Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination.

Recent studies suggest that the antidepressant effects of the psychedelic 5-HT2A receptor agonist psilocybin are mediated through its modulatory properties on prefrontal and limbic brain regions including the amygdala. To further investigate the effects of psilocybin on emotion processing networks, we studied for the first-time psilocybin's acute effects on amygdala seed-to-voxel connectivity in an event-related face discrimination task in 18 healthy volunteers who received psilocybin and placebo in a double-blind balanced cross-over design. The amygdala has been implicated as a salience detector especially involved in the immediate response to emotional face content. We used beta-series amygdala seed-to-voxel connectivity during an emotional face discrimination task to elucidate the connectivity pattern of the amygdala over the entire brain. When we compared psilocybin to placebo, an increase in reaction time for all three categories of affective stimuli was found. Psilocybin decreased the connectivity between amygdala and the striatum during angry face discrimination. During happy face discrimination, the connectivity between the amygdala and the frontal pole was decreased. No effect was seen during discrimination of fearful faces. Thus, we show psilocybin's effect as a modulator of major connectivity hubs of the amygdala. Psilocybin decreases the connectivity between important nodes linked to emotion processing like the frontal pole or the striatum. Future studies are needed to clarify whether connectivity changes predict therapeutic effects in psychiatric patients.

Effects of a beta-blocker on the cardiovascular response to MDMA (Ecstasy).

BACKGROUND: MDMA (3,4-methylenedioxymethamphetamine, 'Ecstasy') produces tachycardia and hypertension and is rarely associated with cardiovascular and cerebrovascular complications. In clinical practice, beta-blockers are often withheld in patients with stimulant intoxication because they may increase hypertension and coronary artery vasospasm due to loss of beta(2)-mediated vasodilation and unopposed alpha-receptor activation. However, it is unknown whether beta-blockers affect the cardiovascular response to MDMA. METHODS: The effects of the non-selective beta-blocker pindolol (20 mg) on the cardiovascular effects of MDMA (1.6 mg/kg) were investigated in a double-blind placebo-controlled crossover study in 16 healthy subjects. RESULTS: Pindolol prevented MDMA-induced increases in heart rate. Peak values (mean+/-SD) for heart rate were 84+/-13 beats/min after MDMA vs 69+/-7 beats/min after pindolol-MDMA. In contrast, pindolol pretreatment had no effect on increases in mean arterial blood pressure (MAP) after MDMA. Peak MAP values were 115+/-11 mm Hg after MDMA vs 114+/-11 mm Hg after pindolol-MDMA. Pindolol did not change adverse effects of MDMA. CONCLUSION: The results of this study indicate that beta-blockers may prevent increases in heart rate but not hypertensive and adverse effects of MDMA.

Microcalcification after excitotoxicity is enhanced in transgenic mice expressing parvalbumin in all neurones, may commence in neuronal mitochondria and undergoes structural modifications over time.

AIMS: Parenchymal microcalcification in the brain coincides with neurodegenerative diseases, but is also frequently found in neurologically normal individuals. The origin and role of this process are still under debate. Parvalbumin (PV) is a protein acting as a Ca(2+) buffer and Ca(2+) shuttle towards intracellular Ca(2+) sinks, like mitochondria and the endoplasmic reticulum. Constitutively, it is present in a subset of inhibitory neurones. In transgenic mice expressing pan-neuronal PV, the mitochondrial volume is reduced. We tested whether elevated levels of intraneuronal [Ca(2+)] and reduced mitochondrial volume in the neurone interfere with the generation of parenchymal microcalcification. METHODS: The striatum of wild type and transgenic mice was injected with the glutamate receptor agonist ibotenic acid (IBO), which is known to induce not only excitotoxic neurodegeneration, but also parenchymal calcification. Sections were studied by light and electron microscopy at various time points after IBO application. RESULTS: Morphometric analysis 2, 4 and 20 weeks after IBO application revealed microcalcification in transgenic and wild type mice; the calcification process, however, was enhanced and accelerated in the transgenic animals. Ultrastructural analyses suggest neuronal mitochondria as the nucleators of the deposits which consist of hydroxyapatite. The time-dependent changes in size and surface structure of the deposits indicate the presence of biological mechanisms in the brain promoting regression of bioapatites. CONCLUSIONS: The overload of intraneuronal [Ca(2+)] in combination with impaired mitochondrial function activates neuronal microcalcification. It is hypothesized that this process is an alternative/adaptive mechanism of the neurone to reduce further brain damage.

GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies.

