Matthias E. Liechti

Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA ("Ecstasy") in MDMA-Naïve Healthy Volunteers

3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants. It has, therefore, been tentatively classified into a novel pharmacological class termed entactogens. This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA (1.7 mg/kg) in 13 MDMA-naıuml;ve healthy volunteers. MDMA produced an affective state of enhanced mood, well-being, and increased emotional sensitiveness, little anxiety, but no hallucinations or panic reactions. Mild depersonalization and derealization phenomena occurred together with moderate thought disorder, first signs of loss of body control, and alterations in the meaning of percepts. Subjects also displayed changes in the sense of space and time, heightened sensory awareness, and increased psychomotor drive. MDMA did not impair selective attention as measured by the Stroop test. MDMA increased blood pressure moderately, with the exception of one subject who showed a transient hypertensive reaction. This severe increase in blood pressure indicates that the hypertensive effects of MDMA, even at recreational doses, should not be underestimated, particularly in subjects with latent cardiovascular problems. Most frequent acute somatic complaints during the MDMA challenge were jaw clenching, lack of appetite, impaired gait, and restless legs. Adverse sequelae during the following 24 hours included lack of energy and appetite, feelings of restlessness, insomnia, jaw clenching, occasional difficulty concentrating, and brooding. The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants.

Pharmacological characterization of designer cathinones in vitro

Designer β‐keto amphetamines (e.g. cathinones, ‘bath salts’ and ‘research chemicals’) have become popular recreational drugs, but their pharmacology is poorly characterized.

Acute Psychological Effects of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) are Attenuated by the Serotonin Uptake Inhibitor Citalopram

3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug that has been shown to release serotonin (5-HT) and dopamine (DA) in animals. The effect of MDMA on 5-HT release can be blocked by 5-HT uptake inhibitors such as citalopram, suggesting that MDMA interacts with the 5-HT uptake site. It is unknown whether this mechanism is also responsible for the psychological effects of MDMA in humans. We investigated the effect of citalopram pretreatment (40 mg iv) on the psychological effects of MDMA (1.5 mg/kg po) in a double-blind placebo-controlled psychometric study in 16 healthy human volunteers. MDMA produced an emotional state with heightened mood, increased self-confidence and extroversion, moderate derealization, and an intensification of sensory perception. Most of these effects were markedly reduced by citalopram. This finding suggests that the psychological effects of MDMA are mediated via action at the 5-HT uptake site to increase 5-HT release through the carrier, as expected from animal studies.

Psychological and Physiological Effects of MDMA (“Ecstasy”) after Pretreatment with the 5-HT2 Antagonist Ketanserin in Healthy Humans

MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) mainly releases serotonin and dopamine. In animals, pretreatment with 5-HT2 antagonists has been shown to attenuate neurochemical and behavioral effects of MDMA. In humans, the role of 5-HT2 receptors in the action of MDMA has not been studied. We investigated the effect of pretreatment with the 5-HT2A/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-HT2 receptors in the action of MDMA in humans.

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 shortterm 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.

Acute effects of lysergic acid diethylamide in healthy subjects

BACKGROUND After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans. METHODS In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects. RESULTS Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed. CONCLUSIONS In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

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 D2 antagonist haloperidol (1.4 mg IV) in 14 subjects, and (3) the 5-HT2A/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.

Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxymethamphetamine (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

The Norepinephrine Transporter Inhibitor Reboxetine Reduces Stimulant Effects of MDMA (“Ecstasy”) in Humans

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.

To Dope or Not to Dope: Neuroenhancement with Prescription Drugs and Drugs of Abuse among Swiss University Students

Background Neuroenhancement is the use of substances by healthy subjects to enhance mood or cognitive function. The prevalence of neuroenhancement among Swiss university students is unknown. Investigating the prevalence of neuroenhancement among students is important to monitor problematic use and evaluate the necessity of prevention programs. Study aim To describe the prevalence of the use of prescription medications and drugs of abuse for neuroenhancement among Swiss university students. Method In this cross-sectional study, students at the University of Zurich, University of Basel, and Swiss Federal Institute of Technology Zurich were invited via e-mail to participate in an online survey. Results A total of 28,118 students were contacted, and 6,275 students completed the survey. Across all of the institutions, 13.8% of the respondents indicated that they had used prescription drugs (7.6%) or drugs of abuse including alcohol (7.8%) at least once specifically for neuroenhancement. The most frequently used prescription drugs for neuroenhancement were methylphenidate (4.1%), sedatives (2.7%), and beta-blockers (1.2%). Alcohol was used for this purpose by 5.6% of the participants, followed by cannabis (2.5%), amphetamines (0.4%), and cocaine (0.2%). Arguments for neuroenhancement included increased learning (66.2%), relaxation or sleep improvement (51.2%), reduced nervousness (39.1%), coping with performance pressure (34.9%), increased performance (32.2%), and experimentation (20%). Neuroenhancement was significantly more prevalent among more senior students, students who reported higher levels of stress, and students who had previously used illicit drugs. Although “soft enhancers”, including coffee, energy drinks, vitamins, and tonics, were used daily in the month prior to an exam, prescription drugs or drugs of abuse were used much less frequently. Conclusions A significant proportion of Swiss university students across most academic disciplines reported neuroenhancement with prescription drugs and drugs of abuse. However, these substances are rarely used on a daily basis and more sporadically used prior to exams.