[FG] Liechti MatthiasHead of Research Unit Prof. Dr.Matthias Emanuel Liechti Dr.Deborah RudinOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 17 foundShow per page10 10 20 50 Lysergic acid diethylamide (LSD) in palliative care: a randomised, double-blind, active-placebo controlled phase II study Research Project | 3 Project MembersTerminally ill patients often experience significant psychosocial distress having depressed mood, death anxiety, pain, and an overall poor quality of life. Recent evidence from pilot studies suggests that serotonergic psychedelics, including lysergic acid diethylamide (LSD) and psilocybin, produce significant and sustained reductions of depressive symptoms and anxiety, along with increases in quality of life and life meaning in patients suffering from life-threatening diseases. Additionally, serotonergic psychedelics may produce antinociceptive effects. Differential effects of classic serotonergic hallucinogens: pharmacokinetics-pharmacodynamics, pharmaco-fMRI, and role of 5-HT2 receptors Research Project | 1 Project MembersLSD, Psilocybin und Meskalin sind Halluzinogene welche wegen ihrer bewusstseinsverändernden Wirkung konsumiert werden. LSD und Psilocybin werden zudem untersucht als Medikamente für Patienten mit z.B. Depression. Die pharmakologischen Eigenschaften dieser Substanzen sind beim Menschen noch ungenügend studiert. Daher untersuchen wir in einer ersten Placebo-kontrollierten Studie die Wirkung verschiedener Dosen von LSD (0, 25, 50, 100, 200 µg) bei 16 gesunden Versuchspersonen. Dabei erhält jede Versuchsperson jede Dosis in zufälliger Reihenfolge. Zudem wird der Wirkmechanismus am Serotonin 5-HT 2 Rezeptor getestet indem wir den Rezeptor vor der Gabe einer hohen LSD Dosis blockieren und sehen ob die Wirkung damit auch blockiert werden kann. Sollte sich z.T. die Wirkung nicht ganz aufheben lassen, können andere Rezeptoren auch eine Rolle spielen. Tatsächlich bindet LSD auch an Serotonin 5-HT1 und Dopamine D1 und D2 Rezeptoren. Während LSD vor allem früher in der psychiatrischen Forschung verwendet wurde, wird aktuell primär Psilocybin untersucht. Die pharmakologischen Effekte von LSD und Psilocybin könnten unterschiedlich sein. Dies wurde bis anhin nicht geprüft. Daher werden wir in einer zweiten Studie verschiedene Dosen LSD (100 and 200 µg) und Psilocybin (15 and 30 mg) direkt miteinander vergleichen bei 30 gesunden Versuchspersonen. Dies wird Auskunft geben zur Wirkung beider Substanzen, zu Unterschieden und zur Vergleichbarkeit der Dosierung. Zu LSD und Psilocybin fehlen viele pharmakologische Daten. So werden wir den Abbau und die Ausscheidung von LSD und Psilocybin untersuchen und wie lange diese Substanzen in welchen Konzentrationen im Körper nachweisbar sind. Dies ist z.B. aus legalen Gründen wichtig. In einer dritten Studie werden wir drei verschiedene serotonerge Halluzinogene miteinander vergleichen und auch ihre Effekte auf die Hirnfunktion und Gefühlsverarbeitung mittels Emotionstests und funktioneller Hirnbildgebung (fMRI)untersuchen. Die Untersuchung verwendet ein verblindetes Cross-over-Design (LSD [100 µg], Psilocybin [15 mg], Meskalin [300 mg]) and Placebo) bei 30 gesunden Personen. Es werden psychometrische Messungen erfolgen und Tests von Emotionsverarbeitung und funktionellen Hirnvernetzung. Hinzu kommen Messungen von autonomen Funktionen, Hormonmessungen und Messungen der Substanzkonzentrationen und Tests wie diese mit den Effekten in Verbindung stehen (PK-PD Modellierung). Insgesamt werden diese Studien ein neues und einzigartiges pharmakologisches Datenset generieren zur Pharmakolgie von drei klassischen Halluzinogenen. Die Studien werden unser Verständnis bereichern bezüglich der Entstehung von veränderten Bewusstseinszuständen. Die Daten sind wichtig für die Psychologie, Psychiatrie, und forensischer Toxikologie. Auch werden Grundlage geschaffen für die Entwicklung von Medikamenten. Effects of psychoactive substances on emotion processing in humans: role of serotonin, dopamine and 5-HT2A receptors Research Project | 2 Project MembersDie hirnchemischen Prozesse, welche Gefühle hervorrufen und die Wirkung von psychoaktiven Substanzen vermitteln sind ungenügend untersucht. Von speziellem Interesse sind die Neurotransmitter Serotonin und Dopamin sowie die Serotonin 5-HT2A Rezeptoren, da diese durch psychoaktive Drogen und Medikamente stimuliert werden. MDMA (Ecstasy) setzt im Gehirn Serotonin frei und löst angenehme Gefühle aus. MDMA wird als Freizeitdroge missbraucht aber auch als Medikament in der Behandlung post-traumatischer Stressstörungen untersucht. Stimulanzien wie Methylphenidat (Ritalin) und Modafinil aktivieren das Dopaminsystem und werden als Neuroenhancer und Medikamente verwendet. LSD und Psilocybin sind Psychedelika welche die 5-HT2A Rezeptoren aktivieren und sowohl als Drogen verwendet werden, wie auch als Medikamente für die Behandlung von Angst untersucht werden. Im vorliegenden Projekt wird untersucht, wie diese psychoaktive Substanzen die Gefühlsverarbeitung beim Menschen beeinflussen. Dabei wird die Wirkung von MDMA, Methylphenidat, Modafinil und Placebo auf in einer Crossover-Studie bei 24 gesunden Personen untersucht. Eine weitere Studie untersucht Unterschiede in der Wirkung von MDMA, LSD, Placebo und Psilocybin ebenfalls bei 24 Personen. Durch die Verwendung dieser Substanzen erhalten die Forscher Einblick in die Rolle von Serotonin (5-HT Freisetzung und direkte 5-HT2A Rezeptor-Aktivierung) und Dopamin bei der Entstehung und Verarbeitung von Gefühlen. Folgende Tests werden durchgeführt: subjektive Gefühle mittels validierter Fragebogen , Hormone, Erkennen von Basisemotionen in Gesichtern, Messung von emotionaler und kognitiver Empathie, Soziale Wertorientierung im Verhaltenstest, funktionelle Magnetresonanzmessung im Hirnscanner (fMRI) zur Messung der Aktivität verschiedener Hirnzentern (BOLD Response) unter Ruhebedingungen (resting state) und währen der Gefühlsverarbeitung (Gesichtsemotionen) und dem Hirnblutfluss (ASL). Speziell werden Änderungen in der funktionellen Vernetzung des Gehirns erfasst. Die Hypothese ist, dass Substanzen welche das Serotonin-System aktivieren die Empathie und Prosozialiät steigern und die Wahrnehmung negativer Gefühle abschwächen sowie die Hirnaktivität im Angstzentrum (Amygdala) reduzieren. Dies ist die erste Studie zu Wirkunterschieden von MDMA, LSD und Psilocybin. Die Studie wird einen wichtigen Beitrag zum Verständnis der Wirkung psychoaktiver Subtanzen leisten und Einsicht in die Neurochemie der Gefühlsverarbeitung generell erlauben. The role of the dopamine/norepinephrine transporters (SLC6A3/2) and of genetic polymorphisms in the effects of MDMA (ecstasy) Research Project | 1 Project MembersBackground: Abuse of amphetamine-type substances including MDMA (ecstasy) is prevalent in our society. MDMA releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) by interacting with the respective monoamine transporters. DA is implicated in the addictive properties of drugs of abuse and DA and NE possible also in drug-induced euphoria. 