[(18)F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [(18)F]altanserin useful for application in humans. We introduced thermal heating for drying of [(18)F]fluoride as well as for the reaction instead of microwave heating. We furthermore describe solid phase extraction and HPLC procedures for quantitative determination of [(18)F]altanserin and metabolites in plasma. The time course of arterial plasma activity with and without metabolite correction was determined. 90 min after bolus injection, 38.4% of total plasma activity derived from unchanged [(18)F]altanserin. Statistical comparison of kinetic profiles of [(18)F]altanserin metabolism in plasma samples collected in the course of two ongoing studies employing placebo, the serotonin releaser dexfenfluramine and the hallucinogen psilocybin, revealed the same tracer metabolism. We conclude that metabolite analysis for correction of individual plasma input functions used in tracer modeling is not necessary for [(18)F]altanserin studies involving psilocybin or dexfenfluramine treatment.

Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

GABA(B) receptor expression and cellular localization in gerbil hippocampus after transient global ischemia.

Using in situ hybridization, the expression of the GABA receptor subtype B subunit 1 (GABA(B) R1) and subunit 2 (GABA(B) R2) following transient global ischemia in the gerbil hippocampus was investigated. In sham-operated animals, mRNAs of both subunits were mainly detected in hippocampal pyramidal cells and interneurons with lower expression levels of the GABA(B) R2 in the CA1 field. Four days after transient cerebral ischemia, neuronal message decreased in conjunction with neuronal death and both receptor subunits disappeared from the pyramidal cell layer. However, GABA(B) R1 and GABA(B) R2 were still expressed in a few cells. In situ hybridization of the GABA synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) remained unchanged after the ischemic insult. Double-labeling experiments revealed that in the postischemic hippocampus GABA(B) R1 and GABA(B) R2 were not present in GFAP-reactive astrocytes, but that the surviving parvalbumin-containing interneurons possessed GABA(B) R1 and GABA(B) R2 mRNA.

[Hallucinogens, amphetamines and entactogens]. / Halluzinogene, Amphetamine und Entactogene.

MDMA ("Ecstasy") and its analogues such as MDE and MDA are amphetamine derivatives reported to produce an altered state with emotional overtones. Since more than ten years, ecstasy is after cannabis the most frequently used recreational drug by young adults, particularly in the so-called techno-scene. However, according to a recent survey there is an increasing trend for a revival of classic amphetamine and hallucinogen abuse, possibly due to the concern about the potential neurotoxicity and somatic risks associated with ecstasy use. Of the hallucinogens consumed, psilocybin containing mushroom ("magic mushrooms"), but also LSD are at the forefront. The present contribution summarizes the psychological and somatic effects of hallucinogens, amphetamines, and entactogens.

Prepulse inhibition deficits in patients with panic disorder.

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is reduced in several neuropsychiatric disorders that are characterized by deficits in inhibition or gating of intrusive or irrelevant stimuli. Clinically, panic disorder (PD) patients have been described as having difficulties in inhibition of responding to sensory and cognitive events. Because such difficulties may be due to failures in early stages of information processing, we examined PPI in patients with PD. Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-, 240-, and 2,000-ms interstimulus intervals) were assessed in patients with panic disorder (m/f = 10, 10) and age- and gender-matched healthy controls (m/f = 11, 10). PD patients were assessed with structured clinical interview for DSM-IV criteria with benzodiazepine treatment as an exclusion criterion. Panic disorder patients exhibited normal startle reactivity, reduced habituation, and significantly reduced PPI in the 30-, 60-, and 240-ms prepulse conditions. Within the PD group, the patients with high trait and state anxiety exhibited less PPI than patients with low trait and state anxiety. Furthermore, in PD patients, decreased PPI correlated significantly with high trait but not state anxiety. These data indicate that early stages of sensory information processing are abnormal in patients with PD. These observed deficits in PPI could reflect a more generalized difficulty in suppressing or gating information in panic disorder. The correlation between high trait anxiety and deficient PPI supports the hypothesis that sensorimotor gating abnormalities are an enduring feature of subjects with PD.

A systems model of altered consciousness: integrating natural and drug-induced psychoses.

Increasing evidence from neuroimaging and behavioral studies suggests that functional disturbances within cortico-striato-thalamic pathways are critical to psychotic symptom formation in drug-induced and possibly also naturally occurring psychoses. Recent basic and clinical research with psychotomimetic drugs, such as the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, and the serotonin-2A (5-HT(2A)) receptor agonist, psilocybin, suggest that the hallucinogenic effects of these drugs arise, at least in part, from their common capacity to disrupt thalamo-cortical gating of external and internal information to the cortex. Deficient gating of sensory and cognitive information is thought to result in an overloading inundation of information and subsequent cognitive fragmentation and psychosis. Cross-species studies of homologues gating functions, such as prepulse inhibition of the startle reflex, in animal and human models of psychosis corroborate this view and provide a translational testing mechanism for the exploration of novel pathophysiologic and therapeutic hypotheses relevant to psychotic disorders, such as the group of schizophrenias.

