The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α2-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α2-adrenergic receptor agonists in the prevention of psychostimulant dependence.
The sympathomimetic amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy; C11H15NO2) releases norepinephrine (NE), serotonin [5-hydroxytryptamine (5-HT)], and dopamine from nerve terminals via their corresponding presynaptic monoamine transporters (Rudnick and Wall, 1992; Rothman et al., 2001; Verrico et al., 2007). The psychotropic and cardiostimulant effects of MDMA in humans seem to depend on the transporter-mediated release of NE and 5-HT. Both the subjective and cardiovascular responses to MDMA can be reduced by blocking the NE or 5-HT transporter by using selective transporter inhibitors (Liechti et al., 2000; Farré et al., 2007; Tancer and Johanson, 2007; Hysek et al., 2011). The release of NE has been shown to critically mediate the effects of psychostimulants (Rothman et al., 2001; Sofuoglu et al., 2009), including MDMA (Hysek et al., 2011; Newton, 2011). However, MDMA-induced increases in extracellular monoamines may also result from impulse-dependent vesicular/exocytotic release or transmitter uptake inhibition (Seiden et al., 1993; Florin et al., 1994; Hondebrink et al., 2011). The vesicular release of NE is under negative feedback control mediated by presynaptic α2-adrenergic receptors (Buccafusco, 1992; Starke, 2001), and α2 receptors are thereby involved in noradrenergic function, including vascular contraction, blood pressure control, body temperature regulation, arousal, and memory (Starke, 2001). Clonidine is an α2-adrenergic receptor agonist and sympatholytic drug that reduces noradrenergic activity by decreasing the impulse-mediated vesicular release of NE (Buccafusco, 1992; Philipp et al., 2002). In healthy subjects, clonidine dose-dependently suppressed plasma levels of NE (Veith et al., 1984), blood pressure (Mitchell et al., 2005), and cardiac output, lowered body temperature (Bexis and Docherty, 2005), and had sedative effects (Hall et al., 2001). These sympatholytic effects of clonidine are opposite to the clinical effects of sympathomimetic drugs, including MDMA. Therefore, clonidine has been recommended in the treatment of MDMA intoxication (Green et al., 1995; Liechti, 2003), and it is routinely used to control sympathetic activation during withdrawal from drugs of abuse.
In rats, clonidine blocked the behavioral response and hippocampal and prefrontal NE release after treatment with cocaine or low doses of amphetamine (Florin et al., 1994; Carey et al., 2008). Clonidine may therefore reduce stimulant-induced NE release and the associated behavioral effects of psychostimulants and may even be used in the treatment of stimulant addiction. In fact, clonidine prevented amphetamine-induced psychomotor stimulation (Vanderschuren et al., 2003), cue-induced cocaine seeking in rats (Smith and Aston-Jones, 2011), and drug craving in cocaine users (Jobes et al., 2011).
The effects of clonidine on the acute response to psychostimulants have not yet been evaluated in humans. In the present study, we assessed the interactive pharmacodynamic effects of clonidine and MDMA in healthy subjects. We expected that clonidine would reduce the effects of MDMA in humans to the extent that the clinical effects of MDMA are mediated by the exocytotic release of NE.
Materials and Methods
We used a double-blind, placebo-controlled, randomized, crossover design with four experiential conditions (placebo-placebo, clonidine-placebo, placebo-MDMA, and clonidine-MDMA) in a balanced order. The washout periods between sessions were 10 to 14 days long. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines on Good Clinical Practice and approved by the Ethics Committee of the Canton of Basel, Switzerland. The use of MDMA in healthy subjects was authorized by the Swiss Federal Office of Public Health, Bern, Switzerland. The study was registered at http://clinicaltrials.gov (NCT01136278).
The subjects completed a screening session, four test sessions, and an end-of-study visit. The test sessions were conducted in a quiet hospital research ward with no more than two research subjects present per session. Before undergoing the test sessions, the subjects were asked about potential health problems. Drug tests and urine tests to determine pregnancy were also performed. An indwelling intravenous catheter was placed in the antecubital vein for blood sampling. Clonidine (150 μg p.o.) or placebo was administered at 8:00 AM. MDMA (125 mg p.o.) or placebo was administered at 9:00 AM. A standardized lunch was served at 12:00 PM, and the subjects were sent home at 3:00 PM. Outcome measures were assessed repeatedly before and after drug administration.
Sixteen healthy subjects (eight men and eight women) with a mean ± S.D. age of 25.4 ± 4.9 years were recruited on the University of Basel campus. The exclusion criteria included the following; 1) age <18 or >45 years, pregnancy determined by a urine test before each test session; 2) body mass index <18.5 kg/m2 or >25 kg/m2; 3) personal or family (first-degree relative) history of psychiatric disorder (determined by the structured clinical interview for Axis I and Axis II disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (Wittchen et al., 1997) supplemented by the SCL-90-R Symptom Checklist (Derogatis et al., 1976; Schmitz et al., 2000), Freiburg Personality Inventory (Fahrenberg et al., 1984), and Trait Scale of the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1970); 4) the regular use of medications; 5) chronic or acute physical illness assessed by physical examination, electrocardiogram, standard hematology, and chemical blood analyses; 6) smoking more than 10 cigarettes per day; 7) a lifetime history of using illicit drugs more than five times, with the exception of cannabis; 8) illicit drug use within the last 2 months; and 9) illicit drug use during the study determined by urine tests conducted before the test sessions by using TRIAGE 8 (Biosite, San Diego, CA). The subjects were asked to abstain from excessive alcohol consumption between test sessions and limit alcohol use to one glass on the day before each test session. All of the subjects were nonsmokers. Twelve subjects had previously used cannabis. Five subjects reported using illicit drugs once, in which one subject had tried lysergic acid diethylamide, ecstasy, and psilocybin, two had tried cocaine and psilocybin, one had tried ecstasy, and one had tried psilocybin. All of the subjects were phenotyped for CYP2D6 activity by using dextromethorphan as the probe drug. Eight extensive, seven intermediate, and one poor CYP2D6 metabolizer were identified in the study. The female subjects were investigated during the follicular phase (days 2–14) of their menstrual cycle when the reactivity to amphetamines is expected to be similar to men (White et al., 2002). All of the subjects provided their written informed consent before participating in the study, and they were paid for their participation.
(±)MDMA hydrochloride (C11H15NO2; Lipomed AG, Arlesheim, Switzerland) was obtained from the Swiss Federal Office of Public Health and prepared as gelatin capsules (100 and 25 mg). Identical placebo (lactose) capsules were prepared. MDMA was administered in a single absolute oral dose of 125 mg, corresponding to a dose of 1.88 ± 0.28 mg/kg body weight. Clonidine tablets (150 μg; Catapresan; Boehringer Ingelheim GmbH, Basel, Switzerland) were encapsulated within opaque gelatin capsules, and identical placebo (lactose) capsules were prepared. Clonidine (150 μg) or placebo was administered 1 h before MDMA (125 mg) or placebo administration. Oral medication administration was supervised by study personnel.
Subjective measures were assessed by using Visual Analog Scales (VAS) (Hysek et al., 2011), the Adjective Mood Rating Scale (AMRS) (Janke and Debus, 1978), the 5-Dimensions of Altered States of Consciousness (5D-ASC) (Dittrich, 1998; Studerus et al., 2010), and the STAI (Spielberger et al., 1970). VAS included any drug effect, good drug effect, bad drug effect, drug liking, drug high, stimulated, tiredness, closeness to others, and open (Farré et al., 2007; Tancer and Johanson, 2007; Kolbrich et al., 2008; Hysek et al., 2011). The VAS were presented as 100-mm horizontal lines marked “not at all” on the left and “extremely” on the right. The VAS for closeness to others and open were bidirectional (± 50 mm). The VAS were administered 1 h before and 0, 0.33, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 5 h after MDMA or placebo administration. The 60-item Likert-type scale short version of the AMRS (Janke and Debus, 1978) was administered 1 h before and 1.25, 2, and 5 h after MDMA or placebo administration. The AMRS contains subscales for activity, inactivation, extroversion and introversion, well being, emotional excitation, anxiety-depression, and dreaminess. The 5D-ASC rating scale measures alterations in mood, perception, experience of self in relation to environment, and thought disorder (Studerus et al., 2010). The 5D-ASC rating scale comprises five subscales or dimensions (Dittrich, 1998) and 11 lower-order scales (Studerus et al., 2010). The 5D-ASC dimension oceanic boundlessness (27 items) measures derealization and depersonalization associated with positive emotional states ranging from heightened mood to euphoric exaltation. The dimension anxious ego dissolution (21 items) summarizes ego disintegration and loss of self-control, two phenomena associated with anxiety. The corresponding lower-order scales included: disembodiment, impaired control of cognition, and anxiety. The dimension visionary restructuralization (18 items) consists of the lower-order scales complex imagery, elementary imagery, audiovisual synaesthesia, and changed meaning of percepts. The dimension auditory alterations (16 items) subsumes auditory (pseudo) hallucinations, and the dimension vigilance reduction (12 items) describes states of drowsiness and impaired alertness and cognitive performance. The global ASC score was determined by adding the oceanic boundlessness, anxious ego dissolution, and visionary restructuralization scores. The 5D-ASC scale was administered 4 h after MDMA or placebo administration. The STAI state-anxiety subscale (Spielberger et al., 1970) was administered 1 h before and 1.25, 2, and 5 h after MDMA or placebo administration.
Physiologic measures were assessed repeatedly 1 h before and 0, 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h after MDMA or placebo administration. Heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured by using an OMRON M7 blood pressure monitor (OMRON Healthcare Europe, Hoofddorp, The Netherlands) in the dominant arm after a resting time of 5 min. Measures were taken twice per time point with an interval of 1 min, and the average was used for analysis. Core (tympanic) temperature was assessed by using a GENIUS 2 ear thermometer (Tyco Healthcare Group, Watertown, NY).
Adverse effects were assessed 1 h before and 3 and 24 h after MDMA or placebo administration by using the List of Complaints (Zerssen, 1976; Hysek et al., 2011). The scale consists of 66 items that yield a total adverse effects score, reliably measuring physical and general discomfort.
Samples of whole blood for the determination of MDMA and 3,4-methylenedioxyamphetamine (MDA; C10H13NO2), the active metabolite of MDMA, were collected 1 h before and 0, 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, and 6 h after MDMA or placebo administration. Blood samples to determine concentrations of NE and epinephrine were taken at 1 h before and 1 and 2 h after MDMA or placebo administration. All blood samples were collected on ice and centrifuged within 10 min at 4°C. The plasma was then stored at −20°C until analysis. The plasma levels of free catecholamines (NE and epinephrine) were determined by high-performance liquid chromatography (HPLC) with an electrochemical detector as described previously (Hysek et al., 2011). The plasma concentrations of MDMA and MDA were determined by using HPLC coupled to tandem mass spectrometry. The analytes were extracted by protein precipitation using methanol (CH4O) that contained 0.1 μg/ml MDMA-d5 (C11H10D5NO2), MDA-d4 (C10H9D4,NO2) (both from Lipomed, Arlesheim, Switzerland), duloxetine-d7 (C18H12D7NOS; Toronto Research Chemicals Inc., North York, ON, Canada), and pholedrine (C10H15NO) (Sigma, Buchs, Switzerland). Chromatographic separation was performed on a Shimadzu HPLC system (Shimadzu, Reinach, Switzerland) that consisted of a HTS PAL autosampler (CTC Analytics, Zwingen, Switzerland), two Shimadzu LC-20 AD pumps controlled by a Shimadzu CBM-20A unit, a Shimadzu CTO-20AD column oven, and a six-port VICI valve (VICI, Schenkon, Switzerland). A Chromolith SpeedROD RP-18e column (50 × 4.6 mm; VWR, Dietikon, Switzerland) was used for the separation of the analytes. Eluent A (0.1% formic acid in water) and eluent B (0.1% formic acid in methanol) were used in the following gradient: 100% A for 0 to 1 min, 20 to 95% B for 1 to 4 min, 95% B for 4 to 5 min, and 100% A for 5 to 6 min. The mobile phases were delivered at a constant flow rate of 0.8 ml/min. The total run time was 6.0 min. The column oven was set at 35°C. The injection volume was 10 μl. Mass spectrometric detection was performed by using a triple quadrupole mass spectrometer (API4000; Applied Biosystems, Rotkreuz, Switzerland) operated in electrospray-ionization positive-ion mode. The samples were quantified by using peak area ratios. The assays were linear in the concentration range of 1 to 1000 ng/ml for MDMA and MDA. The performance of the method was monitored by using quality-control samples at the lower limit of quantification and at two or three concentrations. The interassay accuracy for the quality-control samples ranged from 97.5 to 100% for MDMA and from 95.3 to 103% for MDA. Interassay precision values ranged from 2.8 to 8.0% for MDMA and from 3.8 to 10.5% for MDA.
Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Modeling.
Pharmacokinetics. The data for the plasma concentrations of MDMA and MDA were analyzed by using noncompartmental methods. Maximal plasma concentration (Cmax) and time to Cmax were obtained directly from the concentration-time curves of the observed values. The terminal elimination rate constant (λz) for MDMA was estimated by log-linear regression after semilogarithmic transformation of the data, using the last two to three data points of the terminal linear phase of the concentration-time curve of MDMA. The terminal elimination half-life (t1/2) was calculated by using λz and the equation t1/2 = ln2/λz. The area under the plasma concentration-time curve (0–6 h) was calculated by using the linear trapezoidal rule. Plasma concentrations were determined only up to 6 h after MDMA administration, because the aim of the study was to assess potential changes in plasma levels of MDMA during the time of the pharmacodynamic effects of MDMA. Determining the t1/2 for MDA was not possible, because of its long t1/2, which would require an extended sampling time.
We evaluated the in vivo relationship between the MDMA concentration and the effect of MDMA on mean arterial pressure (MAP) by using a soft-link PK-PD model (Meibohm and Derendorf, 1997). Blood pressure and plasma concentrations were assessed at the same time points. Because we observed clockwise hysteresis in the effect-concentration relationship over time, we used PK-PD data pairs within the ascending part of the individual curves up to the maximal effect (Emax) or Cmax. Our estimation of Emax, which should represent the maximal response portion of the dose-response curve, may already have been affected by acute tolerance. However, Emax values of 100% (scale maximum) or stable high values were reached by most subjects despite possible tolerance. Based on the good brain penetration of MDMA and absence of a time lag, we assumed rapid equilibration between the plasma and central compartment (brain). A sigmoidal dose-response (variable slope) model was fitted to the pooled data of all individuals: E = Emax/(1 + 10(logEC50−Cp) × h) in which E is the observed effect, Cp is the plasma MDMA concentration, EC50 is the plasma concentration at which 50% of the maximal effect is reached, Emax is the maximal effect, and h is the Hill slope. The sigmoidal dose-response model provided the best fit to the data and a better fit than a simple Emax or linear model. Data pooling was used because only a few data pairs were available for each subject. Nonlinear regression was used to obtain parameter estimates.
Values were transformed to differences from baseline. The Emax and AUEC values were determined for repeated measures and compared by one-way General Linear Models repeated-measures analysis of variance (ANOVA) with drug treatment as a factor, using STATISTICA 6.0 software (StatSoft, Tulsa, OK). Tukey post hoc comparisons were performed based on significant main effects of treatment. Additional two-way ANOVAs with the two drug factors, MDMA (MDMA versus placebo) and clonidine (clonidine versus placebo), were used to test for interactive versus additive effects of the two drugs on physiological measures or blood levels of catecholamines. Additional ANOVAs were performed, with drug order as an additional factor, to exclude carryover effects. The criterion for significance was p < 0.05. Mean arterial pressure was calculated from DBP and SBP by using the formula MAP = DBP + (SBP − DBP)/3.
Neuroendocrine and Cardiovascular Effects.
MDMA increased the level of circulating NE, an endocrine marker of sympathetic nervous system activation, and elevated blood pressure and heart rate compared with placebo (Figs. 1a and 2, a and b; Table 1). Clonidine prevented the MDMA-induced increase in plasma NE (Fig. 1a; Table 1). It also attenuated the blood pressure response to MDMA, although reflected only by the AUEC and not Emax (Fig. 2a; Table 1). Clonidine also decreased the level of circulating NE and blood pressure compared with placebo to a similar extent as the reduction in NE and pressure elevations induced by MDMA (Figs. 1a and 2; Table 1). Additional ANOVAs with the two drug factors, MDMA and clonidine, yielded significant main effects of MDMA and clonidine on Emax values of MAP (F1,15 = 106.1 and 18.1, respectively; both p < 0.001) but no MDMA × clonidine interaction (F1,15 = 0.2; p = 0.7), which is consistent with an additive effect of the two drugs. Likewise, the ANOVA of NE levels showed significant main effects of MDMA and clonidine (F1,15 = 41.5 and 34.2, respectively; both p < 0.001) but no MDMA × clonidine interaction (F1,15 = 0.0; p = 1). The circulating levels of epinephrine were not significantly altered by the drugs, and clonidine did not affect the increase in heart rate produced by MDMA (Fig. 2b; Table 1).
