Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2 h apart.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most abused recreational drugs. Its usual pattern of misuse includes repeated doses taken over a short time period that could influence MDMA pharmacology and toxicity. OBJECTIVE: This study aims to evaluate the pharmacokinetics and pharmacologically induced effects of two MDMA consecutive doses separated by 2 h. METHODS: A randomized, double-blind, crossover, and placebo-controlled trial included ten male volunteers participating in two experimental sessions. MDMA was administered as a single 100-mg dose or as a repeated dose (50 mg followed by 100 mg, administered at 2 h apart). Outcome variables included pharmacokinetics, physiological, subjective, and psychomotor effects. RESULTS: Following the repeated doses, plasma concentrations of MDMA were higher than those expected by simple dose accumulation (+16.2 % AUC; +12.8 % C (max)), but those of HMMA and HMA were significantly lower (-29.8 % AUC; -38.2 % C (max)). After the second dose, physiological effects, psychomotor performance, and subjective effects were lower than expected especially for euphoria and stimulation. MDMA-induced increases in diastolic and systolic arterial pressure and body temperature were in the range of those expected following MDMA concentrations. CONCLUSIONS: MDMA pharmacokinetics and metabolic disposition following two doses separated by 2 h show that the contribution of the first dose to the MDMA-induced mechanism-based metabolic inhibition was already apparent. The concentrations of MDMA after the second dose were slightly higher than expected. The effects on blood pressure and temperature after the second administration were slightly higher than those following the first, but for heart rate and subjective variables these were lower than expected considering the MDMA concentrations achieved, suggesting a possible tolerance phenomenon.

Study of paracetamol 1-g oral solution bioavailability.

The aim of this work was to assess paracetamol bioavailability after administering 1 g in oral solution. Eighteen healthy volunteers were selected for this open-label study. A total of 15.4 ml of Gelocatil Oral Solution (Laboratorios Gelos, S.L.), corresponding to 1 g of paracetamol, were administered to fasting subjects. Blood samples were collected at 0 min, 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h. Paracetamol plasma concentrations were determined by reverse-phase high-performance liquid chromatography. The study was conducted without deviations from protocol. Pharmacokinetic data from 18 subjects were allowed for estimating fast and high-paracetamol bioavailability: t(max) 20 min (10-45) [median (range)], C(max) 24. 3 mg/l (6.5) [mean (standard deviation)], AUC(0-t) 64.0 mg h/l (16.1) and AUC(0-00) 68.1 mg h/l (17.9). These results are comparable to those described for Gelocatil Oral Solution given at a 650 mg dose and for immediate release Gelocatil 650 mg tablets. Absorption speed was very fast, similar to that described for other oral-solution formulations, which provides an immediate onset of pain and fever relief. The results of this study show suitable bioavailability for 1 g Gelocatil Oral Solution, with fast-absorption speed that provides an immediate onset of pain and fever relief.

[Study of the extent and rate of bioavailability of ibuprofen tablets]. / Estudio de la biodisponibilidad en magnitud y en velocidad de comprimidos de ibuprofeno.

The extent and rate of bioavailability of ibuprofen tablets were determined in a crossover clinical trial in 18 healthy subjects of both sexes. The study was approved by the local ethical committee and was authorized by the Spanish Medicines Agency. Volunteers signed an informed consent form and were included in accordance with the standard procedures for this type of study. In two distinct sessions participants received a single 600 mg ibuprofen dose as Gelofeno(®) 600 mg tablets (Laboratorios Gelos S.L.), or as the reference formulation, Neobrufen(®) 600 mg tablets. Ibuprofen concentrations in plasma were determined immediately before (0 h) and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 h after drug administration. The pharmacokinetic parameters were then calculated. In all subjects, Gelofeno(®) 600 mg tablets produced plasma concentrations above the quantification limit between 15 and 30 minutes after administration, and in 9 (50%) of these subjects maximal plasma concentrations were reached at 1 h. The median t(max) was 1.25 h, and the average maximal plasma concentration was 40.7 mg/l. Gelofeno(®) 600 mg tablets were bioequivalent both in extent and in rate of bioavailability compared with the reference drug. The formulation showed good tolerability and no medication-related adverse effects were observed.

Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is increasingly used by young people for its euphoric and empathic effects. MDMA presents non-linear pharmacokinetics, probably by inhibition of cytochrome P450 isoform 2D6. Users are known to often take more than one dose per session. This practice could have serious implications for the toxicity of MDMA. OBJECTIVE: To evaluate the pharmacological effects and pharmacokinetics of MDMA following the administration of two repeated doses of MDMA (24 h apart). METHODS: A randomised, double-blind, cross-over, placebo controlled trial was conducted in nine healthy male subjects. Variables included physiological, psychomotor performance, subjective effects, endocrine response and pharmacokinetics. MDMA 100 mg or placebo was administered in two successive doses separated by an interval of 24 h. RESULTS: MDMA produced the prototypical effects of the drug. Following a second dose, plasma concentrations of MDMA increased (AUC 77% and Cmax 29%) in comparison with the first. The increase is greater than those expected by simple accumulation and indicates metabolic inhibition. The pharmacological effects after the second dose were slightly higher than those observed after the first in the majority of variables including blood pressure, heart rate, most subjective effects and cortisol concentrations. The effects were similar in the case of pupil diameter, esophoria and prolactin. CONCLUSIONS: Pharmacological effects after the second administration were higher than those following the first but lower than expected. A disproportionate increase in plasma concentrations in MDMA and MDA was observed most likely due to metabolic inhibition. This inhibition lasts at least 24 h. Further experiments need to be conducted to evaluate its duration.

Cell-mediated immune response in MDMA users after repeated dose administration: studies in controlled versus noncontrolled settings.

Acute administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") produces time-dependent immune dysfunction in humans. Recreational use of MDMA generally includes repeated drug consumption, often in association with other drugs, such as alcohol and cannabis. In the laboratory setting, repeated MDMA administration to healthy MDMA consumers produced a time-dependent immune dysfunction similar to that observed with the ingestion of a single dose, and the first of the two administrations paralleled the time-course of MDMA-induced cortisol stimulation kinetics and MDMA plasma concentrations. A significant decrease in CD4 T-helper cells with simultaneous increase in natural killer (NK) cell and a decrease in functional responsiveness of lymphocytes to mitogenic stimulation was observed. Response to the second dose was either long-lasting compared with the first dose or disproportionate and did not show any parallelism with cortisol and MDMA plasma concentrations. This circumstance extended the critical period during which immunocompetence is highly impaired as a result of MDMA use. Accumulation of MDMA in the body of a poor metabolizer induced higher immunomodulatory effects with statistically significant differences in NK cell function compared with extensive metabolizers. When basal values of lymphocyte subsets were examined in a population of recreational MDMA users participating in different clinical trials, alterations in several immunological parameters were observed. The absolute number of lymphocytes, in particular T lymphocytes and CD4 T-helper cell subsets, showed a trend toward reduced values, although cell counts were within normal limits. By contrast, NK cells in MDMA consumers were reduced to one-third of those from healthy persons. A statistically significant decrease in affected immune parameters was recorded during a 2-year observation period in a subgroup of recreational MDMA users. These permanent alterations in immunologic homeostasis may result in impairment of general health and subsequent increased susceptibility to infection and immune-related disorders.

Effects of repeated doses of MDMA ("ecstasy") on cell-mediated immune response in humans.

Cell-mediated immune response after the administration of two repeated doses of 100 mg 3,4-methylenedioxymethamphetamine (MDMA) at 4-hour and 24-hour intervals was evaluated in two randomised, double-blind and cross-over clinical trials conducted in healthy male MDMA consumers. MDMA produced a time-dependent decrease in the CD4/CD8 T-cell ratio due to a decrease in the number of CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, and a simultaneous increase in natural killer cells. In case of two 100 mg MDMA doses given 4 hour apart, immune alterations produced by the first dose were strengthened by the second one. At 24 hours after treatment, statistically significant residual effects were observed for all the altered immune parameters after the administration of two MDMA doses if compared to single dose and placebo. In the second clinical trial, the second 100 mg MDMA dose given 24 hours after the first dose produced immunological changes significantly greater than those induced by the initial drug administration and which seemed to show a delayed onset. Significant residual effects were observed for all the immune parameters as late as 48 hours after the second dose. These results show that repeated administration of MDMA with both a short and a long time interval between doses extends the critical period following MDMA administration, already observed after a single dose, in which immunocompetence is severely compromised.

Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males.

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

BACKGROUND: Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. METHODS: Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. RESULTS: MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). CONCLUSIONS: Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans.

There is evidence that some heavy users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) show signs of neurotoxicity (a cognitive dysfunction, a larger incidence of psychopathology). It has been postulated that the catechol intermediates of methylenedioxyamphetamines such as 3,4-dihydroxymethamphetamine (HHMA), a metabolite of MDMA, may play a role in their neurotoxicity by formation of thioether adducts. This study describes the first validated method for HHMA determination in plasma and urine by strong cation-exchange solid-phase extraction high-performance liquid chromatography/electrochemical detection (HPLC/ED) analysis. The method has been applied for the determination of HHMA in plasma and urine samples from a clinical study in healthy volunteers of MDMA and provides preliminary kinetic data on this metabolite. HHMA appeared to be a major MDMA metabolite with plasma concentrations as high as the parent compound. Thus, HHMA C(max) (154.5 microg/L) and AUC(0-24h)(1990.9 microg/L h) were similar to those obtained in previously published reports for MDMA (181.6 microg/L and 1465.9 microg/L h, respectively). The 24-h urinary recovery of HHMA accounted for 17.7% of the MDMA dose administered and increases the total 24 h recovery of MDMA and metabolites to 58% of the 100 mg dose administered. The determination of HHMA in plasma and urine samples is of interest in order to establish its relevance in MDMA metabolism and its possible contribution to MDMA neurotoxicity in humans. Its validation showed appropriate accuracy and precision for its use in pharmacokinetic studies.

Sweat testing of MDMA with the Drugwipe analytical device: a controlled study with two volunteers.

Rapid on-site tests for the analysis of drugs of abuse in unconventional specimens (e.g., sweat) have recently been developed. Two healthy volunteers familiar with the effects of methylenedioxymethamphetamine (MDMA) were given 100 mg of the drug as a single oral dose. MDMA and its main metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) were determined in plasma and urine by gas chromatography-mass spectrometry (GC-MS). MDMA was also investigated in sweat with the Drugwipe (an immunochemical strip test). Subjects' armpits were swabbed for 10 s at 0 time (predose) and at 2, 6, 8, 12, and 24 h after MDMA administration. MDMA consumption could be detected using Drugwipe at 2 h and for as long as 12 h after drug administration. However, in one of the volunteers, a faint color change appeared at 0 time, when plasma and urine tested negative for MDMA and did not disappear even 48 h later. Plasma concentrations of MDMA and HMMA measured by GC-MS peaked at 2-4 h, and values greater than 20 ng/mL for MDMA and of 40 ng/mL for HMMA were still detected at 24 h. Urine tested positive by GC-MS for MDMA and HMMA in the 48-h collection period. These findings preliminarily support sweat testing with Drugwipe for monitoring MDMA use.

Acute effects of 3,4-methylenedioxymethamphetamine alone and in combination with ethanol on the immune system in humans.

Cell-mediated immune response and release of cytokines after the administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") alone and in combination with ethanol were assessed in a double blind, randomized, crossover, controlled clinical trial. Six healthy male recreational users of MDMA participated in four different experimental sessions, with a washout interval between sessions of 1 week, in which single oral doses of MDMA (100 mg), ethanol (0.8 g/kg), the combination of both drugs, and placebo were tested. Acute MDMA administration produced a time-dependent immune dysfunction in association with serum concentrations of the drug as well as cortisol stimulation kinetics. Although total leukocyte count remained unchanged, there was a decrease in the CD4 T/CD8 T-cell ratio due to a decrease in both the percentage and absolute number of CD4 T-helper cells and simultaneous increase in natural killer (NK) cells. Ethanol consumption produced a decrease in T-helper cells and B lymphocytes. The combination of MDMA and ethanol caused the highest suppressive effect on CD4 T cells and increasing effect in NK cells. Drugs treatment produced a high increase of immunosuppressive cytokines (transforming growth factor-beta and interleukin-10) and a switch from Th1-type cytokines (interleukin-2 and interferon-gamma) to Th2-type cytokines (interleukin-4 and interleukin-10). Disregulation in the production of pro- and anti-inflammatory cytokines with an unbalance toward anti-inflammatory response was also observed. The immune function shows a trend toward baseline levels at 24 h after MDMA kinetics. This transient defect in immunological homeostasis, if temporarily repeated, might alter the immune response with a risk for the general health status.

[Immunomodulator properties of ecstasy (MDMA)]. / Proprietà immunomodulanti dell'ecstasy (MDMA).

In vitro exposure to ecstasy (3,4-methylenedioxymethamphetamine, MDMA) alters some immune parameters such as T-cell regulatory function, cytotoxic T-lymphocyte activity, natural killer cell activity and macrophage function. Administration of MDMA in rats produces a suppression of lympho-proliferation response and a decrease in circulating lymphocytes, accompanied by an increase in plasma corticosterone. It was postulated a direct action of MDMA on lymphocytes or rather an indirect action mediated by the hypothalamic pituitary adrenal axis (HPA-AXIS) and/or the sympathetic nervous system (SNS). Acute MDMA treatment effected on healthy-volunteers produces an immune dysfunction associated with pharmaceutical characteristics and so with MDMA plasma concentrations. There is a decrease in CD4+ T-cells and functional responsiveness of lymphocytes, while percentage of natural killer cells increases. A contemporary rise of cortisol plasma concentrations supports the hypothesis of MDMA-induced release of corticotrophin-releasing factor from the hypothalamus and subsequent HPA-axis and SNS activation.

Immunomodulating activity of MDMA.

MDMA (3,4-methylenedioxymethamphetamine) use can cause neurochemical, behavioral and endocrine alterations, similar to those produced by exposure to acute stress, suggesting its potential as a "chemical stressor." It is known that stressful stimuli can produce a depression of immune function and an alteration in immune cells distribution. In vitro exposure to MDMA resulted in a modulation of several immune functional parameters such as T-cell regulatory function, cytotoxic T-lymphocyte activity, natural killer cell activity and macrophage function. Administration of MDMA in rats produced a rapid and sustained suppression of induced lymphocytes proliferation and a significant decrease in circulating lymphocytes. These alterations in rat immune function were accompanied by a significant rapid increase in plasma corticosterone concentrations. It was postulated that the result of altered induced proliferation response of lymphocytes could have been due to a combined effect of direct action of MDMA on lymphocytes and to the activation of the hypothalamic pituitary adrenal axis (HPA axis) and/or the sympathetic nervous system (SNS) via central mechanisms. In humans, acute MDMA treatment produced a time-dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in CD4+ T-cells and functional responsiveness of lymphocytes to mitogenic stimulation, while percentage of natural killer cells significantly increased. A rise of cortisol plasma concentrations similar to that observed in the rat model supported the hypothesis of MDMA-induced release of corticotrophin-releasing factor from the median eminence of the hypothalamus and subsequent HPA axis and SNS activation. The present findings indicate that MDMA ingestion may represent a potential health hazard for an increased risk of immune system-related diseases.

Pharmacology of MDMA in humans.

MDMA given at recreational doses (range tested 50 to 150 mg) to healthy volunteers, produced mydriasis and marked increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. MDMA induced changes on oral temperature. The time course of this observation was biphasic, as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed. MDMA induced a slight dose-dependent impairment on psychomotor performance. MDMA produced a marked rise in plasma cortisol and prolactin concentrations. The elimination half-life of MDMA was about 8-9 h. Drug concentrations increased, and a parallel increase in physiologic and hormonal measures was observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4-6 h after drug administration.

Human pharmacology of 3,4-methylenedioxymethamphetamine ("ecstasy"): psychomotor performance and subjective effects.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug of increasing use among youth because of its apparent entactogenic properties, such as euphoria, friendliness, closeness, and empathy. However, experimental studies have shown MDMA to be neurotoxic. Data on pharmacologic actions of MDMA in humans are limited. The authors conducted a randomized, double-blind, crossover, controlled trial to assess psychomotor performance and subjective effects in eight healthy male volunteers. MDMA was given in the same range of doses used for recreational purposes (75 and 125 mg). Amphetamine (40 mg) and placebo were used as reference compounds. For the digit-symbol substitution test (DSST), MDMA-125 produced a mild decrease in responses, and amphetamine produced a mild improvement. For the Maddox wing device, MDMA-125 induced esophoria compared with the other drug conditions. MDMA-125 and MDMA-75 produced increases in feelings of euphoria and well-being, as noted by increases in scores on the Addiction Research Center Inventory (ARCI) MBG and A scales, as well as scores of "stimulated," "good effects," "liking," and "high" on the visual analog scales. Amphetamine administration induced similar effects. At the same time, MDMA-125 enhanced sedation- and dysphoria-related effects (ARCI-PCAG and LSD, "confusion," "drunken," and Profile of Mood States Confusion scale). Mild changes in some body perception-related feelings were also reported after MDMA use, but hallucinations or psychoses were not present. In summary, the short-term administration of MDMA produced marked euphoria, a slight impairment in the performance of psychomotor tasks, and mild changes in body perceptions without hallucinations. These data support the abuse liability of MDMA.