A neural network approach to the acoustic startle reflex and prepulse inhibition.

Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense stimulus is preceded by a weak non-startling prestimulus. PPI is widely used as a model for sensorimotor gating processes and has been shown to be impaired in various neuropsychiatric disorders, including schizophrenia. We have reproduced startle-like behavior and basic PPI modifications with a neural network. The network design was constrained by the attempt (1) to use as few connections as possible and (2) to relate neuroanatomical structures to the simulated network. Performance of the network was evaluated by the behavior of the simulated motor neurons in response to prepulse and pulse stimuli presented with various lead intervals and prepulse intensities. A delayed inhibitory pathway via the pedunculopontine nucleus (PPTg) to the caudal pontine reticular nucleus was found to be a necessary but insufficient requirement to reproduce basic PPI output patterns. Additional requirements included (a) a low threshold at or below the caudal pontine reticular formation, (b) signal amplification in the inhibitory pathway and (c) prolongation of activity in the inhibitory pathway. On the grounds of the most appropriate output patterns of the simulations, we propose a mechanism of sustained activation in the PPTg due to recursive connections. Relations between stimuli, behavior (motor output) and the underlying architecture are discussed. Potentially, this modeling technique can be extended to investigate the impact of drugs and higher brain regions on PPI.

Localization of MDMA-induced brain activity in healthy volunteers using low resolution brain electromagnetic tomography (LORETA).

3,4-Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a psychostimulant drug producing heightened mood and facilitated social communication. In animal studies, MDMA effects are primarily mediated by serotonin (5-HT), but also by dopamine (DA) and possibly noradrenaline (NA). In humans, however, the neurochemical and neurophysiological basis of acute MDMA effects remains unknown. The distribution of active neuronal populations after administration of a single dose of MDMA (1.7 mg/kg) or placebo was studied in 16 healthy, MDMA-naïve volunteers. Thirty-one-channel scalp EEGs during resting with open and closed eyes was analyzed in the different EEG frequency bands. Scalp maps of power showed significant, global differences between MDMA and placebo in both eye conditions and all frequency bands. Low resolution brain electromagnetic tomography (LORETA) was used to compute 3D, functional images of electric neuronal activity from the scalp EEG data. MDMA produced a widespread decrease of slow and medium frequency activity and an increase of fast frequency activity in the anterior temporal and posterior orbital cortex, concomitant with a marked enhancement of mood, emotional arousal and increased extraversion. This activation of frontotemporal areas indicates that the observed enhancement of mood and possibly the increased extroversion rely on modulation of limbic orbitofrontal and anterotemporal structures known to be involved in emotional processes. Comparison of the MDMA-specific EEG pattern with that of various 5-HT, DA, and NA agonists indicates that serotonin, noradrenaline, and, to a lesser degree, dopamine, contribute to the effects of MDMA on EEG, and possibly also on mood and behavior.

Gender differences in the subjective effects of MDMA.

RATIONALE: 3.4-Methylenedioxymethamphetamine (MDMA) mainly releases serotonin (5-HT) and is contained in the recreational drug Ecstasy. 5-HT is known to play an important role in mood and anxiety disorders, for which there is a female preponderance. To date, there are no systematic data on gender differences in the subjective effects of MDMA. OBJECTIVES: The present work analyzed the pooled data from three controlled studies on the psychological and physiological effects of MDMA in healthy volunteers with no or minimal MDMA experience. A particular focus of the analyses were possible gender differences. METHODS: A total of 74 subjects (54 male, 20 female) participated in all three studies. MDMA in oral doses ranging from 70-150 mg (1.35-1.8 mg/kg) was administered under double-blind placebo-controlled conditions. Subjective peak changes were assessed by standardized psychometric rating scales. Physiological measures were blood pressure, heart rate, and peripheral body temperature. Adverse drug effects were assessed during the experimental session and after 24 h. RESULTS: Psychoactive effects of MDMA were more intense in women than in men. Women especially had higher scores for MDMA-induced perceptual changes, thought disturbances, and fear of loss of body control. The dose of MDMA positively correlated with the intensity of perceptual changes in women. Acute adverse effects and sequelae were also more frequent in female than in male subjects. In contrast, men showed higher increases in blood pressure than woman. CONCLUSIONS: The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the 5-HT-releasing effects of MDMA. Our results also indicate that increasing doses of MDMA produce more hallucinogen-like perceptual alterations, particularly in women.