5-HT mediates many of the acute effects of MDMA. However, it is not clear whether DA/NE transporter (SLC6A3/2)-mediated DA/NE release contributes to the acute effects of MDMA in humans. In addition, marked interindividual differences exist in the euphoric response to psychostimulants and in the risk of developing drug addiction and polymorphisms in gens that code for monoamine transporters and receptors are likely to critically contribute to interindividual variations in the response to amphetamines including MDMA. Furthermore, MDMA is primarily metabolized by the polymorphic CYP 2D6 enzyme. Variance in the CYP2D6 geno- and phenotype may therefore be associated with interindividual differences in plasma concentrations and associated toxicity produced by MDMA. Aim: We aim to evaluate the role of the DA/NET transporter and genetic polymorphism in monoamine transporters/receptors and different CYPs including CYP2D6 in the human pharmacology and toxicology of MDMA. Method: In study 1, we will investigate the effects of a pretreatment with the DA/NE transporter inhibitor bupropion on the acute effects of MDMA in 16 healthy subjects using a randomized placebo-controlled four-period factorial study design. The primary hypothesis is that bupropion will reduce the positive mood effects of MDMA. Secondary outcomes include cardiovascular effects, emotion recognition, empathic effects, pupillometry, and neuroendocrine effects, pharmacokinetics of MDMA, and adverse effects. Failure to demonstrate inhibition of the response to MDMA by bupropion would support 5-HT as the primary mediator. After the completion of study 1 the data will be pooled with all our previous comprehensive clinical data to form a large and worldwide unique cohort of MDMA-treated subjects (N=142). In study 2 we will then analyze associations between the response to MDMA and genetic polymorphisms and haplotypes in transporter/receptors involved in monoaminergic neurotransmission in this pooled sample and in an international larger sample (N=222). All subjects will also be tested for CYP2D6 pheno- and CYP2D6/2C19/2B6/1A2 genotypes involved in the metabolism of MDMA. Significance: This is the first study to investigate the role of the DA transporter in the mechanism of action of MDMA in humans. It is also the first pharmacogenetic study to assess the contribution of genetic variations in the monaminergic system to the effects of MDMA. Worldwide, there are no similarly large cohorts that would allow for the testing of these associations including also CYP pheno- and genotype data. The study will contribute to our understanding of the role of DA/NE vs. SERT and in particular the genetic determinants underlying the interindividual differences in the effects of amphetamine-like substances. Psychological, physiological, endocrine, and pharmacokinetic effects of LSD in a controlled study Research Project | 2 Project MembersBackground: Lysergic acid diethylamide (LSD) is the prototype hallucinogen used recreationally worldwide. In the 50-70s, LSD was also used to study psychotic-like states in normals ("model psychosis") and in "psycholytic psychotherapy". Clinical research using LSD has been prohibited in most countries over the last 30 years and there is now a renewed interest in the pharmacology of this substance. Potential research and therapeutic uses of LSD are now re-recognized and may include its use in brain research, treatment of cluster headache, and aid in psychotherapy and in terminally ill patients. Recently, a first placebo-controlled study in patients suffering from anxiety associated with advanced-stage life threatening diseases has been completed in Switzerland. However, most initial studies conducted with LSD do not meet todays' research standards and many effects of the substance including those on the endocrine system and the pharmacokinetic-pharmacodynamic relationship are unknown. Study aim: To characterize the acute psychological, physiological, endocrine, and pharmacokinetic, as well as long-term psychological effects of LSD in humans (psychotherapists). Methods: Placebo-controlled, double-blind, randomized two-phase cross-over study to test the effects of LSD (200 mg) or placebo in 16 well-educated middle aged healthy human subjects. Outcome measures of acute effects will include: validated psychometric tests, physiological effects, neuroendocrine measures, plasma concentration-time profiles of LSD, and adverse effects. Additionally, long-term psychological effects of LSD will be assessed 1 and 12 months after the experience. Significance. LSD is the most famous psychedelic substance. LSD is continued to be used recreationally. There is also a professional need for more clinical data on its role in experimental research and possible therapeutic applications (headache, psychotherapy, palliative medicine). This would be the first placebo-controlled and methodologically sound evaluation of the pharmacological and long-term psychological effects of LSD in humans. In addition, the endocrine effects of LSD are unknown. A better and contemporary understanding of the pharmacology of LSD is important in the light of its widespread recreational and potential scientific uses. The study will provide a first and solid account of the clinical pharmacological characteristics of the drug that are very likely to form a basis for further studies. Such ensuing experimental work in the near future may include the use of LSD in a psychotherapeutic setting in professional therapists as participants and a functional magnetic resonance imaging study to define the neuronal correlates of the effects of LSD. Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs. Emotionale und soziale Effekte von MDMA und Methylphenidat Research Project | 1 Project MembersIn this project we will investigate the emotional and prosocial effects of 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) and methylphenidate in healthy subjects. MDMA is used recreationally for its euphoric effects and in clinical trials in patients with posttraumatic stress disorder. Methylphenidate is used therapeutically in the treatment of attention deficit hyperactivity disorder but also abused to enhance performance. We will assess emotional effects of MDMA and methylphenidate alone and in combination in a placebo-controlled cross-over design using validated psychometric tools and established assessments of emotional face recognition, cognitive empathy, and prosocial behavior as outcome measures. We hypothesize that the two psychostimulants will elevate mood, shift emotion recognition towards a more positive perception of feelings while negatively affecting accuracy. MDMA and methylphenidate and also differentially alter cognitive empathy and social value orientation measures. In addition, we will assess whether methylphenidate will attenuate emotional effects of MDMA in humans and MDMA-induced dopamine and norepinephrine release in vitro and in vivo. Thus, the project will include both a pharmacological interaction study in humans and preclinical experiments. Together the studies aim at an understanding of the pharmacology underlying the mood and potential prosocial effects of psychostimulants. The project is designed as an extension of our SNF project to assess the mechanism of action of MDMA. We include an assessment of the effects of methylphenidate which is increasingly used in our society and focus on mood processing and sociobehavioral effects of MDMA and methylphenidate that have not yet been studied. It is also expected that the present project will provide us with important data to attract funding for a larger study on the social effects of psychostimulants. Interactive effects of doxazosin and MDMA in healthy subjects Research Project | 1 Project MembersNo Description available Duloxetine/Clonidine-MDMA Studies Research Project | 1 Project MembersInteraction-Studies of Duloxetine or Clonidin with MDMA. Support in the form of personnel that is directly paid by the fund. Wissenschaftsfonds Departement of Internal Medicine of the University Hospital. Interaction of Duloxetine and MDMA Research Project | 1 Project Members3,4-methylenedioxymethamphetamine (MDMA, ecstasy ) is widely used by young people for its euphoric effects. MDMA releases serotonin (5-HT), norepinephrine (NE), and dopamine through an interaction with the corresponding presynaptic monoamine uptake transporter. 5-HT transport inhibitors block MDMA-induced 5-HT release in vitro or in animals and also attenuate the subjective and cardiovascular response to MDMA in humans. NE transport inhibitors similarly prevent the MDMA-induced release of NE in cell assays and attenuate behavioral effects of MDMA in animals. Here, we suggest evaluating effects of pretreatment with the combined 5-HT and NE transport blocker duloxetine on the pharmacodynamics and pharmacokinetics of MDMA. This approach is used to assess the role of 5-HT and NE in the mediation of MDMA s effects in humans. The study will use a randomized double-blind cross-over design with four experimental sessions. Duloxetine (120 mg) or placebo will be administered 16 h and 4 h before the administration of MDMA (125 mg) or placebo to 16 healthy volunteers. Subjective and cardiovascular responses and plasma samples for pharmacokinetics will be repeatedly assessed throughout the experiments. We hypothesize that duloxetine will attenuate the subjective and cardiovascular response to MDMA. Such a result would indicat that MDMA produces its psychological and physiological effects in humans mainly by transporter-mediated release of 5-HT and NE. 12 12 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 17 foundShow per page10 10 20 50 Lysergic acid diethylamide (LSD) in palliative care: a randomised, double-blind, active-placebo controlled phase II study Research Project | 3 Project MembersTerminally ill patients often experience significant psychosocial distress having depressed mood, death anxiety, pain, and an overall poor quality of life. Recent evidence from pilot studies suggests that serotonergic psychedelics, including lysergic acid diethylamide (LSD) and psilocybin, produce significant and sustained reductions of depressive symptoms and anxiety, along with increases in quality of life and life meaning in patients suffering from life-threatening diseases. Additionally, serotonergic psychedelics may produce antinociceptive effects. Differential effects of classic serotonergic hallucinogens: pharmacokinetics-pharmacodynamics, pharmaco-fMRI, and role of 5-HT2 receptors Research Project | 1 Project MembersLSD, Psilocybin und Meskalin sind Halluzinogene welche wegen ihrer bewusstseinsverändernden Wirkung konsumiert werden. LSD und Psilocybin werden zudem untersucht als Medikamente für Patienten mit z.B. Depression. Die pharmakologischen Eigenschaften dieser Substanzen sind beim Menschen noch ungenügend studiert. Daher untersuchen wir in einer ersten Placebo-kontrollierten Studie die Wirkung verschiedener Dosen von LSD (0, 25, 50, 100, 200 µg) bei 16 gesunden Versuchspersonen. Dabei erhält jede Versuchsperson jede Dosis in zufälliger Reihenfolge. Zudem wird der Wirkmechanismus am Serotonin 5-HT 2 Rezeptor getestet indem wir den Rezeptor vor der Gabe einer hohen LSD Dosis blockieren und sehen ob die Wirkung damit auch blockiert werden kann. Sollte sich z.T. die Wirkung nicht ganz aufheben lassen, können andere Rezeptoren auch eine Rolle