Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

Schmid, Yasmin; Rickli, Anna; Schaffner, Antonia; Duthaler, Urs; Grouzmann, Eric; Hysek, Cédric M.; Liechti, Matthias E.

doi:10.1124/jpet.114.222356

Cited by 44 publications

(56 citation statements)

References 53 publications

(74 reference statements)

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“…Seven studies each included 16 subjects (total of 112 subjects) who received 125 mg MDMA twice, once alone and once after pretreatment with a medication (Hysek et al, 2012a;Hysek et al, 2012c;Hysek et al, 2012d;Hysek et al, 2011;Hysek and Liechti, 2012;Hysek et al, 2014b;Schmid et al, 2015b). An additional unpublished study included 24 subjects who received 125 mg MDMA once without pretreatment (ClinTrials.gov ID: NCT01951508).…”

Section: Methodsmentioning

confidence: 99%

“…This was a pooled analysis of nine Phase I double-blind, placebo-controlled, crossover studies in healthy subjects (Hysek et al, 2012a;Hysek et al, 2012c;Hysek et al, 2012d;Hysek et al, 2011;Hysek and Liechti, 2012;Hysek et al, 2014b;Schmid et al, 2014;Schmid et al, 2015b). These studies were all conducted at the University Hospital Basel and included a total of 166 subjects who were all psychiatrically screened and healthy.…”

Section: Methodsmentioning

confidence: 99%

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Safety pharmacology of acute MDMA administration in healthy subjects

2017

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Abstract3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMAassisted psychotherapy. The present study characterized the safety pharmacology of singledose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebocontrolled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2±1.3 h (range: 1.4-8.2 h). The 125 mg dose of MDMA produced greater "good drug effect" ratings than 75 mg. MDMA produced moderate and transient "bad drug effect" ratings, which were greater in women than in men.MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29%, and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose.Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at the end of the study 29±22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women.MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Safety pharmacology of acute MDMA administration in healthy subjects

2017

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“…The method was fully validated, including selectivity, recovery, matrix effects, bias and imprecision, stabilities, and limit of quantification (LOQ) and criteria were fulfilled and LOQs sufficient for the expected plasma concentrations of all analytes except for DHMA (Steuer et al, 2015). All blood plasma samples of a previous study (Schmid et al, 2015) were stored at -20°C prior to analysis. Data on stability of MDMA and its phase I metabolites were previously published and no instability could be observed up to 6 months (Clauwaert et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

“…We used plasma samples from a double-blind, placebo-controlled, crossover study with four experimental test sessions (placebo-placebo, bupropion-placebo, placebo-MDMA, and bupropion-MDMA) that were performed in a counterbalanced order according to a Latin square randomization design as described in detail by Schmid et al (2015). The clinical study was conducted at the University Hospital of Basel in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice and with approval by the Ethics Committee of the Canton of Basel, Switzerland, and the Swiss Agency for Therapeutic Products (Swissmedic).…”

Section: Methodsmentioning

confidence: 99%

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

et al. 2015

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Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples from 16 healthy participants receiving 125 mg of MDMA orally in a controlled study were analyzed using liquid chromatography-tandem mass spectroscopy after chiral derivatization. Pharmacokinetic parameters of R-and S-stereoisomers were determined. Sulfates of 3,4-dihydroxymethamphetamine (DHMA), and sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA) were identified, whereas free phase I metabolites were not detected. Stereoselective differences in C max and AUC 24 were observed with the following preferences: R>S for MDMA and DHMA 4-sulfate; S>R for 3,4-methylenedioxyamphetamine (MDA), DHMA 3-sulfate, and HMMA glucuronide; and no preference in C max for HMMA sulfate. R/S ratios were >1 for all analytes after 24 hours, independent of the initial chiral preference. These are the first data on chiral pharmacokinetics of MDMA phase II metabolites in human plasma in vivo after controlled administration. The main human MDMA metabolites were shown to be sulfate and glucuronide conjugates.

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“…Clinical studies that assess pharmacological interactions between a psychostimulant and receptor-selective antagonists or well-characterized transporter ligands shed light on specific molecular target mediating subjective effects and acute toxicity in humans. For example, our laboratory investigated the mode of action of MDMA in humans by blocking the NET, SERT, or DAT or combinations thereof (Hysek et al, 2011;Hysek et al, 2012c;Hysek et al, 2014;Liechti et al, 2000;Schmid et al, 2014;Schmid et al, 2015). These studies showed that NET and α 1 -adrenergic stimulation are crucially involved in MDMA-induced sympathomimetic activation, including elevations of blood pressure and body temperature (Hysek et al, 2012a;Hysek et al, 2013;Hysek et al, 2011;Schmid et al, 2015) and that the SERT-mediated release of 5-HT is involved in the subjective entactogenic/empathogenic effects of MDMA (Hysek et al, 2012b;Hysek et al, 2012c;Liechti et al, 2000).…”

Section: Methods For Studying Transporter and Receptor Pharmacology Imentioning

confidence: 99%

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Simmler

Liechti

2016

Current Topics in Behavioral Neurosciences

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Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transportermediated monoamine efflux with weak to no activity at pre-or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS.

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Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

Cited by 44 publications

References 53 publications

Safety pharmacology of acute MDMA administration in healthy subjects

Safety pharmacology of acute MDMA administration in healthy subjects

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

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