Matthias E. Liechti

Bio: Matthias E. Liechti is an academic researcher from University Hospital of Basel. The author has contributed to research in topics: MDMA & Medicine. The author has an hindex of 50, co-authored 201 publications receiving 8389 citations. Previous affiliations of Matthias E. Liechti include University of Cambridge & University of Bern.

Pharmacological characterization of designer cathinones in vitro

Abstract: Background and purpose: Designer beta-keto amphetamines (e.g., cathinones, "bath salts," and "research chemicals") have become popular recreational drugs, but their pharmacology is poorly characterized. Experimental approach: We determined the potencies of cathinones to inhibit dopamine (DA), noradrenaline (NA), and serotonin (5-hydroxytryptamine [5-HT]) transport into transporter-transfected human embryonic kidney 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. Key results: Mephedrone, methylone, ethylone, butylone, and naphyrone act as nonselective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone, and butylone also release 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone, and flephedrone act as preferential DA and NA uptake inhibitors and DA releasers, similar to amphetamine and methamphetamine. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) are highly potent and selective DA and NA transporter inhibitors but unlike amphetamines do not release monoamines. The non-beta-keto amphetamines are trace amine-associated receptor 1 ligands, whereas cathinones are not. All cathinones showed high blood-brain barrier permeability in an in vitro model. Mephedrone and MDPV exhibited particularly high permeability. Conclusions and implications: Cathinones have considerable pharmacological differences that form the basis for their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is likely associated with a considerable risk of addiction. (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British Pharmacological Society.

Gender differences in the subjective effects of MDMA.

Abstract: Rationale: 3,4-Methylenedioxymethamphetami- ne (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 con- trolled studies on the psychological and physiological ef- fects of MDMA in healthy volunteers with no or mini- mal MDMA experience. A particular focus of the ana- lyses 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 psychomet- ric rating scales. Physiological measures were blood pressure, heart rate, and peripheral body temperature. Adverse drug effects were assessed during the experi- mental session and after 24 h. Results: Psychoactive ef- fects 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 posi- tively 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 con- trast, men showed higher increases in blood pressure than woman. Conclusions: The fact that equal doses of MDMA per kilogram body weight produce stronger re- sponses 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 increas- ing doses of MDMA produce more hallucinogen-like perceptual alterations, particularly in women.

European Monitoring Centre for Drugs and Drug Addiction

Abstract: INTRODUCTION The issue of social rehabilitation and reintegration (hereafter social reintegration2) is mentioned under the third strategy target of the EU Action Plan 2000–2004. The third EU strategy target is to 'substantially increase the number of successfully treated addicts', and point 3.1.3.4 instructs that 'Member States [are] to ensure that adequate attention is paid to social and professional rehabilitation and reintegration of former addicts'. However, social reintegration is also linked to social exclusion, which is mentioned in chapter 2 of the EU Action Plan, where it is stated that 'the EMCDDA [is] to develop indicators on drug-related crime, the availability of illicit drugs (including at street level) and drug-related social exclusion'. For the EMCDDA, social reintegration comes under strategy target four – that is, as a response to social exclusion – however, target two is clearly also relevant. Social exclusion is often perceived as a cause of problem drug use, although many see it as a consequence of problem drug use. We will not elaborate on this further here, except to note that social exclusion and problem drug use are two phenomena that are very closely interlinked and that social reintegration is a possible response to both. The EMCDDA Programme 2, 'Analysis of responses', set out to identify how social reintegration is understood in each Member State and to map the availability of social reintegration facilities in Member States according to these national perceptions. It became evident at an early stage that this would be a complex task, involving extensive data collection, as national reports generally provided insufficient data on this specific subject. eight countries turned out to be difficult to map and so, in February 2002, the EMCDDA launched a call for tender for a project, 'Mapping social reintegration services in EU countries'. 3 The aim of this project was to describe the state of the art of social reintegration in the following eight countries: The research specifications, to investigate 'the state of the art of social reintegration', suggested that the following should be identified for each of the eight countries: 1 Other contributors will be mentioned in the respective chapters. 2 Our country studies so far have shown that the term 'rehabilitation' is used ambiguously across Europe – from low-threshold refuges, to normal treatment, to actual reintegration into society. For this reason, we shall use the term 'social reintegration' in this report, as this is used much more …

Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

Abstract: Rationale: Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30–500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). Objective: This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. Methods: All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. Results: The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps post-traumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. Conclusions: Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

Abstract: Rationale: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. Objective: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Methods: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Results: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Conclusions: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

Abstract: The amphetamine derivative (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug among young people, particularly those involved in the dance culture. MDMA produces an acute, rapid enhancement in the release of both serotonin (5-HT) and dopamine from nerve endings in the brains of experimental animals. It produces increased locomotor activity and the serotonin behavioral syndrome in rats. Crucially, it produces dose-dependent hyperthermia that is potentially fatal in rodents, primates, and humans. Some recovery of 5-HT stores can be seen within 24 h of MDMA administration. However, cerebral 5-HT concentrations then decline due to specific neurotoxic damage to 5-HT nerve endings in the forebrain. This neurodegeneration, which has been demonstrated both biochemically and histologically, lasts for months in rats and years in primates. In general, other neurotransmitters appear unaffected. In contrast, MDMA produces a selective long-term loss of dopamine nerve endings in mice. Studies on the mechanisms involved in the neurotoxicity in both rats and mice implicate the formation of tissue-damaging free radicals. Increased free radical formation may result from the further breakdown of MDMA metabolic products. Evidence for the occurrence of MDMA-induced neurotoxic damage in human users remains equivocal, although some biochemical and functional data suggest that damage may occur in the brains of heavy users. There is also some evidence for long-term physiological and psychological changes occurring in human recreational users. However, such evidence is complicated by the lack of knowledge of doses ingested and the fact that many subjects studied are or have been poly-drug users.