spielen. Tatsächlich bindet LSD auch an Serotonin 5-HT1 und Dopamine D1 und D2 Rezeptoren. Während LSD vor allem früher in der psychiatrischen Forschung verwendet wurde, wird aktuell primär Psilocybin untersucht. Die pharmakologischen Effekte von LSD und Psilocybin könnten unterschiedlich sein. Dies wurde bis anhin nicht geprüft. Daher werden wir in einer zweiten Studie verschiedene Dosen LSD (100 and 200 µg) und Psilocybin (15 and 30 mg) direkt miteinander vergleichen bei 30 gesunden Versuchspersonen. Dies wird Auskunft geben zur Wirkung beider Substanzen, zu Unterschieden und zur Vergleichbarkeit der Dosierung. Zu LSD und Psilocybin fehlen viele pharmakologische Daten. So werden wir den Abbau und die Ausscheidung von LSD und Psilocybin untersuchen und wie lange diese Substanzen in welchen Konzentrationen im Körper nachweisbar sind. Dies ist z.B. aus legalen Gründen wichtig. In einer dritten Studie werden wir drei verschiedene serotonerge Halluzinogene miteinander vergleichen und auch ihre Effekte auf die Hirnfunktion und Gefühlsverarbeitung mittels Emotionstests und funktioneller Hirnbildgebung (fMRI)untersuchen. Die Untersuchung verwendet ein verblindetes Cross-over-Design (LSD [100 µg], Psilocybin [15 mg], Meskalin [300 mg]) and Placebo) bei 30 gesunden Personen. Es werden psychometrische Messungen erfolgen und Tests von Emotionsverarbeitung und funktionellen Hirnvernetzung. Hinzu kommen Messungen von autonomen Funktionen, Hormonmessungen und Messungen der Substanzkonzentrationen und Tests wie diese mit den Effekten in Verbindung stehen (PK-PD Modellierung). Insgesamt werden diese Studien ein neues und einzigartiges pharmakologisches Datenset generieren zur Pharmakolgie von drei klassischen Halluzinogenen. Die Studien werden unser Verständnis bereichern bezüglich der Entstehung von veränderten Bewusstseinszuständen. Die Daten sind wichtig für die Psychologie, Psychiatrie, und forensischer Toxikologie. Auch werden Grundlage geschaffen für die Entwicklung von Medikamenten. Effects of psychoactive substances on emotion processing in humans: role of serotonin, dopamine and 5-HT2A receptors Research Project | 2 Project MembersDie hirnchemischen Prozesse, welche Gefühle hervorrufen und die Wirkung von psychoaktiven Substanzen vermitteln sind ungenügend untersucht. Von speziellem Interesse sind die Neurotransmitter Serotonin und Dopamin sowie die Serotonin 5-HT2A Rezeptoren, da diese durch psychoaktive Drogen und Medikamente stimuliert werden. MDMA (Ecstasy) setzt im Gehirn Serotonin frei und löst angenehme Gefühle aus. MDMA wird als Freizeitdroge missbraucht aber auch als Medikament in der Behandlung post-traumatischer Stressstörungen untersucht. Stimulanzien wie Methylphenidat (Ritalin) und Modafinil aktivieren das Dopaminsystem und werden als Neuroenhancer und Medikamente verwendet. LSD und Psilocybin sind Psychedelika welche die 5-HT2A Rezeptoren aktivieren und sowohl als Drogen verwendet werden, wie auch als Medikamente für die Behandlung von Angst untersucht werden. Im vorliegenden Projekt wird untersucht, wie diese psychoaktive Substanzen die Gefühlsverarbeitung beim Menschen beeinflussen. Dabei wird die Wirkung von MDMA, Methylphenidat, Modafinil und Placebo auf in einer Crossover-Studie bei 24 gesunden Personen untersucht. Eine weitere Studie untersucht Unterschiede in der Wirkung von MDMA, LSD, Placebo und Psilocybin ebenfalls bei 24 Personen. Durch die Verwendung dieser Substanzen erhalten die Forscher Einblick in die Rolle von Serotonin (5-HT Freisetzung und direkte 5-HT2A Rezeptor-Aktivierung) und Dopamin bei der Entstehung und Verarbeitung von Gefühlen. Folgende Tests werden durchgeführt: subjektive Gefühle mittels validierter Fragebogen , Hormone, Erkennen von Basisemotionen in Gesichtern, Messung von emotionaler und kognitiver Empathie, Soziale Wertorientierung im Verhaltenstest, funktionelle Magnetresonanzmessung im Hirnscanner (fMRI) zur Messung der Aktivität verschiedener Hirnzentern (BOLD Response) unter Ruhebedingungen (resting state) und währen der Gefühlsverarbeitung (Gesichtsemotionen) und dem Hirnblutfluss (ASL). Speziell werden Änderungen in der funktionellen Vernetzung des Gehirns erfasst. Die Hypothese ist, dass Substanzen welche das Serotonin-System aktivieren die Empathie und Prosozialiät steigern und die Wahrnehmung negativer Gefühle abschwächen sowie die Hirnaktivität im Angstzentrum (Amygdala) reduzieren. Dies ist die erste Studie zu Wirkunterschieden von MDMA, LSD und Psilocybin. Die Studie wird einen wichtigen Beitrag zum Verständnis der Wirkung psychoaktiver Subtanzen leisten und Einsicht in die Neurochemie der Gefühlsverarbeitung generell erlauben. The role of the dopamine/norepinephrine transporters (SLC6A3/2) and of genetic polymorphisms in the effects of MDMA (ecstasy) Research Project | 1 Project MembersBackground: Abuse of amphetamine-type substances including MDMA (ecstasy) is prevalent in our society. MDMA releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) by interacting with the respective monoamine transporters. DA is implicated in the addictive properties of drugs of abuse and DA and NE possible also in drug-induced euphoria. 5-HT mediates many of the acute effects of MDMA. However, it is not clear whether DA/NE transporter (SLC6A3/2)-mediated DA/NE release contributes to the acute effects of MDMA in humans. In addition, marked interindividual differences exist in the euphoric response to psychostimulants and in the risk of developing drug addiction and polymorphisms in gens that code for monoamine transporters and receptors are likely to critically contribute to interindividual variations in the response to amphetamines including MDMA. Furthermore, MDMA is primarily metabolized by the polymorphic CYP 2D6 enzyme. Variance in the CYP2D6 geno- and phenotype may therefore be associated with interindividual differences in plasma concentrations and associated toxicity produced by MDMA. Aim: We aim to evaluate the role of the DA/NET transporter and genetic polymorphism in monoamine transporters/receptors and different CYPs including CYP2D6 in the human pharmacology and toxicology of MDMA. Method: In study 1, we will investigate the effects of a pretreatment with the DA/NE transporter inhibitor bupropion on the acute effects of MDMA in 16 healthy subjects using a randomized placebo-controlled four-period factorial study design. The primary hypothesis is that bupropion will reduce the positive mood effects of MDMA. Secondary outcomes include cardiovascular effects, emotion recognition, empathic effects, pupillometry, and neuroendocrine effects, pharmacokinetics of MDMA, and adverse effects. Failure to demonstrate inhibition of the response to MDMA by bupropion would support 5-HT as the primary mediator. After the completion of study 1 the data will be pooled with all our previous comprehensive clinical data to form a large and worldwide unique cohort of MDMA-treated subjects (N=142). In study 2 we will then analyze associations between the response to MDMA and genetic polymorphisms and haplotypes in transporter/receptors involved in monoaminergic neurotransmission in this pooled sample and in an international larger sample (N=222). All subjects will also be tested for CYP2D6 pheno- and CYP2D6/2C19/2B6/1A2 genotypes involved in the metabolism of MDMA. Significance: This is the first study to investigate the role of the DA transporter in the mechanism of action of MDMA in humans. It is also the first pharmacogenetic study to assess the contribution of genetic variations in the monaminergic system to the effects of MDMA. Worldwide, there are no similarly large cohorts that would allow for the testing of these associations including also CYP pheno- and genotype data. The study will contribute to our understanding of the role of DA/NE vs. SERT and in particular the genetic determinants underlying the interindividual differences in the effects of amphetamine-like substances. Psychological, physiological, endocrine, and pharmacokinetic effects of LSD in a controlled study Research Project | 2 Project MembersBackground: Lysergic acid diethylamide (LSD) is the prototype hallucinogen used recreationally worldwide. In the 50-70s, LSD was also used to study psychotic-like states in normals ("model psychosis") and in "psycholytic psychotherapy". Clinical research using LSD has been prohibited in most countries over the last 30 years and there is now a renewed interest in the pharmacology of this substance. Potential research and therapeutic uses of LSD are now re-recognized and may include its use in brain research, treatment of cluster headache, and aid in psychotherapy and in terminally ill patients. Recently, a first placebo-controlled study in patients suffering from anxiety associated with advanced-stage life threatening diseases has been completed in Switzerland. However, most initial studies conducted with LSD do not meet todays' research standards and many effects of the substance including those on the endocrine system and the pharmacokinetic-pharmacodynamic relationship are unknown. Study aim: To characterize the acute psychological, physiological, endocrine, and pharmacokinetic, as well as long-term psychological effects of LSD in humans (psychotherapists). Methods: Placebo-controlled, double-blind, randomized two-phase cross-over study to test the effects of LSD (200 mg) or placebo in 16 well-educated middle aged healthy human subjects. Outcome measures of acute effects will include: validated psychometric tests, physiological effects, neuroendocrine measures, plasma concentration-time profiles of LSD, and adverse effects. Additionally, long-term psychological effects of LSD will be assessed 1 and 12 months after the experience. Significance. LSD is the most famous psychedelic substance. LSD is continued to be used recreationally. There is also a professional need for more clinical data on its role in experimental research and possible therapeutic applications (headache, psychotherapy, palliative medicine). This would be the first placebo-controlled and methodologically sound evaluation of the pharmacological and long-term psychological effects of LSD in humans. In addition, the endocrine effects of LSD are unknown. A better and contemporary understanding of the pharmacology of LSD is important in the light of its widespread recreational and potential scientific uses. The study will provide a first and solid account of the clinical pharmacological characteristics of the drug that are very likely to form a basis for further studies. Such ensuing experimental work in the near future may include the use of LSD in a psychotherapeutic setting in professional therapists as participants and a functional magnetic resonance imaging study to define the neuronal correlates of the effects of LSD. Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs. Emotionale und soziale Effekte von MDMA und Methylphenidat Research Project | 1 Project MembersIn this project we will investigate the emotional and prosocial effects of 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) and methylphenidate in healthy subjects. MDMA is used recreationally for its euphoric effects and in clinical trials in patients with posttraumatic stress disorder. Methylphenidate is used therapeutically in the treatment of attention deficit hyperactivity disorder but also abused to enhance performance. We will assess emotional effects of MDMA and methylphenidate alone and in combination in a placebo-controlled cross-over design using validated psychometric tools and established assessments of emotional face recognition, cognitive empathy, and prosocial behavior as outcome measures. We hypothesize that the two psychostimulants will elevate mood, shift emotion recognition towards a more positive perception of feelings while negatively affecting accuracy. MDMA and methylphenidate and also differentially alter cognitive empathy and social value orientation measures. In addition, we will assess whether methylphenidate will attenuate emotional effects of MDMA in humans and MDMA-induced dopamine and norepinephrine release in vitro and in vivo. Thus, the project will include both a pharmacological interaction study in humans and preclinical experiments. Together the studies aim at an understanding of the pharmacology underlying the mood and potential prosocial