No difference in brain activation during cognitive performance between ecstasy (3,4-methylenedioxymethamphetamine) users and control subjects: a [H2(15)O]-positron emission tomography study.

The long-term use of the serotonin-releaser and uptake-inhibitor 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") has been associated with memory impairments and increased liability to depressive mood and anxiety attacks. It is unclear, however, whether these psychologic deviations are reflected in alterations of the underlying neurophysiologic substrate. The authors compared mood and regional cerebral blood flow (rCBF) profiles between regular polytoxic Ecstasy users and Ecstasy-naive controls. Brain activity as indexed by rCBF was measured during cognitive activation by an attentional task using positron emission tomography and [H2(15)O]. Mood was assessed by means of the Hamilton Rating Scale for Depression (HAM-D) and the EWL Mood Rating Scale. Statistical parametric mapping revealed that brain activity did not differ between the two groups. Both groups also performed equally on the cognitive task requiring sustained attention. However, significantly higher levels of depressiveness as determined by the HAM-D and EWL scales were found in Ecstasy-using subjects. These data indicate that, despite differences in mood, polytoxic Ecstasy users do not differ from Ecstasy-naive controls in terms of local brain activity. Heightened depressiveness in the Ecstasy group was consistent with results from previous studies and could be related to serotonergic hypofunction resulting from repeated MDMA consumption. However, this study cannot exclude the possibility that the observed differences are preexisting rather than a result of Ecstasy use.

Effects of MDMA (ecstasy) on prepulse inhibition and habituation of startle in humans after pretreatment with citalopram, haloperidol, or ketanserin.

Prepulse inhibition (PPI) of the acoustic startle response is an operational measure of sensorimotor gating that can be assessed in animals and in humans. Serotonin releasers such as MDMA disrupt PPI and reduce startle habituation in rodents. These effects are prevented by pretreatment with selective serotonin uptake inhibitors, indicating that the effect of MDMA on startle plasticity is largely due to carrier-mediated release of serotonin from presynaptic terminals. In contrast, MDMA has been shown to increase PPI in humans. It is unclear, however, whether the MDMA-induced increase in PPI in humans is also dependent on carrier-mediated serotonin release and which postsynaptic receptors are involved. We investigated the effects of three different pretreatments on the MDMA-induced effects on PPI and habituation in humans. Pretreatments were: (1) the highly selective serotonin uptake inhibitor citalopram (40 mg IV) in 16 subjects, (2) the D(2) antagonist haloperidol (1.4 mg IV) in 14 subjects, and (3) the 5-HT(2A/C) antagonist ketanserin (50 mg PO) in 14 subjects. Each of the three studies used a double-blind placebo-controlled design. All healthy volunteers were examined four times at 2-4-week intervals after placebo, pretreatment, MDMA (1.5 mg/kg PO), and pretreatment plus MDMA. MDMA increased PPI. Habituation was not altered by MDMA, although MDMA-induced individual differences on habituation and psychological symptoms were inversely correlated. Citalopram attenuated the MDMA-induced increase in PPI and most of the psychological effects of MDMA. Neither haloperidol nor ketanserin had any effect on PPI increases produced by MDMA, although each partially attenuated some MDMA-induced psychological effects. Results are consistent with the view that MDMA increases PPI of the acoustic startle reflex in humans via release of presynaptic serotonin.

Brain mechanisms of hallucinogens and entactogens.

This review focuses on recent brain imaging and behavioral studies of sensory gating functions, which assess similarities between the effects of classic hallucinogens (eg, psilocybin), dissociative anesthetics (eg, ketamine), and entactogens (eg, 3,4-methylenedioxymethamphetamine [MDMA]) in humans. Serotonergic hallucinogens and psychotomimetic anesthetics produce overlapping psychotic syndromes associated with a marked activation of the prefrontal cortex (hyperfrontality) and other overlapping changes in temporoparietal, striatal, and thalamic regions, suggesting that both classes of drugs act upon a common final pathway. Together with the observation that both hallucinogens and N-methyl-oaspartate (NMDA) antagonists disrupt sensory gating in rats by acting on 5-hydroxytryptamine (serotonin) 5-HT(2) receptors located in cortico-striato-thalamic circuitry these findings suggest that disruption of cortico-subcortical processing leading to sensory overload of the cortex is a communality of these psychoses. In contrast to hallucinogens, the entactogen MDMA produces an emotional state of positive mood, concomitant with an activation of prefrontolimbiclparalimbic structures and a deactivation of amygdala and thalamus.

Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia.

BACKGROUND: In patients with schizophrenia, deficient generation of mismatch negativity (MMN)-an event-related potential (ERP) indexing auditory sensory ("echoic") memory-and a selective increase of "context dependent" ("BX") errors in the "A-X" version of the Continuous Performance Test (AX-CPT) indicate an impaired ability to form and use transient memory traces. Animal and human studies implicate deficient N-methyl-D-aspartate receptor (NMDAR) functioning in such abnormalities. In this study, effects of the NMDAR antagonists ketamine on MMN generation and AX-CPT performance were investigated in healthy volunteers to test the hypothesis that NMDARs are critically involved in human MMN generation, and to assess the nature of ketamine-induced deficits in AX-CPT performance. METHODS: In a single-blind placebo-controlled study, 20 healthy volunteers underwent an infusion with subanesthetic doses of ketamine. The MMN-to-pitch and MMN-to-duration deviants were obtained while subjects performed an AX-CPT. RESULTS: Ketamine significantly decreased the peak amplitudes of the MMN-to-pitch and MMN-to-duration deviants by 27% and 21%, respectively. It induced performance deficits in the AX-CPT characterized by decreased hit rates and specific increases of errors (BX errors), reflecting a failure to form and use transient memory traces of task relevant information. CONCLUSIONS: The NMDARs are critically involved in human MMN generation. Deficient MMN in schizophrenia thus suggests deficits in NMDAR-related neurotransmission. N-methyl-D-aspartate receptor dysfunction may also contribute to the impairment of patients with schizophrenia in forming and using transient memory traces in more complex tasks, such as the AX-CPT. Thus, NMDAR-related dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia. Arch Gen Psychiatry. 2000;57:1139-1147.

The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine ('Ecstasy') in healthy volunteers.

MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' is a widely used recreational drug that produces a state of heightened mood but also cardiovascular and vegetative side-effects. In animals, MDMA releases serotonin and, to a lesser extent, dopamine and norepinephrine. The release of serotonin can be blocked by serotonin uptake inhibitors such as citalopram. It is unknown to what extent this mechanism is also responsible for the physiological side-effects of MDMA seen in humans. We investigated the effect of citalopram pretreatment (40 mg i.v.) on vegetative and cardiovascular effects of MDMA (1.5 mg/kg p.o.) in a double-blind placebo-controlled study in 16 healthy volunteers. MDMA moderately increased blood pressure and heart rate, slightly elevated body temperature and produced a broad range of acute and short-term side-effects. Citalopram reduced all these MDMA-induced physiological changes except for body temperature. These findings suggest that physiological effects of MDMA in humans are partially due to an interaction of MDMA with the serotonin carrier and a subsequent release of serotonin.

3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy humans.

[H(2)(15)O]-Positron Emission Tomography (PET) was used to examine regional cerebral blood flow (rCBF) after administration of a single oral dose of the serotonin realeaser and uptake inhibitor MDMA (1.7 mg/kg) or placebo to 16 MDMA-naïve subjects. Psychological changes were assessed by psychometric rating scales. MDMA produced distributed changes in regional blood flow including increases in ventromedial frontal and occipital cortex, inferior temporal lobe and cerebellum; and decreases in the motor and somatosensory cortex, temporal lobe including left amygdala, cingulate cortex, insula and thalamus. Concomitant with these changes, subjects experienced heightened mood, increased extroversion, slight derealization and mild perceptual alterations. MDMA also produced increases in blood pressure and several side effects such as jaw clenching, lack of appetite and difficulty concentrating. These results indicate that a distributed cluster of brain areas underlie the various effects of MDMA in humans.

Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans.

MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") mainly releases serotonin and dopamine. In animals, pretreatment with 5-HT(2) antagonists has been shown to attenuate neurochemical and behavioral effects of MDMA. In humans, the role of 5-HT(2) receptors in the action of MDMA has not been studied. We investigated the effect of pretreatment with the 5-HT(2A/C) antagonist ketanserin (50 mg p.o.) on subjective responses to MDMA (1.5 mg/kg p.o.) in 14 healthy volunteers using a double-blind placebo-controlled within-subject design. Subjective effects were rated by psychometric rating scales. Physiological effects measured were blood pressure, heart rate, and body temperature. Adverse effects were assessed during the sessions, and after one and three days. Ketanserin attenuated MDMA-induced perceptual changes, emotional excitation, and acute adverse responses but had little effect on MDMA-induced positive mood, well-being, extroversion, and short-term sequelae. Body temperature was lower under MDMA plus ketanserin compared to MDMA alone. The results suggest a contributing role for 5-HT(2) receptors in the action of MDMA in humans.