Non-linear pharmacokinetics of MDMA ('ecstasy') in humans.

AIMS: 3,4-Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers. METHODS: A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA). RESULTS: As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent. CONCLUSIONS: It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.

Response patterns of the Spanish version of the 49-item short form of the Addiction Research Center Inventory after the use of sedatives, stimulants, and opioids.

This report examines the validity of the Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI) for measuring subjective effects after the use of sedatives, stimulants, and opioids. Data from four clinical trials in which this questionnaire was used have been analyzed. The Spanish ARCI short form was found to be sensitive in measuring subjective effects after the administration of alcohol, triazolam, and flunitrazepam (sedatives), cocaine (stimulants), and morphine, pentazocine, and naloxone (opioids) and to distinguishing among them. The response patterns were similar to those previously reported for the same drugs with the English version of ARCI. It is concluded that Spanish version of the 49-item short form of ARCI is a valid instrument for assessing the subjective effects of psychoactive drugs in the Spanish-speaking population context.

Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans.

The cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were assessed in a double-blind, randomized, crossover, and controlled (placebo and amphetamine) clinical trial. Eight men with experience in the recreational use of MDMA participated in four 10-h experimental sessions with a 1-week washout period. Single oral doses of 125 mg and 75 mg of MDMA, 40 mg of amphetamine, and placebo were given. Both MDMA doses significantly increased blood pressure (increases of 40 mm Hg in systolic blood pressure), heart rate (increases of 30 beats/min), and pupillary diameter (mydriasis) as compared with placebo. Oral temperature did not show significant changes in any drug-active condition. Plasma cortisol levels showed a statistically significant increase after MDMA administration. Prolactin levels only increased after high dose of MDMA. Cmax values for 125-mg and 75-mg MDMA doses were 236.4 and 130.9 ng/ml, and Tmax was observed at 2.4 and 1.8 h, respectively. Elimination half-life was 8.6 h and 7.7 h for high and low MDMA doses, respectively. Amphetamine half-life was 15 h. Between 8 and 9% of the doses of MDMA appeared in plasma in the form of 3,4-methylenedioxyamphetamine. The important cardiovascular effects observed after MDMA administration in laboratory conditions at rest (increases of 40 mm Hg in systolic blood pressure and 30 beats/min in pulse rate) could be relevant in terms of toxicity in real-life conditions (e.g., crowded places and physical activity).

Immunomodulating properties of MDMA alone and in combination with alcohol: a pilot study.

Cell-mediated immune response after the administration of MDMA alone and in combination with alcohol was evaluated in a randomized, double-blind, double-dummy, cross-over pilot clinical trial conducted in four healthy MDMA consumers who received single oral doses of 75 mg MDMA (n = 2) or 100 mg MDMA (n = 2), alcohol (0.8 mg/kg), MDMA and alcohol, or placebo. Acute MDMA treatment produced a time-dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in the CD4 T/CD8 T-cell ratio as well as in the percentage of mature T lymphocytes, probably because of a decrease in both the percentage and absolute number of T helper cells. The decrease in CD4 T-cell counts and in the functional responsiveness of lymphocytes to mitogenic stimulation was dose-dependent. The correlation between MDMA pharmacokinetics and the profile of MDMA-induced immune dysfunction suggests that alteration of the immune system may be mediated by the central nervous system. Alcohol consumption produced a decrease in T helper cells, B lymphocytes, and PHA-induced lymphocyte proliferation. Combined MDMA and alcohol produced the greatest suppressive effect on CD4 T-cell count and PHA-stimulated lymphoproliferation. Immune function was partially restored at 24 hours. These results provide the first evidence that recreational use of MDMA alone or in combination with alcohol alters the immunological status.