effects of psychostimulants. The project is designed as an extension of our SNF project to assess the mechanism of action of MDMA. We include an assessment of the effects of methylphenidate which is increasingly used in our society and focus on mood processing and sociobehavioral effects of MDMA and methylphenidate that have not yet been studied. It is also expected that the present project will provide us with important data to attract funding for a larger study on the social effects of psychostimulants. Interactive effects of doxazosin and MDMA in healthy subjects Research Project | 1 Project MembersNo Description available Duloxetine/Clonidine-MDMA Studies Research Project | 1 Project MembersInteraction-Studies of Duloxetine or Clonidin with MDMA. Support in the form of personnel that is directly paid by the fund. Wissenschaftsfonds Departement of Internal Medicine of the University Hospital. Interaction of Duloxetine and MDMA Research Project | 1 Project Members3,4-methylenedioxymethamphetamine (MDMA, ecstasy ) is widely used by young people for its euphoric effects. MDMA releases serotonin (5-HT), norepinephrine (NE), and dopamine through an interaction with the corresponding presynaptic monoamine uptake transporter. 5-HT transport inhibitors block MDMA-induced 5-HT release in vitro or in animals and also attenuate the subjective and cardiovascular response to MDMA in humans. NE transport inhibitors similarly prevent the MDMA-induced release of NE in cell assays and attenuate behavioral effects of MDMA in animals. Here, we suggest evaluating effects of pretreatment with the combined 5-HT and NE transport blocker duloxetine on the pharmacodynamics and pharmacokinetics of MDMA. This approach is used to assess the role of 5-HT and NE in the mediation of MDMA s effects in humans. The study will use a randomized double-blind cross-over design with four experimental sessions. Duloxetine (120 mg) or placebo will be administered 16 h and 4 h before the administration of MDMA (125 mg) or placebo to 16 healthy volunteers. Subjective and cardiovascular responses and plasma samples for pharmacokinetics will be repeatedly assessed throughout the experiments. We hypothesize that duloxetine will attenuate the subjective and cardiovascular response to MDMA. Such a result would indicat that MDMA produces its psychological and physiological effects in humans mainly by transporter-mediated release of 5-HT and NE. 12 12
Lysergic acid diethylamide (LSD) in palliative care: a randomised, double-blind, active-placebo controlled phase II study Research Project | 3 Project MembersTerminally ill patients often experience significant psychosocial distress having depressed mood, death anxiety, pain, and an overall poor quality of life. Recent evidence from pilot studies suggests that serotonergic psychedelics, including lysergic acid diethylamide (LSD) and psilocybin, produce significant and sustained reductions of depressive symptoms and anxiety, along with increases in quality of life and life meaning in patients suffering from life-threatening diseases. Additionally, serotonergic psychedelics may produce antinociceptive effects.
Differential effects of classic serotonergic hallucinogens: pharmacokinetics-pharmacodynamics, pharmaco-fMRI, and role of 5-HT2 receptors Research Project | 1 Project MembersLSD, Psilocybin und Meskalin sind Halluzinogene welche wegen ihrer bewusstseinsverändernden Wirkung konsumiert werden. LSD und Psilocybin werden zudem untersucht als Medikamente für Patienten mit z.B. Depression. Die pharmakologischen Eigenschaften dieser Substanzen sind beim Menschen noch ungenügend studiert. Daher untersuchen wir in einer ersten Placebo-kontrollierten Studie die Wirkung verschiedener Dosen von LSD (0, 25, 50, 100, 200 µg) bei 16 gesunden Versuchspersonen. Dabei erhält jede Versuchsperson jede Dosis in zufälliger Reihenfolge. Zudem wird der Wirkmechanismus am Serotonin 5-HT 2 Rezeptor getestet indem wir den Rezeptor vor der Gabe einer hohen LSD Dosis blockieren und sehen ob die Wirkung damit auch blockiert werden kann. Sollte sich z.T. die Wirkung nicht ganz aufheben lassen, können andere Rezeptoren auch eine Rolle spielen. Tatsächlich bindet LSD auch an Serotonin 5-HT1 und Dopamine D1 und D2 Rezeptoren. Während LSD vor allem früher in der psychiatrischen Forschung verwendet wurde, wird aktuell primär Psilocybin untersucht. Die pharmakologischen Effekte von LSD und Psilocybin könnten unterschiedlich sein. Dies wurde bis anhin nicht geprüft. Daher werden wir in einer zweiten Studie verschiedene Dosen LSD (100 and 200 µg) und Psilocybin (15 and 30 mg) direkt miteinander vergleichen bei 30 gesunden Versuchspersonen. Dies wird Auskunft geben zur Wirkung beider Substanzen, zu Unterschieden und zur Vergleichbarkeit der Dosierung. Zu LSD und Psilocybin fehlen viele pharmakologische Daten. So werden wir den Abbau und die Ausscheidung von LSD und Psilocybin untersuchen und wie lange diese Substanzen in welchen Konzentrationen im Körper nachweisbar sind. Dies ist z.B. aus legalen Gründen wichtig. In einer dritten Studie werden wir drei verschiedene serotonerge Halluzinogene miteinander vergleichen und auch ihre Effekte auf die Hirnfunktion und Gefühlsverarbeitung mittels Emotionstests und funktioneller Hirnbildgebung (fMRI)untersuchen. Die Untersuchung verwendet ein verblindetes Cross-over-Design (LSD [100 µg], Psilocybin [15 mg], Meskalin [300 mg]) and Placebo) bei 30 gesunden Personen. Es werden psychometrische Messungen erfolgen und Tests von Emotionsverarbeitung und funktionellen Hirnvernetzung. Hinzu kommen Messungen von autonomen Funktionen, Hormonmessungen und Messungen der Substanzkonzentrationen und Tests wie diese mit den Effekten in Verbindung stehen (PK-PD Modellierung). Insgesamt werden diese Studien ein neues und einzigartiges pharmakologisches Datenset generieren zur Pharmakolgie von drei klassischen Halluzinogenen. Die Studien werden unser Verständnis bereichern bezüglich der Entstehung von veränderten Bewusstseinszuständen. Die Daten sind wichtig für die Psychologie, Psychiatrie, und forensischer Toxikologie. Auch werden Grundlage geschaffen für die Entwicklung von Medikamenten.
Effects of psychoactive substances on emotion processing in humans: role of serotonin, dopamine and 5-HT2A receptors Research Project | 2 Project MembersDie hirnchemischen Prozesse, welche Gefühle hervorrufen und die Wirkung von psychoaktiven Substanzen vermitteln sind ungenügend untersucht. Von speziellem Interesse sind die Neurotransmitter Serotonin und Dopamin sowie die Serotonin 5-HT2A Rezeptoren, da diese durch psychoaktive Drogen und Medikamente stimuliert werden. MDMA (Ecstasy) setzt im Gehirn Serotonin frei und löst angenehme Gefühle aus. MDMA wird als Freizeitdroge missbraucht aber auch als Medikament in der Behandlung post-traumatischer Stressstörungen untersucht. Stimulanzien wie Methylphenidat (Ritalin) und Modafinil aktivieren das Dopaminsystem und werden als Neuroenhancer und Medikamente verwendet. LSD und Psilocybin sind Psychedelika welche die 5-HT2A Rezeptoren aktivieren und sowohl als Drogen verwendet werden, wie auch als Medikamente für die Behandlung von Angst untersucht werden. Im vorliegenden Projekt wird untersucht, wie diese psychoaktive Substanzen die Gefühlsverarbeitung beim Menschen beeinflussen. Dabei wird die Wirkung von MDMA, Methylphenidat, Modafinil und Placebo auf in einer Crossover-Studie bei 24 gesunden Personen untersucht. Eine weitere Studie untersucht Unterschiede in der Wirkung von MDMA, LSD, Placebo und Psilocybin ebenfalls bei 24 Personen. Durch die Verwendung dieser Substanzen erhalten die Forscher Einblick in die Rolle von Serotonin (5-HT Freisetzung und direkte 5-HT2A Rezeptor-Aktivierung) und Dopamin bei der Entstehung und Verarbeitung von Gefühlen. Folgende Tests werden durchgeführt: subjektive Gefühle mittels validierter Fragebogen , Hormone, Erkennen von Basisemotionen in Gesichtern, Messung von emotionaler und kognitiver Empathie, Soziale Wertorientierung im Verhaltenstest, funktionelle Magnetresonanzmessung im Hirnscanner (fMRI) zur Messung der Aktivität verschiedener Hirnzentern (BOLD Response) unter Ruhebedingungen (resting state) und währen der Gefühlsverarbeitung (Gesichtsemotionen) und dem Hirnblutfluss (ASL). Speziell werden Änderungen in der funktionellen Vernetzung des Gehirns erfasst. Die Hypothese ist, dass Substanzen welche das Serotonin-System aktivieren die Empathie und Prosozialiät steigern und die Wahrnehmung negativer Gefühle abschwächen sowie die Hirnaktivität im Angstzentrum (Amygdala) reduzieren. Dies ist die erste Studie zu Wirkunterschieden von MDMA, LSD und Psilocybin. Die Studie wird einen wichtigen Beitrag zum Verständnis der Wirkung psychoaktiver Subtanzen leisten und Einsicht in die Neurochemie der Gefühlsverarbeitung generell erlauben.
The role of the dopamine/norepinephrine transporters (SLC6A3/2) and of genetic polymorphisms in the effects of MDMA (ecstasy) Research Project | 1 Project MembersBackground: Abuse of amphetamine-type substances including MDMA (ecstasy) is prevalent in our society. MDMA releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) by interacting with the respective monoamine transporters. DA is implicated in the addictive properties of drugs of abuse and DA and NE possible also in drug-induced euphoria. 5-HT mediates many of the acute effects of MDMA. However, it is not clear whether DA/NE transporter (SLC6A3/2)-mediated DA/NE release contributes to the acute effects of MDMA in humans. In addition, marked interindividual differences exist in the euphoric response to psychostimulants and in the risk of developing drug addiction and polymorphisms in gens that code for monoamine transporters and receptors are likely to critically contribute to interindividual variations in the response to amphetamines including MDMA. Furthermore, MDMA is primarily metabolized by the polymorphic CYP 2D6 enzyme. Variance in the CYP2D6 geno- and phenotype may therefore be associated with interindividual differences in plasma concentrations and associated toxicity produced by MDMA. Aim: We aim to evaluate the role of the DA/NET transporter and genetic polymorphism in monoamine transporters/receptors and different CYPs including CYP2D6 in the human pharmacology and toxicology of MDMA. Method: In study 1, we will investigate the effects of a pretreatment with the DA/NE transporter inhibitor bupropion on the acute effects of MDMA in 16 healthy subjects using a randomized placebo-controlled four-period factorial study design. The primary hypothesis is that bupropion will reduce the positive mood effects of MDMA. Secondary outcomes include cardiovascular effects, emotion recognition, empathic effects, pupillometry, and neuroendocrine effects, pharmacokinetics of MDMA, and adverse effects. Failure to demonstrate inhibition of the response to MDMA by bupropion would support 5-HT as the primary mediator. After the completion of study 1 the data will be pooled with all our previous comprehensive clinical data to form a large and worldwide unique cohort of MDMA-treated subjects (N=142). In study 2 we will then analyze associations between the response to MDMA and genetic polymorphisms and haplotypes in transporter/receptors involved in monoaminergic neurotransmission in this pooled sample and in an international larger sample (N=222). All subjects will also be tested for CYP2D6 pheno- and CYP2D6/2C19/2B6/1A2 genotypes involved in the metabolism of MDMA. Significance: This is the first study to investigate the role of the DA transporter in the mechanism of action of MDMA in humans. It is also the first pharmacogenetic study to assess the contribution of genetic variations in the monaminergic system to the effects of MDMA. Worldwide, there are no similarly large cohorts that would allow for the testing of these associations including also CYP pheno- and genotype data. The study will contribute to our understanding of the role of DA/NE vs. SERT and in particular the genetic determinants underlying the interindividual differences in the effects of amphetamine-like substances.
