Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans : lost in translation

We greatly appreciate the comments offered by Drs Rolle, Takematsu, and Hoffman and the opportunity to put our work into a wider perspective. We share the view that our work does not reflect the clinical situation but rather provides a proof of mechanism study, which aims to help to translate preclinical findings (Sprague et al., 2005) into the clinic. As we noted in the discussion of our work (Hysek et al., 2012b) the primary goal of the study was to investigate the role of adrenoceptors in the mechanism of action of MDMA in humans. Therefore, the study provided only indirect support for the use of carvedilol in the treatment of stimulant toxicity in which carvedilol would be administered following the ingestion of Ecstasy or other stimulants. Furthermore, we noted the limitation that the MDMA-induced increase in body temperature in our study was moderate and we do not know whether carvedilol would also be effective in cases of severe hyperthermia following ecstasy use

Telomerase related studies in thyroid cancer

Follicular thyroid neoplasms are diagnostically challenging. On histologic evaluation, it can be difficult, resource-consuming, and observer-dependent to pinpoint the exact location of capsular or vascular invasion. In some cases, it is impossible to do so unequivocally – for those, the term “follicular tumor of uncertain malignant potential” (FT-UMP) was created. On cytologic evaluation, it is less challenging but rather hardly possible to distinguish follicular thyroid adenoma (FTA) from follicular thyroid carcinoma (FTC). With the advent of molecular analyses in clinical diagnostic settings, many mutational events have been associated with specific cancers. Amongst those, two point mutations in the TERT promoter region, named C228T and C250T have been of particular interest as they have been associated with malignant properties in thyroid tumors in general and a worse prognosis with a higher frequency of relapse in particular. This thesis aims to improve the diagnostic accuracy for thyroid tumors in general and for follicular thyroid tumors in particular through the implementation of TERT promoter mutational screening. Study I evaluates the role of TERT promoter mutational screening in a clinical series of FT-UMPs and how this analysis aids in detecting relapse-prone tumors. This could help alter adjuvant treatment modalities even in the absence of clearcut histopathological evidence of malignant potential. Study II shows that digital droplet PCR (ddPCR) can improve the sensitivity for the detection of TERT promoter mutations in follicular thyroid tumors and can even detect TERT promoter mutations when they occur subclonal and are heterogeneously distributed in FT-UMPs. Study III validates TERT promoter mutational testing on preoperative material in the form of frozen pellets from thyroid FNAC material. We were able to show that ddPCR is a reliable analysis for cytologic material and may help to identify high-risk cases and triage them to a more aggressive treatment plan up-front, underlining the markers' diagnostic and prognostic value. Study IV tries to evaluate 5hmC immunoreactivity as an expressional analysis to pinpoint TERT promoter mutations in FTCs. Even though the study was able to show that the loss of 5hmC immunoreactivity may signify TERT promoter mutations in subsets of FTCs, we could not prove its clinical value to predict the TERT promoter mutational status. Further studies are therefore warranted. In summary, the findings in this thesis highlight the clinical importance of TERT promoter mutational screening in follicular thyroid neoplasms. Furthermore, we were able to show that ddPCR is a reliable technique for interrogating specific mutations of the TERT promoter

Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex

Rationale: Pupillometry can be used to characterize autonomic drug effects. Objective: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. Methods: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design. Results: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. Conclusions: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute toleranc

MDMA enhances "mind reading” of positive emotions and impairs "mind reading” of negative emotions

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) increases sociability. The prosocial effects of MDMA may result from the release of the "social hormone” oxytocin and associated alterations in the processing of socioemotional stimuli. Materials and methods: We investigated the effects of MDMA (125mg) on the ability to infer the mental states of others from social cues of the eye region in the Reading the Mind in the Eyes Test. The study included 48 healthy volunteers (24 men, 24 women) and used a double-blind, placebo-controlled, within-subjects design. A choice reaction time test was used to exclude impairments in psychomotor function. We also measured circulating oxytocin and cortisol levels and subjective drug effects. Results: MDMA differentially affected mind reading depending on the emotional valence of the stimuli. MDMA enhanced the accuracy of mental state decoding for positive stimuli (e.g., friendly), impaired mind reading for negative stimuli (e.g., hostile), and had no effect on mind reading for neutral stimuli (e.g., reflective). MDMA did not affect psychomotor performance, increased circulating oxytocin and cortisol levels, and produced subjective prosocial effects, including feelings of being more open, talkative, and closer to others. Conclusions: The shift in the ability to correctly read socioemotional information toward stimuli associated with positive emotional valence, together with the prosocial feelings elicited by MDMA, may enhance social approach behavior and sociability when MDMA is used recreationally and facilitate therapeutic relationships in MDMA-assisted psychotherapeutic setting

Acute Effects of Lysergic Acid Diethylamide on Circulating Steroid Levels in Healthy Subjects

Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, although the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, although its influence on plasma steroid levels over time has not yet been characterised in humans. The effects of LSD (200 μg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomised, double-blind, placebo-controlled, cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone and 11-dehydrocorticosterone compared to placebo. The mean maximum concentration of LSD was reached at 1.7 h. Mean peak psychedelic effects were reached at 2.4 h, with significant alterations in mental state from 0.5 h to > 10 h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5 h and 1.9 h, and significant elevations were observed 1.5-6 h and 1-3 h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens or mineralocorticoids compared to placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance

CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals

The role of genetic polymorphisms in cytochrome (CYP) 2D6 involved in the metabolism of 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) is unclear. Effects of genetic variants in CYP2D6 on the pharmacokinetics and pharmacodynamic effects of MDMA were characterized in 139 healthy individuals (70 men, 69 women) in a pooled analysis of eight double-blind, placebo-controlled crossover studies. In CYP2D6 poor metabolizers, the maximum concentrations (Cmax) of MDMA and its active metabolite 3,4-methylene-dioxyamphetamine were +15 and +50% higher, respectively, compared with extensive metabolizers and the Cmax of the inactive metabolite 4-hydroxy-3-methoxymethamphetamine was 50-70% lower. Blood pressure and subjective drug effects increased more rapidly after MDMA administration in poor metabolizers than in extensive metabolizers. In conclusion, the disposition of MDMA and its effects in humans are altered by polymorphic CYP2D6 activity, but the effects are small because of the autoinhibition of CYP2D6

Acute Effects of 3,4-Methylenedioxymethamphetamine and Methylphenidate on Circulating Steroid Levels in Healthy Subjects

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-h plasma steroid profiles. Sixteen healthy subjects (eight men, eight women) were treated with single doses of MDMA (125 mg), methylphenidate (60 mg), MDMA + methylphenidate, and placebo on four separate days using a cross-over study design. Cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstendione, and testosterone were repeatedly measured up to 24-h using liquid-chromatography tandem mass-spectroscopy. MDMA significantly increased the plasma concentrations of cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone and also tended to moderately increase aldosterone levels compared with placebo. MDMA also increased the sum of cortisol + cortisone and the cortisol/cortisone ratio, consistent with an increase in glucocorticoid production. MDMA did not alter the levels of cortisone, DHEA, DHEAS, androstendione, or testosterone. Methylphenidate did not affect any of the steroid concentrations, and it did not change the effects of MDMA on circulating steroids. In summary, the serotonin releaser MDMA has acute effects on circulating steroids. These effects are not observed after stimulation of the dopamine and norepinephrine systems with methylphenidate. The present findings support the view that serotonin rather than dopamine and norepinephrine mediates the acute pharmacologically-induced stimulation of the hypothalamic-pituitary-adrenal axis in the absence of other stressors. © 2014 S. Karger AG, Basel

Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users

We conducted a meta-analysis on the available data from studies investigating SERTs in ecstasy users and polydrug using controls. From 7 studies we compared data from 157 ecstasy users and 148 controls across 14 brain regions. The main effect suggested ecstasy/MDMA related SERT reductions (SMD = 0.52, 95% CIs [0.40, 0.65]; Z = 8.36, p < .01, I2 = 89%). A significant effect of subgroups (X2 = 37.41, df = 13, p < .01, I2 = 65.3%) suggested differential effects across brain ROIs. Ecstasy users showed significant SERT reductions in 11 out of the 14 regions, including every neocortical and limbic region analysed. Greatest effects were observed in the occipital cortex (SMD = 1.09, 95% CIs [0.70, 1.48]). No group effects were observed in subcortical areas of the caudate, putamen and midbrain. Literature on Postsynaptic 5HT2A receptor imaging was synthesised with these results. We conclude that, in line with preclinical data, serotonin axons with the longest projections from the raphe nuclei appear to be most affected by ecstasy/MDMA use

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transporter-mediated monoamine efflux with weak to no activity at pre- or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS