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α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans.
Hysek CM, Fink AE, Simmler LD, Donzelli M, Grouzmann E, Liechti ME
(2013) J Clin Psychopharmacol 33: 658-66
MeSH Terms: Adrenergic alpha-1 Receptor Antagonists, Adult, Affect, Blood Pressure, Body Temperature, Cross-Over Studies, Double-Blind Method, Doxazosin, Drug Interactions, Epinephrine, Female, Healthy Volunteers, Heart Rate, Humans, Male, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Receptors, Adrenergic, alpha-1, Switzerland, Young Adult
Show Abstract · Added August 3, 2013
Preclinical studies implicate a role for α₁-noradrenergic receptors in the effects of psychostimulants, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The present study evaluated the effects of the α₁-noradrenergic receptor antagonist doxazosin on the acute pharmacodynamic and pharmacokinetic response to MDMA in 16 healthy subjects. Doxazosin (8 mg/d) or placebo was administered for 3 days before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, 4-session, crossover design. Doxazosin reduced MDMA-induced elevations in blood pressure, body temperature, and moderately attenuated positive mood but enhanced tachycardia associated with MDMA. The results indicate that α₁-adrenergic receptors contribute to the acute cardiostimulant and to a minor extent possibly also to the thermogenic and euphoric effects of MDMA in humans.
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20 MeSH Terms
Human ecstasy (MDMA) polydrug users have altered brain activation during semantic processing.
Watkins TJ, Raj V, Lee J, Dietrich MS, Cao A, Blackford JU, Salomon RM, Park S, Benningfield MM, Di Iorio CR, Cowan RL
(2013) Psychopharmacology (Berl) 227: 41-54
MeSH Terms: Adolescent, Adult, Brain, Female, Humans, Illicit Drugs, Magnetic Resonance Imaging, Male, Memory, N-Methyl-3,4-methylenedioxyamphetamine, Prospective Studies, Psychomotor Performance, Semantics, Young Adult
Show Abstract · Added July 28, 2015
RATIONALE - Ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) polydrug users have verbal memory performance that is statistically significantly lower than that of control subjects. Studies have correlated long-term MDMA use with altered brain activation in regions that play a role in verbal memory.
OBJECTIVES - The aim of our study was to examine the association of lifetime ecstasy use with semantic memory performance and brain activation in ecstasy polydrug users.
METHODS - A total of 23 abstinent ecstasy polydrug users (age = 24.57 years) and 11 controls (age = 22.36 years) performed a two-part functional magnetic resonance imaging (fMRI) semantic encoding and recognition task. To isolate brain regions activated during each semantic task, we created statistical activation maps in which brain activation was greater for word stimuli than for non-word stimuli (corrected p < 0.05).
RESULTS - During the encoding phase, ecstasy polydrug users had greater activation during semantic encoding bilaterally in language processing regions, including Brodmann areas 7, 39, and 40. Of this bilateral activation, signal intensity with a peak T in the right superior parietal lobe was correlated with lifetime ecstasy use (r s = 0.43, p = 0.042). Behavioral performance did not differ between groups.
CONCLUSIONS - These findings demonstrate that ecstasy polydrug users have increased brain activation during semantic processing. This increase in brain activation in the absence of behavioral deficits suggests that ecstasy polydrug users have reduced cortical efficiency during semantic encoding, possibly secondary to MDMA-induced 5-HT neurotoxicity. Although pre-existing differences cannot be ruled out, this suggests the possibility of a compensatory mechanism allowing ecstasy polydrug users to perform equivalently to controls, providing additional support for an association of altered cerebral neurophysiology with MDMA exposure.
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14 MeSH Terms
Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study.
Hysek CM, Simmler LD, Nicola VG, Vischer N, Donzelli M, Krähenbühl S, Grouzmann E, Huwyler J, Hoener MC, Liechti ME
(2012) PLoS One 7: e36476
MeSH Terms: 3,4-Methylenedioxyamphetamine, Adult, Biological Transport, Duloxetine Hydrochloride, Female, Humans, Laboratories, Male, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Placebo Effect, Receptors, Adrenergic, Serotonin, Serotonin Plasma Membrane Transport Proteins, Thiophenes
Show Abstract · Added August 3, 2013
UNLABELLED - This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence.
TRIAL REGISTRATION - Clinicaltrials.gov NCT00990067.
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15 MeSH Terms
Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans.
Hysek C, Schmid Y, Rickli A, Simmler LD, Donzelli M, Grouzmann E, Liechti ME
(2012) Br J Pharmacol 166: 2277-88
MeSH Terms: Adrenergic Antagonists, Adult, Area Under Curve, Body Temperature, Carbazoles, Carvedilol, Catecholamines, Cross-Over Studies, Drug Interactions, Female, Heart Rate, Humans, Male, N-Methyl-3,4-methylenedioxyamphetamine, Propanolamines, Young Adult
Show Abstract · Added August 3, 2013
BACKGROUND AND PURPOSE - The use of ± 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') is associated with cardiovascular complications and hyperthermia.
EXPERIMENTAL APPROACH - We assessed the effects of the α(1) - and β-adrenoceptor antagonist carvedilol on the cardiostimulant, thermogenic and subjective responses to MDMA in 16 healthy subjects. Carvedilol (50 mg) or placebo was administered 1 h before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, four-period crossover design. KEY RESULTS Carvedilol reduced MDMA-induced elevations in blood pressure, heart rate and body temperature. Carvedilol did not affect the subjective effects of MDMA including MDMA-induced good drug effects, drug high, drug liking, stimulation or adverse effects. Carvedilol did not alter the plasma exposure to MDMA.
CONCLUSIONS AND IMPLICATIONS - α(1) - and β-Adrenoceptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans but not to its psychotropic effects. Carvedilol could be useful in the treatment of cardiovascular and hyperthermic complications associated with ecstasy use.
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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16 MeSH Terms
Effects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers.
Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E, Hoener MC, Liechti ME
(2012) J Pharmacol Exp Ther 340: 286-94
MeSH Terms: 3,4-Methylenedioxyamphetamine, Adrenergic alpha-2 Receptor Agonists, Adult, Affect, Blood Pressure, Body Temperature, Brain, Clonidine, Consciousness, Cross-Over Studies, Double-Blind Method, Drug Interactions, Emotions, Epinephrine, Female, Heart Rate, Humans, Male, Mental Processes, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Young Adult
Show Abstract · Added August 3, 2013
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.
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Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects.
Simmler LD, Hysek CM, Liechti ME
(2011) J Clin Endocrinol Metab 96: 2844-50
MeSH Terms: Adult, Arginine Vasopressin, Cross-Over Studies, Duloxetine Hydrochloride, Female, Glycopeptides, Humans, Male, N-Methyl-3,4-methylenedioxyamphetamine, Osmolar Concentration, Serotonin Agents, Serotonin Uptake Inhibitors, Sex Characteristics, Thiophenes
Show Abstract · Added August 3, 2013
BACKGROUND - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) misuse is associated with hyponatremia particularly in women. Hyponatremia is possibly due to inappropriate secretion of plasma arginine vasopressin (AVP).
OBJECTIVE - To assess whether MDMA increases plasma AVP and copeptin in healthy male and female subjects and whether effects depend on MDMA-induced release of serotonin and norepinephrine. Copeptin, the C-terminal part of the AVP precursor preprovasopressin, is cosecreted with AVP and can be determined more reliably.
METHODS - We used a randomized placebo-controlled crossover design. Plasma and urine osmolalities as well as AVP and copeptin levels were measured in 16 healthy subjects (eight female, eight male) at baseline and after MDMA (125 mg) administration. In addition, we tested whether effects of MDMA on AVP and copeptin secretion can be prevented by pretreatment with the serotonin and norepinephrine transporter inhibitor duloxetine (120 mg), which blocks MDMA-induced transporter-mediated release of serotonin and norepinephrine.
RESULTS - MDMA significantly elevated plasma copeptin levels at 60 min and at 120 min compared with placebo in women but not in men. The copeptin response to MDMA in women was prevented by duloxetine. MDMA also nonsignificantly increased plasma AVP levels in women, and the effect was prevented by duloxetine. Although subjects drank more water after MDMA compared with placebo administration, MDMA tended to increase urine sodium levels and urine osmolality compared with placebo, indicating increased renal water retention.
CONCLUSION - MDMA increased plasma copeptin, a marker for AVP secretion, in women but not in men. This sex difference in MDMA-induced AVP secretion may explain why hyponatremia is typically reported in female ecstasy users. The copeptin response to MDMA is likely mediated via MDMA-induced release of serotonin and/or norepinephrine because it was prevented by duloxetine, which blocks the interaction of MDMA with the serotonergic and noradrenergic system.
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14 MeSH Terms
The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans.
Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, Liechti ME
(2011) Clin Pharmacol Ther 90: 246-55
MeSH Terms: 3,4-Methylenedioxyamphetamine, Adrenergic Uptake Inhibitors, Adult, Blood Pressure, Cross-Over Studies, Double-Blind Method, Drug Interactions, Female, Hallucinogens, Heart Rate, Humans, Male, Morpholines, N-Methyl-3,4-methylenedioxyamphetamine, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Reboxetine, Young Adult
Show Abstract · Added August 3, 2013
This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE, increases in blood pressure and heart rate, subjective drug high, stimulation, and emotional excitation. These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4-methylenedioxyamphetamine (MDA) in plasma. The results demonstrate that transporter-mediated NE release has a critical role in the cardiovascular and stimulant-like effects of MDMA in humans.
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Human Ecstasy use is associated with increased cortical excitability: an fMRI study.
