Tancer M, Johanson C-E (2003) Reinforcing, subjective and physiological effects of MDMA in humans; A comparison with d-amphetamine and mCPP. Drug and Alcohol Dependence 72: 33-44.
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Purpose: Psychological, neuropsychological, neuroendocrine; to compare MDMA, mCPP (serotonin releaser and 5HT2C agonist), and d-amphetamine (dopamine and norepinephrine releaser) on subjective, reinforcing (rewarding) and physiological effects in Ecstasy users.

Design: Randomized, placebo-controlled, double-blind within-subjects experimental design, with drug type (placebo, MDMA, d-amphetamine and mCPP) and drug dose (1 or 2 mg/kg MDMA, 10 or 20 mg d-amphetamine, and 0.5 or 0.75 mg/kg mCPP) serving as within-subject factors. All subjects were enrolled in all conditions and underwent assessment of subjective, physiological, neuroendocrine and rewarding drug effects for each condition.

Subjects: 12 Ecstasy-experienced volunteers (6 men, 6 women, average age 22.3 years (range = 18-31, 10 White, 2 Asian American, 1 Native American) presumably residing in the Detroit (Mich.) area. No information provided on subject recruiting procedures.

Criteria for Inclusion Healthy, ages 18-35 with no major physical or mental disorders, no diagnosis of substance dependence except for nicotine, not pregnant or lactating, having reported at least 6 experiences with stimulants, including 3 or more experiences with Ecstasy, and no more than 50 experiences with stimulants, PCP, opiates or sedatives. Absence of all psychoactive use (including alcohol) on the study day, with abstinence verified through urinary and breath analysis (for ethanol) prior to participation in each session.

Measures: Mood and Alterations in Consciousness Assessed via short version (40 rather than 550 items) of the Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), Hallucinogen Rating Scale (HRS), and visual analog scales (VAS) for alert, anxious, bad drug effect, Confusion, Down, Friendly, Good Drug Effect, High, Hungry, Irritable, Liking, Miserable, On Edge, Sedated, Self-Conscious, Social, Stimulated, Talkative, Tired). Subjects completed nearly all measures (except HRS) immediately prior to drug administration, and all measures for 5 h post-drug,.

Physiological Effects Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and body temperature (BT) were all assessed hourly after drug administration.

Salivary Cortisol Measured via radioimmunoassay applied to saliva collected 15 min pre-drug and hourly post-drug.

Reinforcing Effects Reinforcing (rewarding) drug effects were measured at the end of each session via Multiple Choice Procedure (MCP). Participants made 20 independent choices between the drug they received on a session and either giving up or receiving money, with each choice assigned a numerical value (i.e. 1 to 20 for session 1). Reinforcing drug value was defined as the money amount (negative or positive) where the participant switched from receiving drug to either receiving or giving up money, also called crossover value. [Choices had consequences, as each participant awarded one of his or her choices by blind lottery at the end of the study, either a selected study drug, giving up or receiving money.]

Drug Identification Subjects asked to guess identity of drug administered via an end-of-session questionnaire, with possible identities being stimulant, sedative, empathogen [entactogen, MDMA-like drug], hallucinogen or placebo.

Analyses: Repeated measures 2-way analysis of variance (ANOVA) was used to examine differences in physiological effects, cortisol assay, and nearly all subjective effects (ARCI, HRS, POMS, and VAS). Session served as one repeated measure (placebo, 1 mg/kg MDMA, 2 mg/kg MDMA, 10 mg d-amphetamine, 20 mg d-amphetamine, 0.5 mg/kg mCPP, and 0.75 mg/kg mCPP) and time of measurement as another repeated measure (1, 2, 3, 4 or 5 h post-drug), with p. set at 0.05. Significant drug x time effects were further tested with 3 post-hoc simple effects tests comparing the higher dose of each test drug (e.g. 2 mg/kg MDMA, 20 mg d-amphetamine and 0.75 mg/kg mCPP) with placebo at time of peak (most different from placebo) effect.

Reinforcing Effects, Drug Liking A one-way analysis of variance (ANOVA) was used to examine MCP and end of session drug liking, with session (placebo, 1 mg/kg MDMA, 2 mg/kg MDMA, 10 mg d-amphetamine, 20 mg d-amphetamine, 0.5 mg/kg mCPP, and 0.75 mCPP) serving as a factor. Details of significance not provided, but p. apparently set at 0.05. Significant effects were tested post-hoc if conditions differed from each other.

Relationship between Drug Liking and Reinforcing Effects Binomial correlations were performed on end of session drug liking and MCP crossover value for each session to establish whether reinforcing drug effects were associated with self-reported drug liking.

Drug Identification No statistical analyses were applied to examine the drug identification measure.

Results: Mood and Alterations in Consciousness (Comparisons apparently not made between lower and higher doses of each drug, or at least these were not presented). ARCI MDMA increased Amphetamine, BG (energy), MBG (euphoria), and LSD (dysphoria) scores, and decreased PCAG (sedation) scores. MDMA effects on Amphetamine score were higher than d-amphetamine, and peaked earlier (Hour 2 for MDMA, Hour 3 for d-amphetamine or mCPP. MDMA and d-amphetamine both increased BG and decreased PCAG scores, though peak MDMA effects appeared an hour earlier in both cases. Only MDMA (and not d-amphetamine or mCPP) increased MBG scores, with peak increase at Hour 2. Both MDMA and mCPP (but not d-amphetamine) increased LSD scores, with peak increase from both drugs at Hour 1. Only mCPP significantly decreased BG scores and increased PCAG scores. POMS MDMA increased scores on Positive Mood, Elation, Confusion and Anxiety, with the two negative mood items (anxiety, confusion) peaking at Hour 1 and the two positive items (elation, positive mood) peaking at Hour 2. d-amphetamine increased Elation only, with peak at Hour 3, and mCPP increased anxiety and confusion, and decreased Elation and Positive mood, peak values at Hour 1. MDMA produced increases in Anxiety and Confusion similar to mCPP effects, and MDMA produced higher Elation scores than d-amphetamine. HRS MDMA increased scores on 5 of 6 HRS scales (Affect, Cognition, Intensity, Perception and Soma [somatic effects]). mCPP had the same profile as MDMA, whereas d-amphetamine increased only Affect, Cognition, Intensity and Soma scores. MDMA produced the greatest changes in HRS scores and d-amphetamine the smallest, with mCPP in the middle, except in the case of Cognition, wherein MDMA and mCPP effects were similar in magnitude. MDMA produced peak changes in all significantly higher HRS scores at Hour 1, most mCPP peak changes occurred at Hour 1 (Affect peak at Hour 2), and d-amphetamine peak changes, except for Affect occurred at Hour 2, (peak change in Affect was at Hour 3). VAS All three drugs increased Friendly, Good Drug Effect, Liking, Stimulated and Talkative, and decreased Hungry. MDMA and d-amphetamine increased Social, and MDMA and mCPP increased High. MDMA effects on these VAS scores were greater than either mCPP or d-amphetamine. MDMA peak changes in Good Drug Effect, Liking, Social and Talkative appeared at Hour 2, peak changes in High and Stimulated appeared at Hour 1, peak increase in Friendly appeared at Hour 3 and peak decrease in Hungry appeared at Hour 4. Peak VAS changes occurred at similar times for MDMA and mCPP, except that peak mCPP Liking scores were at Hour 3 instead of 2. Some peak changes in VAS produced by d-amphetamine occurred at the same time as MDMA (decreased Hunger at Hour 4, Friendly at Hour 3), but most d-amphetamine peak changes occurred later (Liking, Social, Stimulated, Talkative all at Hour 3 instead of Hours 2 or 1). End of Session Liking Both doses of MDMA were liked more than placebo, as was the higher dose of d-amphetamine (20 mg) and the lower dose of mCPP (0.5 mg/kg). 10 mg d-amphetamine and 0.75 mg/kg mCPP were not liked more than placebo. 2 mg/kg MDMA was liked more than 20 mg d-amphetamine.

Physiological Effects - 2 mg/kg MDMA, 20 mg d-amphetamine and 0.75 mg/kg mCPP all increased SBP and DBP over placebo values, with greatest changes produced by MDMA, followed by d-amphetamine, and the smallest change produced by mCPP. Only MDMA and d-amphetamine significantly increased HR above placebo levels, with MDMA effects greater than d-amphetamine (increase of 20 versus 10 BPM). d-amphetamine produced the greatest changes in BT, with lesser increases produced by MDMA and mCPP. Peak increase in SBP, DBP and HR after MDMA occurred at Hour 1, and peak increase in BT occurred at Hour 2. By contrast, peak changes in SBP after d-amphetamine occurred at Hour 3, peak change in DBP at Hour 1, peak change in HR at Hour 3 and peak change in BT at Hour 4. Peak changes in SBP and DBP after mCPP also appeared at Hour 1 (as with MDMA), but peak change in BT appeared at Hour 4; no peak change in HR occurred after mCPP.

Salivary Cortisol 2 mg/kg MDMA and 0.75 mg/kg mCPP increased cortisol above placebo levels at 3 (MDMA) and 2 (mCPP) h post-drug, with MDMA increases in salivary cortisol higher than increases after mCPP. Neither dose of d-amphetamine increased salivary cortisol at any point in time.

Reinforcing Effects 2 mg/kg MDMA and 20 mg d-amphetamine had higher crossover values than placebo, indicating greater rewarding effects. Apparently 1 mg/kg MDMA, 10 mg d-amphetamine, and both 0.5 and 0.75 mg/kg mCPP failed to produce crossover effects that were significantly higher than placebo. [Chart presentation indicates that 1 mg/kg MDMA and 10 mg d-amphetamine had higher crossover values than 0.75 mg/kg mCPP, but this is not significant. Likewise, the crossover value for 2 mg/kg MDMA was higher, but not significantly higher, than the value for 20 mg d-amphetamine.]

Drug Liking and Reinforcing Effects There was a significant (and apparently positive) relationship between MCP crossover value and end-of-session Drug Liking for both 0.5 and 0.75 mg/kg mCPP. There were no significant correlations between end-of-session Drug Liking and crossover values for either dose of d-amphetamine or MDMA.

Drug Identification 9 of 12 subjects correctly identified placebo. 5 of 12 identified d-amphetamine as a stimulant (not specifying reference doses), whereas 3 to 5 identified d-amphetamine as placebo and 1-2 identified it as an empathogen (MDMA-like drug). Both doses of MDMA and mCPP were identified as empathogens or hallucinogens by 8 to 10 of 12 people, and labeled as placebo by no more than 1 person.

Overall Effects: The effects of MDMA were compared with those of d-amphetamine, a stimulant and dopaminergic drug, and mCPP, a serotonin releaser and 5HT2C receptor agonist, in 12 Ecstasy-experienced individuals. Comparisons between higher and lower doses of the same test drug were only presented on occasion, with most comparisons described being between the higher doses of the 3 test drugs. 2 mg/kg MDMA increased positive mood (such as POMS Elation, ARCI MBG, VAS Friendly and Social), but also increased negative mood (ARCI LSD score, POMS Anxiety, Confusion). Changes in negative mood tended to peak an hour earlier than changes in positive mood (Hour 1 versus Hour 2 or 3). MDMA and d-amphetamine both increased positive mood and elation, whereas MDMA and mCPP both increased negative mood (such as anxiety and dysphoria). Both MDMA and mCPP increased scores on 5 of the 6 HRS scales, and d-amphetamine increased scores on 4 scales (it did not increase Perception scores). With the exception of HRS Cognition scores, MDMA produced the greatest increases in HRS scores, and d-amphetamine the smallest changes. All three drugs increased some VAS scores (such as Good Drug Effect, Liking, and Stimulated), and all three drugs decreased Hungry. MDMA and d-amphetamine increased Social, and MDMA and mCPP increased "high." Peak changes in mood and alteration in consciousness tended to occur later after d-amphetamine than after MDMA or mCPP. MDMA produced a peak increase in Stimulated and High at Hour 1, whereas peak increase in most positive mood changes at Hour 2 or 3, and peak reduction in hunger was at Hour 4. All 3 drugs significantly elevated SBP and DBP, but only MDMA and d-amphetamine significantly elevated HR. Though all 3 drugs elevated BT, only d-amphetamine significantly elevated BT above placebo. Peak changes in physiological MDMA effects occurred at Hour 1 for all but BT, where peak change occurred at Hour 2. Physiological effects of MDMA and mCPP followed a similar time course, (except peak change in BT at Hour 4). In contrast, MDMA did not share a similar time course of effects with d-amphetamine. In most cases, d-amphetamine peak changes occurred later than those seen after MDMA. 2 mg/kg MDMA and 0.75 mg/kg mCPP both significantly elevated salivary cortisol, whereas d-amphetamine did not. Peak changes in cortisol after MDMA occurred at Hour 3, and peak cortisol changes after mCPP occurred at Hour 2. Both doses of MDMA were liked more than placebo when measured at end of session. Subjects considered 2 mg/kg MDMA and 20 mg d-amphetamine significantly worth more than placebo, at least when worth was defined as the amount of money they were willing to receive or give up in lieu of the drug. Subjects did not consider 1 mg/kg MDMA, 10 mg d-amphetamine, and both 0.5 and 0.75 mg/kg mCPP significantly more valuable than placebo. End of session drug liking was not correlated with the apparent worth of MDMA, or any of the other drugs tested. MDMA was consistently identified as an empathogen [entactogen, MDMA-like drug] or hallucinogen. It is notable that mCPP was also identified in the same manner. By contrast, only 5 of 12 subjects correctly identified amphetamine as a stimulant, and 2 people identified amphetamine as an empathogen.

Adverse Effects: None specifically listed in this paper. However, MDMA increased ARCI LSD (dysphoria) score, POMS Anxiety and Confusion scores, and decreased VAS Hungry scores. Elevation in blood pressure and heart rate was not above the normal range.

Comments: This is the first report that directly compared the subjective and physiological effects of MDMA with the effects of a psychostimulant and a serotonin releaser. The study is notable for examining temporal (time-related) aspects of drug effects as well as cross-drug comparisons. Findings indicated that increased negative feelings and sympathomimetic effects (elevated blood pressure and heart rate) peak during the first hour after drug administration. This may mean that monitoring for these acute effects is most important during this time period. Interestingly, most peak changes in positive mood occurred 2 hours post-drug, an hour after the initial peak in physiological effects and negative mood states. This is the second of two reports by the same co-authors (see Tancer and Johanson 2001), with the current paper presenting full within-subjects comparison of drug effects. This is the first published report that assessed MDMA effects with the HRS, a measure originally designed to assess effects of psychedelic drugs, such as DMT or psilocybin. It is thus surprising that two of 3 drugs (MDMA and mCPP), neither considered psychedelic, increased scores on 5 of 6 HRS scales. These findings suggest that the factors assessed by the HRS are not uniquely associated with psychedelics. While it is notable that participants reported feeling friendly and social after MDMA, participants also reported experiencing these markers of entactogenic effects after mCPP (friendly) and d-amphetamine (friendly, social). Finding that subjects assign high worth to MDMA is congruent with findings from case reports and retrospective studies of MDMA-associated abuse liability (Cottler et al. 2001; Jansen 1995; Topp et al. 1999; Von Sydow et al. 2002). However, it should be remembered that subjects were selected specifically for their past use of Ecstasy and minimal use of other drugs, so it is perhaps not surprising that most subjects considered MDMA to be rewarding.

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