Overall, clonidine had no effect on the psychotropic response to MDMA. It did not significantly affect the MDMA-induced increases in VAS ratings of subjective effects or AMRS scores (Figs. 3 and 4; Table 1), although it weakly but nonsignificantly attenuated good drug effect, drug liking, and drug high produced by MDMA (Fig. 3). Clonidine alone increased the VAS score for tiredness and the AMRS score for inactivation compared with placebo (Figs. 3 and 4; Table 1). Clonidine had no effect on the robust changes produced by MDMA on the 5D-ASC rating scale (Fig. 5). Neither clonidine nor MDMA altered the state anxiety scale scores on the STAI (Table 1).
MDMA increased the total adverse effects score on the List of Complaints both 3 and 24 h after administration compared with placebo (Table 1). The adverse effects of clonidine and MDMA were additive (Table 1). Thus, clonidine did not affect the untoward effects of MDMA. The frequently reported adverse effects of MDMA included a lack of appetite (n = 11), restlessness (n = 11), thirst (n = 10), sweating (n = 8), and bruxism (n = 8). Tiredness was typically reported after administration of clonidine-placebo and clonidine-MDMA (n = 11 and 10, respectively). No severe adverse effects were reported.
Pharmacokinetics and PK-PD Relationship.
Clonidine did not affect the plasma concentration-time curves of MDMA or MDA (Fig. 6, a and b; Table 2). The pharmacokinetic parameters of MDMA did not depend on CYP2D6 phenotype. However, the sample was small, and only one subject was a poor metabolizer. Figure 6, c and d shows the effects of MDMA on blood pressure in terms of plasma concentration. The hysteresis loop shows that the MDMA-induced changes in MAP returned to baseline within 6 h when MDMA concentrations were still high (clockwise hysteresis), which is consistent with acute pharmacodynamic tolerance (Fig. 6c). Clonidine reduced the MDMA-induced blood pressure response for all MDMA plasma concentrations, which is reflected by a downward shift in the concentration-pressure effect curve of MDMA (Fig. 6c). This shift was similar to the blood pressure-lowering effect of clonidine alone compared with placebo. Thus, the effects of the drugs were additive. Clonidine did not affect the EC50 value of the concentration-pressure effect curve of MDMA (Fig. 6d).
In the present study, the α2-adrenergic receptor agonist clonidine reduced the elevations in the plasma concentration of NE and increases in blood pressure in response to MDMA. However, clonidine decreased plasma NE levels and blood pressure to a similar extent as the decreases in the response to MDMA when its effects were compared with placebo. Thus, the sympatholytic effects of clonidine and the sympathomimetic effects of MDMA were additive with no interaction between the effects of MDMA and clonidine on the noradrenergic system. In addition, clonidine did not affect the psychotropic effects of MDMA, although clonidine was used in this study in a relatively high single dose that produced sympatholytic effects, including lower plasma NE levels, decreased blood pressure, and sedation on all psychometric scales compared with placebo, which are findings consistent with previous studies (Keränen et al., 1978; Anavekar et al., 1982).
We used the sympatholytic drug clonidine to block the MDMA-induced impulse-dependent vesicular release of NE (Florin et al., 1994). The fact that clonidine did not interact with the clinical effects of MDMA in the present study indicates that the vesicular release of NE is not involved in the mediation of the effects of MDMA in humans. The finding indirectly supports the view that the effects of MDMA in humans primarily depend on the transporter-mediated release of NE, 5-HT, and possibly dopamine (Liechti et al., 2000; Hysek et al., 2011). A preclinical study that used microdialysis in rats showed that clonidine reduced the NE response only to a low dose of amphetamine, but clonidine became less effective as the dose of amphetamine increased (Florin et al., 1994). This result suggests that amphetamine acts primarily as a transporter-mediated NE releaser at higher doses (Florin et al., 1994). In contrast to our study, clonidine prevented behavior relevant to stimulant addiction, including amphetamine-induced psychomotor stimulation (Vanderschuren et al., 2003), cue-induced cocaine seeking in rats (Smith and Aston-Jones, 2011), and drug craving in cocaine users (Jobes et al., 2011). Altogether, the previous preclinical studies and our clinical findings indicate that amphetamines, including MDMA, do not increase NE impulse flow and their action in humans depends on transporter-mediated monoamine release that is not altered by clonidine.