Bauernfeind AL, Dietrich MS, Blackford JU, Charboneau EJ, Lillevig JG, Cannistraci CJ, Woodward ND, Cao A, Watkins T, Di Iorio CR, Cascio C, Salomon RM, Cowan RL
(2011) Neuropsychopharmacology 36: 1127-41
MeSH Terms: Adolescent, Adult, Brain, Brain Mapping, Cerebrovascular Circulation, Female, Geniculate Bodies, Humans, Magnetic Resonance Imaging, Male, N-Methyl-3,4-methylenedioxyamphetamine, Serotonin Agents, Visual Cortex, Visual Pathways, Young Adult
Show Abstract · Added February 15, 2016
The serotonergic neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy), is a highly popular recreational drug. Human recreational MDMA users have neurocognitive and neuropsychiatric impairments, and human neuroimaging data are consistent with animal reports of serotonin neurotoxicity. However, functional neuroimaging studies have not found consistent effects of MDMA on brain neurophysiology in human users. Several lines of evidence suggest that studying MDMA effects in visual system might reveal the general cortical and subcortical neurophysiological consequences of MDMA use. We used 3 T functional magnetic resonance imaging during visual stimulation to compare visual system lateral geniculate nucleus (LGN) and Brodmann Area (BA) 17 and BA 18 activation in 20 long abstinent (479.95±580.65 days) MDMA users and 20 non-MDMA user controls. Lifetime quantity of MDMA use was strongly positively correlated with blood oxygenation level-dependent (BOLD) signal intensity in bilateral LGN (r(s)=0.59; p=0.007), BA 17 (r(s)=0.50; p=0.027), and BA 18 (r(s)=0.48; p=0.031), and with the spatial extent of activation in BA 17 (r(s)=0.059; p=0.007) and BA 18 (r(s)=0.55; p=0.013). There were no between-group differences in brain activation in any region, but the heaviest MDMA users showed a significantly greater spatial extent of activation than controls in BA 17 (p=0.031) and BA 18 (p=0.049). These results suggest that human recreational MDMA use may be associated with a long-lasting increase in cortical excitability, possibly through loss of serotonin input to cortical and subcortical regions. When considered in the context of previous results, cortical hyper-excitability may be a biomarker for MDMA-induced serotonin neurotoxicity.
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Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine.
Field JR, Henry LK, Blakely RD
(2010) J Biol Chem 285: 11270-80
MeSH Terms: Biological Transport, Cytoplasm, Humans, Kinetics, Models, Biological, Mutagenesis, Site-Directed, Mutation, N-Methyl-3,4-methylenedioxyamphetamine, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Serotonin, Serotonin Agents, Serotonin Plasma Membrane Transport Proteins, Water
Show Abstract · Added July 10, 2013
The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine). Homology modeling of human SERT (hSERT), based on high resolution structures of the microbial SLC6 family member LeuT(Aa), along with biochemical studies of wild type and mutant transporters, predicts transmembrane (TM) domains 1, 3, 6, and 8 comprise the 5-HT-binding pocket. We utilized the substituted cysteine accessibility method along with surface and site-specific biotinylation to probe TM6 for aqueous accessibility and differential interactions with 5-HT and psychostimulants. Our results are consistent with TM6 being composed of an aqueous-accessible, alpha-helical extracellular domain (TM6a) that is separated by a central, unwound section from a cytoplasmically localized domain (TM6b) with limited aqueous accessibility. The substitution G338C appears to lock hSERT in an outward-facing conformation that, although accessible to aminoethylmethanethiosulfonate-biotin, 5-HT, and citalopram, is incapable of inward 5-HT transport. Transport of 5-HT by G338C can be partially restored by the TM1 mutation Y95F. With regard to methanethiosulfonate (MTS) inactivation of uptake, TM6a Cys mutants demonstrate Na(+)-dependent [2-(trimethylammonium)ethyl]-MTS sensitivity. Studies with the centrally located substitution S336C reveal features of a common binding pocket for 5-HT and 3,4-methylenedioxymethamphetamine (MDMA). Interestingly, the substitution I333C reveals an MDMA-induced conformation not observed with 5-HT. In the context of prior studies on TM1, our findings document shared and unique features of TM6 contributing to hSERT aqueous accessibility, ligand recognition, and conformational dynamics.
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Drugs, biogenic amine targets and the developing brain.
Frederick AL, Stanwood GD
(2009) Dev Neurosci 31: 7-22
MeSH Terms: Adult, Amphetamine-Related Disorders, Animals, Behavior, Biogenic Amines, Brain, Brain Chemistry, Child, Child Development, Cocaine-Related Disorders, Environmental Pollutants, Female, Humans, N-Methyl-3,4-methylenedioxyamphetamine, Pregnancy, Psychotropic Drugs, Substance-Related Disorders, Toxins, Biological
Show Abstract · Added January 20, 2015
Defects in the development of the brain have a profound impact on mature brain functions and underlying psychopathology. Classical neurotransmitters and neuromodulators, such as dopamine, serotonin, norepinephrine, acetylcholine, glutamate and GABA, have pleiotropic effects during brain development. In other words, these molecules produce multiple diverse effects to serve as regulators of distinct cellular functions at different times in neurodevelopment. These systems are impacted upon by abuse of a variety of illicit drugs, neurotherapeutics and environmental contaminants. In this review, we describe the impact of drugs and chemicals on brain formation and function in animal models and in human populations, highlighting sensitive periods and effects that may not emerge until later in life.
2009 S. Karger AG, Basel.
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18 MeSH Terms