Psychological, physiological, endocrine, and pharmacokinetic effects of LSD in a controlled study Research Project | 2 Project MembersBackground: Lysergic acid diethylamide (LSD) is the prototype hallucinogen used recreationally worldwide. In the 50-70s, LSD was also used to study psychotic-like states in normals ("model psychosis") and in "psycholytic psychotherapy". Clinical research using LSD has been prohibited in most countries over the last 30 years and there is now a renewed interest in the pharmacology of this substance. Potential research and therapeutic uses of LSD are now re-recognized and may include its use in brain research, treatment of cluster headache, and aid in psychotherapy and in terminally ill patients. Recently, a first placebo-controlled study in patients suffering from anxiety associated with advanced-stage life threatening diseases has been completed in Switzerland. However, most initial studies conducted with LSD do not meet todays' research standards and many effects of the substance including those on the endocrine system and the pharmacokinetic-pharmacodynamic relationship are unknown. Study aim: To characterize the acute psychological, physiological, endocrine, and pharmacokinetic, as well as long-term psychological effects of LSD in humans (psychotherapists). Methods: Placebo-controlled, double-blind, randomized two-phase cross-over study to test the effects of LSD (200 mg) or placebo in 16 well-educated middle aged healthy human subjects. Outcome measures of acute effects will include: validated psychometric tests, physiological effects, neuroendocrine measures, plasma concentration-time profiles of LSD, and adverse effects. Additionally, long-term psychological effects of LSD will be assessed 1 and 12 months after the experience. Significance. LSD is the most famous psychedelic substance. LSD is continued to be used recreationally. There is also a professional need for more clinical data on its role in experimental research and possible therapeutic applications (headache, psychotherapy, palliative medicine). This would be the first placebo-controlled and methodologically sound evaluation of the pharmacological and long-term psychological effects of LSD in humans. In addition, the endocrine effects of LSD are unknown. A better and contemporary understanding of the pharmacology of LSD is important in the light of its widespread recreational and potential scientific uses. The study will provide a first and solid account of the clinical pharmacological characteristics of the drug that are very likely to form a basis for further studies. Such ensuing experimental work in the near future may include the use of LSD in a psychotherapeutic setting in professional therapists as participants and a functional magnetic resonance imaging study to define the neuronal correlates of the effects of LSD.
Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs.
Emotionale und soziale Effekte von MDMA und Methylphenidat Research Project | 1 Project MembersIn this project we will investigate the emotional and prosocial effects of 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) and methylphenidate in healthy subjects. MDMA is used recreationally for its euphoric effects and in clinical trials in patients with posttraumatic stress disorder. Methylphenidate is used therapeutically in the treatment of attention deficit hyperactivity disorder but also abused to enhance performance. We will assess emotional effects of MDMA and methylphenidate alone and in combination in a placebo-controlled cross-over design using validated psychometric tools and established assessments of emotional face recognition, cognitive empathy, and prosocial behavior as outcome measures. We hypothesize that the two psychostimulants will elevate mood, shift emotion recognition towards a more positive perception of feelings while negatively affecting accuracy. MDMA and methylphenidate and also differentially alter cognitive empathy and social value orientation measures. In addition, we will assess whether methylphenidate will attenuate emotional effects of MDMA in humans and MDMA-induced dopamine and norepinephrine release in vitro and in vivo. Thus, the project will include both a pharmacological interaction study in humans and preclinical experiments. Together the studies aim at an understanding of the pharmacology underlying the mood and potential prosocial effects of psychostimulants. The project is designed as an extension of our SNF project to assess the mechanism of action of MDMA. We include an assessment of the effects of methylphenidate which is increasingly used in our society and focus on mood processing and sociobehavioral effects of MDMA and methylphenidate that have not yet been studied. It is also expected that the present project will provide us with important data to attract funding for a larger study on the social effects of psychostimulants.
Interactive effects of doxazosin and MDMA in healthy subjects Research Project | 1 Project MembersNo Description available
Duloxetine/Clonidine-MDMA Studies Research Project | 1 Project MembersInteraction-Studies of Duloxetine or Clonidin with MDMA. Support in the form of personnel that is directly paid by the fund. Wissenschaftsfonds Departement of Internal Medicine of the University Hospital.
Interaction of Duloxetine and MDMA Research Project | 1 Project Members3,4-methylenedioxymethamphetamine (MDMA, ecstasy ) is widely used by young people for its euphoric effects. MDMA releases serotonin (5-HT), norepinephrine (NE), and dopamine through an interaction with the corresponding presynaptic monoamine uptake transporter. 5-HT transport inhibitors block MDMA-induced 5-HT release in vitro or in animals and also attenuate the subjective and cardiovascular response to MDMA in humans. NE transport inhibitors similarly prevent the MDMA-induced release of NE in cell assays and attenuate behavioral effects of MDMA in animals. Here, we suggest evaluating effects of pretreatment with the combined 5-HT and NE transport blocker duloxetine on the pharmacodynamics and pharmacokinetics of MDMA. This approach is used to assess the role of 5-HT and NE in the mediation of MDMA s effects in humans. The study will use a randomized double-blind cross-over design with four experimental sessions. Duloxetine (120 mg) or placebo will be administered 16 h and 4 h before the administration of MDMA (125 mg) or placebo to 16 healthy volunteers. Subjective and cardiovascular responses and plasma samples for pharmacokinetics will be repeatedly assessed throughout the experiments. We hypothesize that duloxetine will attenuate the subjective and cardiovascular response to MDMA. Such a result would indicat that MDMA produces its psychological and physiological effects in humans mainly by transporter-mediated release of 5-HT and NE.