The pharmacokinetic and other pharmacodynamic interactions between clonidine and MDMA need to be considered in the interpretation of the present findings. First, MDMA metabolism involves CYP2D6-mediated O-demethylation to 3,4-dihydroxymethamphetamine and N-demethylation to MDA by CYP2B6 and CYP3A4 (Segura et al., 2005). Clonidine is not known to affect cytochrome P450 function. As expected, clonidine did not alter the plasma-concentration time curves for MDMA or MDA in the present study. Second, both clonidine and MDMA bind to α2-adrenergic receptors (Battaglia et al., 1988; Lavelle et al., 1999), and some α2 agonistic actions in the peripheral NE system have been documented for MDMA in vitro (Lavelle et al., 1999). However, in contrast to clonidine, MDMA increased plasma NE levels and blood pressure in the present and previous studies (Dumont et al., 2009; Hysek et al., 2011), indicating that the α2 agonistic effects of MDMA are not relevant for its main action in humans or are outweighed by the transporter-mediated release of NE and other monoamines.
Our study has a few limitations. First, only single doses of MDMA and clonidine were used. A dose-response study was not feasible because we did not want to expose our subjects to more than two doses of MDMA in a crossover design. The doses of both drugs were selected in the upper dose range, and both drugs produced marked effects. Unknown is whether clonidine affects the response to low doses of MDMA. Second, the clinical effects of clonidine may be attributable to actions at other binding sites. For example, clonidine binds to the imidazoline binding site with very high affinity (Buccafusco et al., 1995), and this binding site is also involved in the mediation of the pressure-lowering effects of clonidine (Ernsberger et al., 1990).
The present study further characterized the pharmacodynamic and pharmacokinetic effects of a single dose of 125 mg of MDMA in healthy male and female subjects with no or only single previous MDMA use. MDMA produced cardiovascular-stimulant effects, positive mood, emotional stimulation, and extroversion, confirming previous studies in healthy subjects (Liechti et al., 2000; Dumont and Verkes, 2006; Hysek et al., 2010, 2011) and MDMA users (Farré et al., 2007; Tancer and Johanson, 2007; Kolbrich et al., 2008). The study documented the phenomenon of rapid acute tolerance to the effects of MDMA. The Emax in blood pressure was observed within 60 to 120 min, and Cmax was reached within 120 to 180 min after MDMA administration. In addition, the plasma levels of MDMA remained close to Cmax for several hours, whereas the pharmacodynamic effects returned to baseline more rapidly. Furthermore, half-maximal effects (EC50) of MDMA on blood pressure were observed at plasma concentrations of MDMA of approximately 50 ng/ml, which was 4-fold lower than the Cmax of MDMA. Acute tolerance to the effects of psychostimulant drugs, including MDMA, cocaine, and nicotine, has been described previously (Van Dyke et al., 1978; Porchet et al., 1987; Hysek et al., 2011). This pharmacodynamic tolerance could be attributable to receptor or transporter down-regulation or desensitization (Meibohm and Derendorf, 1997; Robertson et al., 2009), the more rapid distribution of drug to the brain than to venous blood (Porchet et al., 1987), or the functional depletion of presynaptic monoamine stores so that no more transmitter can be released despite high concentrations of MDMA.
In summary, our findings support the hypothesis that the effects of MDMA in humans do not depend on the vesicular release of NE but on transporter-mediated monoamine release. The clinical implications of the present study are that clonidine could be of limited use in the treatment of hypertensive reactions in psychostimulant users. In contrast, the lack of an effect of clonidine on the euphoria produced by MDMA does not indicate a role for α2-adrenergic receptor agonists in the prevention of psychostimulant dependence, despite their utility in the treatment of withdrawal from drugs of abuse.
Participated in research design: Hysek and Liechti.
Conducted experiments: Hysek, Brugger, Simmler, Bruggisser, Donzelli, Grouzmann, and Hoener.
Performed data analysis: Hysek, Simmler, and Liechti.
Wrote or contributed to the writing of the manuscript: Hysek and Liechti.
We thank C. Bläsi, L. Baseglia, S. Müller, and S. Purschke for assistance with study management and M. Arends for editorial assistance.
This study was supported by the Swiss National Science Foundation [Grant 323230_126231]; and the Science Pool of the Department of Internal Medicine, University Hospital Basel, Basel, Switzerland.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
- Adjective Mood Rating Scale
- analysis of variance
- area under the effect-time curve
- maximal plasma concentration
- 5-Dimensions of Altered States of Consciousness
- diastolic blood pressure
- maximal effect
- high-performance liquid chromatography
- 5-hydroxytryptamine (serotonin)
- mean arterial pressure
- systolic blood pressure
- State-Trait Anxiety Inventory
- Visual Analog Scale
- oceanic boundlessness
- anxious ego dissolution
- visionary restructuralization
- vigilance reduction.
- Received September 26, 2011.
- Accepted October 26, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics