This double blind, placebo-controlled study evaluated subjective effects for 29 h and physiological effects for 167 h after 1.0 and 1.6 mg/kg oral MDMA administration in eight healthy men and women with prior MDMA experience. Doses were chosen to reflect typical recreational doses taken in the community; all but one participant identified both doses as active MDMA.
MDMA produced dose-dependent increases in heart rate and blood pressure, similar to those previously reported 8, 22, 23
. Peak effects occurred within the first 1 – 2 h after drug administration, with no delayed or secondary peaks (). These effects are presumably due to MDMA’s activation of the sympathetic nervous system 24
. No acute cardiotoxic effects were observed in this controlled laboratory setting, similar to previous reports 5, 6, 18, 25
This finding cannot necessarily be generalized to the community setting. Participants were rigorously screened to meet stringent medical eligibility criteria. MDMA could have more pronounced effects in individuals with compromised health, genetic predisposition, or other unknown vulnerability factors. This study administered pure MDMA alone. In the community, MDMA is of unknown purity and may be taken with other substances. In this study, subjects were seated calmly in a cool room and kept well hydrated throughout the period of MDMA administration. It is likely that vigorous exercise, high ambient temperatures, and dehydration, such as often occur at raves 26
, are contributory factors in any acute cardiotoxic response experienced after recreational MDMA use.
Hyperthermia has been observed in hospital admissions following recreational MDMA ingestion 24, 27–29
. In the present study, MDMA had no significant effect on tympanic temperature; temperatures were always ≤ 38.2°C and individual increases never exceeded 1.9°C. In prior studies, comparable doses produced significant increases in mean oral or core body temperature of ≤ 0.6°C in the first 4 h after dosing 8, 25, 30
. One study noted that temperatures never exceeded 38°C 11
. Different sites of measurement or different ambient temperatures could partially explain differences between studies. A higher ambient temperature of 30°C was associated with greater temperature response to controlled MDMA administration 30
. Research participants do not experience the increased motor activity experienced by many recreational users. In addition, inadequate hydration is not an issue in a laboratory setting. These findings point to the effects of high environmental temperature, decreased fluid intake, increased physical activity, and/or co-ingestion of other illicit and licit substances, often experienced by recreational users at dance clubs and raves, as possible factors in MDMA-associated hyperthermia. Another possibility is that MDMA does not directly cause hyperthermia, but re-regulates the hypothalamus, responsible for intrinsic temperature control 31
, to prevent heat dissipation and maintenance of temperature when challenged by external factors.
Mydriasis was observed in the current study, with pupil diameter increases of up to 4 mm. Dilated pupils can negatively affect driving ability in daylight 32
by increasing glare sensitivity and decreasing contrast sensitivity, and at night, when, despite improved light sensitivity, headlight glare can be distracting. When these deficits are combined with MDMA’s subjective effects, including mind racing and high, it is likely that driving skills could be further impaired. Pupil size is routinely evaluated by drug recognition experts (DRE), including police officers specially trained in recognizing signs and symptoms of drugs in drivers. Our data support increased pupil size as a marker for ingestion of MDMA 33
Ability to concentrate was the only subjective variable not affected by MDMA in this study. The literature presents mixed results on the effects of MDMA on concentration that may be due to differences in dosing environment, prior illicit drug use, or method of assessment. Our finding of no effect using VAS is consistent with other VAS results noted after 75 and 125 mg MDMA 10
. However, studies using the Subjective Drug Effects Questionnaire 7
, List of Complaints 6
, and Vegetative Lability Scale 25
reported impaired concentration following MDMA doses of 1.5 – 1.7 mg/kg. Two studies that observed significant responses included subjects with limited or no experience with recreational drugs 6, 25
, while the current and previous studies administering VAS included experienced illicit drug users 10
. It is possible that, compared to past self-administered illicit drug experiences, the laboratory setting produced less of an effect on concentration.
The stimulatory effect of MDMA (increased energy level and mind racing) is consistent with previous studies administering 1.1 – 2.1 mg/kg MDMA 10, 11, 22, 23, 34–36
. Although the current study was the first to explicitly measure mind racing, this parameter previously was reported by a single subject as an undesirable side effect of use 3
. Subjective high also is consistent with other investigations after 0.9 – 2.1 mg/kg MDMA 7, 10, 22, 23, 34–36
; a lower dose (0.5 mg/kg) did not produce a significant high 7
The increased feeling of closeness to others observed in this study is consistent with the putative entactogenic effect of MDMA. In contrast, a previous investigation found no significant change in this variable (also assessed with VAS) after 0.5 and 1.5 mg/kg, although there was a trend toward significance after the higher dose 7
. Participants’ comfort in the dosing environment and familiarity with research staff could contribute to this difference.
The predominantly positive subjective effects of MDMA observed in this study are consistent with its appeal to recreational users. Prolonged effects of high, heightened senses, and feelings of closeness to others presumably contribute to MDMA’s abuse potential. Motivation for treatment may be hindered by the relatively few immediately undesirable sequelae 25
MDMA’s psychoactive effects had a longer duration than its physiological effects. This is consistent with the longer elimination half-life of R
, thought to be responsible for its subjective effects, as compared to S
-MDMA, which reportedly is more amphetamine-like 37
and, therefore, likely the cause of the physiological effects.
Dose also influenced duration of effects. Some physiological () and subjective () parameters returned to pre-dose levels earlier after the low dose than after the high (Table 1). Further support for the influence of dose comes from participants’ responses regarding the duration of their MDMA experience. More than 75% of participants reported that effects lasted longer after the high dose, even in situations where they reported both the 1.0 and 1.6 mg/kg doses as high doses.
Although MDMA plasma concentrations were significantly correlated with heart rate, SBP, DBP, temperature, energy level, feelings of closeness to others, mind racing, heightened senses, and high, correlation coefficients were low and clinically insignificant, eliminating the ability to predict effects from single plasma concentrations.
This study has several strengths compared to previously published human experimental studies of MDMA administration. First, our protocol included African-American and female participants, groups not well represented in prior studies. Although the sample sizes were not large enough to allow subgroup analyses, their inclusion does improve the external validity (generalizability) of the study. Second, all participants were abstinent from MDMA and other psychoactive substances for at least 12 hours prior to dosing, ensuring that there were no residual drug effects during study sessions. Many prior studies either did not report abstinence status of subjects or relied on self-report. Third, all subjects were required to have a positive biological test documenting MDMA use prior to inclusion. Fourth, data collection continued for 29 h (subjective effects) and 167 h (physiological effects) after dosing, allowing evaluation for possible delayed or secondary effects. Finally, dosing sessions occurred with subjects in a calm, quiet environment with controlled ambient temperature and limits on motor activity, permitting determination of MDMA’s influence alone on sympathomimetic and hyperthermic effects. Although previous studies have included some of these design features, this study incorporated all of these features to provide maximum scientific rigor.
In conclusion, this placebo-controlled, double-blind human laboratory study found that oral MDMA, when administered in typical recreational doses (1.0 and 1.6 mg/kg) to experienced MDMA users free of acute MDMA or other drug effects (due to ≥ 12 h abstinence), produced dose-dependent increases in heart rate and systolic and diastolic blood pressure and subjective responses of high, heightened senses, and mind racing. All effects resolved within 4–6 hours, with no delayed or secondary peaks. There were no significant effects on tympanic temperature, respiratory rate, or blood oxygenation. These findings suggest that oral MDMA produces short-term effects on cardiovascular function and psychological state, but that its temperature effects may depend on environmental and subject factors such as ambient temperature and levels of hydration and motor activity. This rigorous characterization of the physiological and subjective responses to MDMA provides data on possible mechanisms involved in its toxicity and reasons for abuse, and may contribute to drug abuse prevention and treatment efforts.