.65	2.04	0.30
High	5.86	9.18	0.29	0.47	1.82	0.20
Irregular or Racing Heartbeat	5.49	5.32	1.76	0.48	0.66	0.50
Like Drug	13.88	9.84	0.64	0.69	1.96	0.30
Pay For	10.71	6.18	0.89	0.57	1.95	0.36
Performance Impaired	2.61	2.94	1.92	0.38	0.64	0.52
Rush	13.42	5.79	0.15	0.54	1.90	0.14
Shaky or Jittery	3.78	3.35	3.62	0.58	0.82	0.72
Stimulated	6.22	6.07	0.47	0.59	1.75	0.26
Take Again	5.62	9.34	1.20	0.71	1.67	0.41
Talkative or Friendly	2.16	3.19	0.61	0.46	1.21	0.29
Physiological Indices
Systolic Blood Pressure	8.60	4.40	1.08	0.76	1.22	0.39

Table 2.

Means and standard error of the mean for measures with a statistically significant outcome in the ANOVA.

Measure	Means (SEM)
	d-Amphetamine (0 mg) and Methamphetamine				d-Amphetamine (40 mg) and Methamphetamine
	0 mg	10 mg	20 mg	30 mg	0 mg	10 mg	20 mg	30 mg
Self-Administration (# Ratios Completed)	0.63 (0.63)	7.75 (1.29)	8.88 (0.79)	8.88 (0.79)	0.25 (0.25)	5.75 (1.75)	7.13 (1.58)	8.00 (1.25)
Adjective-Rating Scale
Stimulated	6.75 (2.57)	10.88 (1.88)	11.75 (1.77)	14.13 (2.15)	6.25 (1.80)	9.25 (2.02)	9.75 (1.77)	10.25 (1.88)
Drug-Effect Questionnaire
Active, Alert, Energetic	7.88 (3.13)	30.13 (10.97)	32.38 (12.34)	37.50 (12.09)	11.50 (7.32)	22.38 (11.26)	29.38 (8.99)	31.25 (9.54)
Any Effect	6.13 (3.34)	29.88 (9.85)	34.25 (10.41)	46.25 (9.83)	3.75 (1.42)	20.13 (11.41)	26.88 (7.05)	33.75 (7.01)
Good Effect	5.75 (3.24)	30.38 (9.51)	34.13 (10.73)	44.25 (9.74)	3.75 (1.52)	18.38 (11.74)	25.75 (7.44)	34.50 (7.65)
High	6.50 (3.33)	29.25 (9.49)	33.00 (10.42)	42.50 (9.85)	4.13 (1.59)	20.75 (11.53)	27.88 (7.27)	33.50 (7.26)
Irregular or Racing Heartbeat	2.88 (1.16)	5.88 (2.74)	7.38 (3.59)	22.50 (8.86)	1.88 (0.74)	3.50 (1.49)	4.13 (1.71)	6.88 (2.92)
Like Drug	6.75 (2.90)	36.00 (10.44)	39.13 (10.95)	44.75 (10.00)	3.50 (1.28)	21.25 (11.17)	29.25 (8.68)	35.25 (7.93)
Pay For	4.63 (2.34)	30.50 (10.86)	31.25 (12.63)	39.25 (12.16)	3.25 (1.36)	18.25 (11.22)	27.13 (9.02)	30.00 (9.30)
Performance Impaired	2.38 (0.98)	6.13 (3.00)	5.25 (2.81)	22.38 (11.34)	2.25 (1.29)	3.13 (1.23)	5.00 (2.77)	5.13 (2.20)
Rush	5.00 (2.93)	23.13 (9.99)	28.00 (10.81)	34.00 (11.31)	1.63 (0.82)	16.00 (12.04)	20.75 (8.27)	28.38 (9.58)
Shaky or Jittery	2.25 (0.90)	26.13 (11.40)	5.25 (2.64)	21.88 (8.68)	2.88 (1.23)	5.00 (2.27)	7.63 (3.90)	8.50 (4.10)
Stimulated	7.13 (3.68)	27.25 (9.97)	28.88 (11.02)	35.75 (10.58)	3.63 (1.63)	17.50 (10.79)	25.00 (7.91)	26.63 (8.59)
Take Again	6.25 (2.78)	45.00 (13.03)	47.00 (13.57)	53.13 (12.13)	4.00 (1.80)	22.00 (11.63)	28.75 (9.24)	42.75 (11.83)
Talkative or Friendly	13.25 (5.40)	31.38 (11.85)	30.50 (12.52)	38.75 (12.95)	11.75 (7.75)	23.63 (12.84)	27.25 (10.00)	27.63 (10.22)
Physiological Indices
Systolic Blood Pressure	120.50 (3.71)	133.00 (3.87)	131.50 (1.85)	133.13 (3.86)	119.63 (2.10)	125.13 (3.14)	125.00 (2.33)	128.00 (2.36)

Subject-Rated Effects of Methamphetamine During d-Amphetamine Maintenance

Adjective Rating Scale

ANOVA revealed only a main effect of methamphetamine for scores on the Stimulant scale of the Adjective Rating Scale (F_3,21 = 8.9). Methamphetamine increased these scores as a function of dose regardless of the maintenance condition. There were no significant effects on the Sedative scale of the Adjective Rating Scale (data not shown; Tables 1 and 2).

Visual Analog Scales

ANOVA revealed a significant interaction of methamphetamine and d-amphetamine for ratings of Shaky or Jittery (F_3,21 = 3.6). The 10 and 30 mg methamphetamine doses increased these ratings during placebo maintenance but not during d-amphetamine maintenance. Similar increases in ratings were not observed following the 20 mg methamphetamine dose during placebo maintenance (data not shown; Tables 1 and 2).

ANOVA revealed main effects of methamphetamine and d-amphetamine (F_3,21 values > 5.8, F_1,21 values > 5.6, respectively), but not an interaction of these factors, for ratings of Any Effect, Good Effects, High, Like Drug, Pay For, Rush, Stimulated, and Willing to Take Again. Methamphetamine generally increased these ratings as a function of dose during both placebo and d-amphetamine maintenance. These ratings were lower during d-amphetamine maintenance relative to placebo maintenance (Figure 1; Tables 1 and 2).

ANOVA revealed only a main effect of methamphetamine for ratings of Active, Alert, Energetic (F_3,21 = 5.3); Irregular or Racing Heartbeat (F_3,21 = 5.5); and Talkative or Friendly (F_3,21 = 3.2). Maintenance on d-amphetamine had no effect on methamphetamine-induced ratings of Active, Alert, Energetic; Irregular or Racing Heartbeat; or Talkative or Friendly (data not shown; Tables 1 and 2).

Physiological Effects of Methamphetamine During d-Amphetamine Maintenance

ANOVA revealed main effects of methamphetamine and d-amphetamine, but not an interaction of these factors, for systolic blood pressure (F_3,21 = 4.4, F_1,21 = 8.6, respectively). Methamphetamine generally increased systolic blood pressure as a function of dose during both placebo and d-amphetamine maintenance. The pressure-increasing effects of methamphetamine on systolic blood pressure were attenuated during d-amphetamine maintenance relative to placebo maintenance (Figure 1; Tables 1 and 2). There were no significant effects on heart rate, diastolic pressure or body temperature.

DISCUSSION

Active intranasal methamphetamine was self-administered at near maximal levels, which is consistent with the findings of previous research that showed intranasal methamphetamine functioned as a robust reinforcer (17). d-Amphetamine maintenance did not significantly reduce self-administration of methamphetamine, which is consistent with the results of two clinical trials that showed d-amphetamine treatment did not significantly reduce methamphetamine use compared to placebo (18, 19). One of these clinical trials showed a trend toward a decrease in methamphetamine use (19). Data from the present study also showed a clear, albeit non-significant, trend of a downward shift in self-administration during d-amphetamine maintenance. Despite the downward trend in self-administration produced by d-amphetamine administration here, the utility of d-amphetamine for managing methamphetamine use disorders seems limited given the negative findings from at least two clinical trials and the small effect size observed for d-amphetamine maintenance in this study, although a fine-grain analysis of treatment responders may yield more promising outcomes (20). Overall, the concordance between the self-administration data and results of clinical trials shows that self-administration has predictive validity for outcomes that have been observed in clinical trials (9, 10).

Methamphetamine administered alone dose dependently increased positive subject-rated drug-effects (e.g., Like Drug; Willing to Take Again), which is consistent with the results of previous research (e.g., 21–24). d-Amphetamine maintenance attenuated some of the positive subject-rated drug-effects, which is consistent with a previous study that showed 45 mg/day d-amphetamine reduced the subject-rated drug-effects of methamphetamine (8). The attenuation of subject-rated drug-effects indicates that subject-rated drug-effects may have less predictive validity to model results observed in the clinic, leading to false positives. Other medications have also reduced the subject-rated drug-effects of stimulants, but were not effective clinically (21, 25–29). Finally, methamphetamine dose dependently increased systolic blood pressure and d-amphetamine maintenance attenuated these increases, compared to placebo maintenance. These findings are consistent with the results of prior studies that showed intranasal methamphetamine is safe and well-tolerated in a controlled laboratory setting (8, 16, 17, 22–24) and that d-amphetamine maintenance reduces some of the cardiovascular effects of methamphetamine (8). The attenuation of cardiovascular effects of methamphetamine during d-amphetamine maintenance may be attributable to participants developing cross-tolerance to the cardiovascular effects of stimulants.

The present study has limitations that are worth noting, which can direct future research. First, the present study tested a relatively modest dose of d-amphetamine and it is possible that a higher dose may be more effective for reducing methamphetamine self-administration. The trend toward a decrease in self-administration of the lowest dose of methamphetamine during d-amphetamine maintenance compared to placebo maintenance supports this notion. However, higher doses, up to 110 mg/day have been tested in previous clinical trials and did not significantly reduce methamphetamine use compared to placebo (18, 19), which suggests that the lack of a reduction of self-administration of methamphetamine during d-amphetamine maintenance may not be solely due to the dose tested. Second, methamphetamine was insufflated. Different routes of administration result in varying rates of onset and a faster rate of onset may contribute to increased abuse liability. For example, intravenous administration of cocaine results in a slower rate of onset than smoked cocaine (30). Other studies have shown that ratings of drug-effects were higher followed smoked cocaine compared to equivalent intravenous cocaine doses and in a choice procedure, participants chose to self-administer smoked cocaine more than equivalent intravenous cocaine doses (31, 32). Future studies should test the efficacy of d-amphetamine for reducing methamphetamine administered by other routes (e.g., smoked or injected). Third, the sample size was relatively small. The sample size was chosen based on other human laboratory studies that tested the behavioral effects of methamphetamine alone and during maintenance on potential medications to treat methamphetamine abuse that detected statistically significant effects (8, 23, 27, 33). This sample size was sufficient to detect changes in the reinforcing effects of cocaine following d-amphetamine maintenance (11). A power analysis was conducted using the effect sizes observed in this study to determine the number of participants that would need to complete the study in order for it to be sufficiently powered to detect an interaction between methamphetamine and d-amphetamine. The power analysis showed that 25 participants would need to complete the study. The number of individuals who would need to complete the study combined with the negative clinical results guided the decision end the study rather than choosing to expose more individuals to a medication that does not appear to reduce methamphetamine use. Fourth, the participants in the present study were non-treatment seeking stimulant users and it is possible that d-amphetamine could produce greater reductions in methamphetamine use in a population that is seeking treatment, as the participants in the present study did not have any intention of decreasing their stimulant use. Non-treatment seeking stimulant users were enrolled in the present study due to ethical considerations of providing individuals who are seeking treatment with methamphetamine, but d-amphetamine has been tested in clinical trials to reduce methamphetamine abuse in treatment seeking populations and did not produce significant reductions in methamphetamine use (18, 19). Fifth, demographic variables could have impacted the results of the study, as the sample size was small, which is supported by previous analyses of treatment responders in clinical trials (20). To address this limitation, Pearson Correlations were used and demonstrate limited relationships between demographics (age, years of education, weight, days used stimulants in the last month, and years of stimulant use) and number of ratios completed for each of the eight methamphetamine and d-amphetamine combinations. Age, days used stimulants in the last month, and years of stimulant use were not significantly correlated with the number of ratios completed for any of the methamphetamine and d-amphetamine dose combinations. There was a significant positive correlation between weight and number of ratios completed for the combination of 20 mg methamphetamine and 40 mg d-amphetamine. There was also a significant positive correlation between years of education and number of ratios completed for the combination of 10 mg methamphetamine and 0 mg d-amphetamine.

Overall, d-amphetamine did not significantly reduce self-administration of methamphetamine, even though there was a downward shift of the dose-response curve. These findings combined with the previous clinical trial results suggest that d-amphetamine may not be a viable treatment for methamphetamine use disorders. Other agonist type medications with different pharmacological effects (e.g., DA reuptake inhibition) may demonstrate better efficacy for managing methamphetamine use disorders (34). That is, dopamine transport blockers (e.g., methylphenidate and bupropion) may have improved efficacy for amphetamine use disorders compared to dopamine releasers (e.g., d-amphetamine and methamphetamine) (reviewed in: 34, 35). Conversely, dopamine releasers (e.g., d-amphetamine and methamphetamine) have improved efficacy for cocaine abuse compared to dopamine transport blockers (reviewed in: 5–7, 34). d-Amphetamine maintenance reduced cocaine subject-rated drug-effects and self-administration in human laboratory studies and has reduced cocaine use in clinical trials (11, 36–39). Although their pharmacological and behavioral effects overlap significantly, unique pharmacological approaches may be needed for amphetamine and cocaine use disorders.