Fatal combination of moclobemide overdose and whisky

The antidepressant moclobemide (Aurorix) is a reversible inhibitor of monoamine oxidase-A. Pure moclobemide overdose is considered to be relatively safe. Mixed drug overdoses including moclobemide are potentially lethal, especially when serotonergical drugs are involved. So far, only one fatality due to moclobemide mono-overdose has been reported. We report here on a fatality following the ingestion of a moclobemide overdose in combination with half a bottle of whisky. Although dietary restrictions during moclobemide therapy are not considered necessary, the combination of large quantities of moclobemide and tyramine-containing products seems to be lethal, probably because monoamine oxidase-A selectivity is overwhelmed after massive overdoses. Since there is no specific antidote and treatment is only symptomatic, the severity of an overdose with moclobemide must not be underestimated.     

A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder

Introduction: The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT). Methods: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response. Results: Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide. Conclusion: Both SSRI's and RIMA's decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.     

Pill content, dose and resulting plasma concentrations of 3,4-methylendioxymethamphetamine (MDMA) in recreational 'ecstasy' users

Aims To improve our understanding of the pharmacology of ‘ecstasy’ in recreational environments; in particular, to describe the composition of ecstasy pills, patterns of ecstasy use and the relationship between dose of 3,4‐methylendioxymethamphetamine (MDMA) and resulting plasma concentrations. Design, setting and participants A naturalistic observational study of 56 experienced ‘ecstasy’ users in recreational settings in Australia. Measurements Drug use patterns (number of pills consumed, other drugs consumed). drug content of pills and resultant plasma concentrations of MDMA and related drugs were assessed by gas chromatography/mass spectrometry (GC/MS). Findings Ecstasy pills generally contained MDMA, but this was often combined with other drugs such as 3,4‐methylendioxyethylamphetamine (MDEA) and methamphetamine. The dose of MDMA per pill ranged from 0 to 245 mg and users consumed from one‐half to five pills, with the total dose consumed ranging up to 280 mg. Plasma concentrations of MDMA increased with number of pills consumed and cumulative MDMA dose. Use of larger numbers of pills was associated with extended exposure to the drug. Conclusions MDMA is the major active drug in ecstasy pills, but there is a high degree of variation in doses. Use of multiple pills over the course of one session is common and results in a sustained increase in MDMA plasma concentrations over a number of hours. This is likely to lead to a much greater exposure of the brain to MDMA than would be predicted from controlled single‐dose pharmacokinetic studies.     

Aplastic anaemia following exposure to 3,4-methylenedioxymethamphetamine ('Ecstasy')

Summary. We report two cases of aplastic anaemia following exposure to 'Ecstasy' (MDMA, 3,4-methylenedioxymethamphetamine). In both cases the aplastic anaemia resolved spontaneously 7–9 weeks after presentation. Long-term bone marrow culture study of one patient demonstrated complete normalization of haemopoiesis at time of haematological recovery, suggesting either that damage to the haemopoietic stem cell had been only transient, or that a more mature, committed progenitor cell was the target. Because MDMA may have been a factor in the aetiology of the bone marrow suppression in these two cases, we recommend close haematological monitoring of young adults presenting with toxicity from MDMA, and a detailed history of exposure to recreational drugs in all new patients presenting with aplastic anaemia.     

Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease

Valvular heart disease, inducing valvular regurgitation, has been described in users of drugs such as anorectic agents and ergot derivates. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") also leads in vitro to the proliferation of cardiac valvular interstitial cells by activation of the 5-hydroxytryptamine 2B receptor. The aim of this study was to determine the occurrence of valvulopathy in young adults taking MDMA. Twenty-nine subjects using or having used MDMA and 29 gender- and age-matched controls were blindly evaluated with echocardiography. Eight subjects (28%) who took MDMA had abnormal echocardiographic results using the United States Food and Drug Administration's criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group (p = 0.0045). Six (21%) subjects had mitral regurgitation of 1/4 and 4 (14%) of > or =2/4, compared with none in the control group (p = 0.002). The mean mitral regurgitant area ratios (jet/atrium) were 12 +/- 9.8% and 5 +/- 1.3%, respectively (p = 0.007). Tricuspid regurgitation > or =2/4 was present in 13 MDMA users (45%) and absent in controls (p <0.001). The mean tricuspid regurgitant area ratios were 19 +/- 9.5% and 9 +/- 4.5%, respectively (p <0.001). Four MDMA users (14%) had mild aortic regurgitation (p = 0.11). Valvular "strands" were present in 6 MDMA users (21%) and in none of the controls (p = 0.02). In conclusion, MDMA may lead to mild to moderate valvular heart disease and valvular strands.     

Chronic 3,4-methylenedioxymethamphetamine (MDMA) use: effects on mood and neuropsychological function?

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in animals. There is now preliminary evidence in humans of 5-HT deficits associated with extensive use of MDMA. In order to begin to describe the cognitive and mood effects of chronic MDMA use, nine individuals with extensive MDMA use histories were studied. Despite the absence of memory deficits on clinical examination, a pattern of mild-to-moderate impairment was observed on both the Initial and Delayed Paragraph Tests of the Wechsler Memory Scale; eight of the subjects had at least mild impairment on at least one test in the neuropsychological battery. Despite previously reported suggestive evidence of 5-HT deficit in this group, none reported depressed mood or met clinical criteria for an affective disorder at the time of testing. These preliminary findings raise concern about possible detrimental effects of MDMA use on neuropsychological function for future systematic study and they highlight important issues regarding the effects of 5-HT deficits on cognitive function and mood regulation.     

Effects of adenosine A2a receptor agonist and antagonist on hippocampal nuclear factor-kB expression preceded by MDMA toxicity

There is an abundance of evidence showing that repeated use of 3,4-methlylenedioxymethamphetamine (MDMA; ecstasy) is associated with brain dysfunction, memory disturbance, locomotor hyperactivity, and hyperthermia. MDMA is toxic to both the serotonergic neurons and dopaminergic system. Adenosine is an endogenous purine nucleoside with a neuromodulatory function in the central nervous system. Nuclear factor kappa-B (NF-kB) plays a pivotal role in the initiation and perpetuation of an immune response by triggering the expression of major inflammatory mediators such as cytokines, chemokines, and adhesion molecules. Here, we investigated the effects of the A2a adenosine receptor (A2a-R) agonist (CGS) and antagonist (SCH) on NF-kB expression after MDMA administration. Male Sprague–Dawley rats were injected to MDMA (10 mg/kg) followed by intraperitoneal injection of either CGS or SCH (0.03 mg/kg each) to animals. The hippocampi were then removed for western blot and RT- PCR analyses. MDMA significantly elevated NF-kB expression. Our results show that administration of CGS following MDMA significantly elevated the NF-kB expression both at mRNA and protein levels. By contrast, administration of the A2a-R antagonist SCH resulted in a decrease in the NF-kB levels. Taken together, these results indicate that, co-administration of A2a agonist (CGS) can protect against MDMA neurotoxic effects by increasing NF-kB expression levels; suggesting a potential application for protection against the neurotoxic effects observed in MDMA users.     

An Experimental Test of Retention in Residential and Outpatient Programs

ABSTRACT

3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) is a selective serotonin (5-HT) neurotoxin in animals. There is now preliminary evidence in humans of 5-HT deficits associated with extensive use of MDMA. In order to begin to describe the cognitive and mood effects of chronic MDMA use, nine individuals with extensive MDMA use histories were studied. Despite the absence of memory deficits on clinical examination, a pattern of mild-to-moderate impairment was observed on both the Initial and Delayed Paragraph Tests of the Wechsler Memory Scale; eight of the subjects had at least mild impairment on at least one test in the neuropsychological battery. Despite previously reported suggestive evidence of 5-HT deficit in this group, none reported depressed mood or met clinical criteria for an affective disorder at the time of testing. These preliminary findings raise concern about possible detrimental effects of MDMA use on neuropsychological function for future systematic study and they highlight important issues regarding the effects of 5-HT deficits on cognitive function and mood regulation.     

Stimulant effects of 3,4-methylenedioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on actual driving during intoxication and withdrawal

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA) is currently one of the most popular drugs of abuse in Europe. Its increasing use over the last decade has led to concern regarding possible adverse effects on driving. The aims of the present study were to investigate the acute effects of MDMA on actual driving performance during the intoxication and withdrawal phase. METHODS: Eighteen recreational MDMA-users (nine males, nine females) aged 21-39 years participated in a double-blind, placebo-controlled, three-way cross-over study. MDMA 75 mg, methylphenidate 20 mg and placebo were administered on day 1 of treatment (intoxication phase). Driving tests were conducted between 3 and 5 hours post-drug. Subjects returned the following day for a repetition of the driving tests between 27 and 29 hours post-drug (withdrawal phase). On-the-road driving tests consisted of a road-tracking test and a car-following test. Its main parameters were standard deviation of lateral position (SDLP), time to speed adaptation (TSA), brake reaction time (BRT) and gain. FINDINGS: MDMA and methylphenidate significantly decreased SDLP in the road-tracking tests by about 2 cm relative to placebo on day 1 (intoxication phase). In addition, MDMA intoxication decreased performance in the car-following test as indicated by a significant rise in the 'overshoot' of the subjects' response to speed decelerations of the leading vehicle. Driving performance was not affected by treatments during withdrawal on day 2. CONCLUSION: Collectively, these data indicate that MDMA is a stimulant drug that may improve certain aspects of the driving task, such as road-tracking performance, but may reduce performance in other aspects of the driving task, such as accuracy of speed adaptation during car-following performance.     

Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin

Aims Alexander T. Shulgin is widely thought of as the ‘father’ of +/?3,4‐methylenedioxymethamphetamine (MDMA). This paper re‐assesses his role in the modern history of this drug. Methods We analysed systematically Shulgin's original publications on MDMA, his publications on the history of MDMA and his laboratory notebook. Results According to Shulgin's book PIHKAL (1991), he synthesized MDMA in 1965, but did not try it. In the 1960s Shulgin also synthesized MDMA‐related compounds such as 3,4‐methylenedioxyamphetamine (MDA), 3‐methoxy‐4,5‐methylenedioxyamphetamine (MMDA) and 3,4‐methylenedioxyethylamphetamine (MDE), but this had no impact on his rediscovery of MDMA. In the mid‐1970s Shulgin learned of a ‘special effect’ caused by MDMA, whereupon he re‐synthesized it and tried it himself in September 1976, as confirmed by his laboratory notebook. In 1977 he gave MDMA to Leo Zeff PhD, who used it as an adjunct to psychotherapy and introduced it to other psychotherapists. Conclusion Shulgin was not the first to synthesize MDMA, but he played an important role in its history. It seems plausible that he was so impressed by its effects that he introduced it to psychotherapist Zeff in 1977. This, and the fact that in 1978 he published with David Nichols the first paper on the pharmacological action of MDMA in humans, explains why Shulgin is sometimes (erroneously) called the ‘father’ of MDMA.     

Diffusion tensor imaging in MDMA users and controls: association with decision making

Diffusion Tensor Imaging (DTI) may provide information regarding effects of 3,4-methylenedioxymethamphetamine (MDMA) use on brain structure. Twelve MDMA users and 20 healthy controls underwent whole brain DTI data acquisition. Fractional anisotropy (FA), mean diffusivity (D(av)), and longitudinal (lambda(1)) and transverse (lambda(T)) diffusivities were compared between MDMA users and controls in 6 regions of the corpus callosum. MDMA users also completed the Barratt Impulsiveness Scale (BIS), and a subset of subjects completed the Iowa Gambling Task (IGT). Results showed significantly smaller lambda(1) in the rostral body of the corpus callosum in MDMA users, with no differences between groups on lambda(T), FA, or D(av). MDMA users also had a significantly higher BIS nonplanning score and greater preference for disadvantageous choices on the IGT. There was a significant positive correlation between lambda(1) in the rostral body of the corpus callosum and advantageous choices on the IGT. Further research on the etiology of these findings is warranted.     

Severe Ketoacidosis Complicated by ‘Ecstasy’ Ingestion and Prolonged Exercise

Ecstasy (3,4-methylenedioxymethamphetamine or MDMA) is used with increasing frequency as a recreational drug. Accumulated evidence over recent years indicates a growing demand for the drug with a corresponding increase in number of reports of adverse effects from its use. There are reported metabolic disturbances due to MDMA use. These, in addition to the prolonged exercise involved in dancing at ‘raves’ where MDMA may be used, may exacerbate ketoacidosis. We report two cases of ketoacidosis complicated by MDMA ingestion.     

QTc abnormalities in deliberate self-poisoning with moclobemide

BACKGROUND: Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. AIMS: To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. METHODS: Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. RESULTS: Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. CONCLUSIONS: Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.     

Places and patterns of drug use in the Scottish dance scene

Interviews were conducted with 135 participants in the Glasgow dance (rave) scene. Drug use in this group was varied and not merely restricted to drugs associated with dance events, such as MDMA (Ecstasy). The setting in which each drug was used varied greatly. Amphetamine, nitrites and Ecstasy were the drugs most commonly used at dance events. Pharmaceuticals were least likely to be used in such settings. However, some drugs, such as Temazepam, were sometimes used prior to or after attending rave events. It is suggested that dance drug users are polydrug users who use drugs in a setting specific fashion. As such it would be wrong to classify such users solely on the grounds of their very visible behaviour in the public arena (at dance events). Other forms of substance use engaged in by this group may have a greater potential for harm than that seen at raves. The implications of these findings are discussed.     

Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial

BACKGROUND: The psychoactive stimulant 3, 4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," is widely used in nonmedical settings. Little is known about its cardiovascular effects. OBJECTIVE: To evaluate the acute cardiovascular effects of MDMA by using transthoracic two-dimensional and Doppler echocardiography. DESIGN: Four-session, ascending-dose, double-blind, placebo-controlled trial. SETTING: Urban hospital. PATIENTS: Eight healthy adults who self-reported MDMA use. INTERVENTION: Echocardiographic effects of dobutamine (5, 20, and 40 microg/kg of body weight per minute) were measured in a preliminary session. Oral MDMA (0.5 and 1.5 mg/kg of body weight) or placebo was administered 1 hour before echocardiographic measurements in three weekly sessions. MEASUREMENTS: Heart rate and blood pressure were measured at regular intervals before and after MDMA administration. Echocardiographic measures of stroke volume, ejection fraction, cardiac output, and meridional wall stress were obtained 1 hour after MDMA administration and during dobutamine infusions. RESULTS: At a dose of 1.5 mg/kg, MDMA increased mean heart rate (by 28 beats/min), systolic blood pressure (by 25 mm Hg), diastolic blood pressure (by 7 mm Hg), and cardiac output (by 2 L/min). The effects of MDMA were similar to those of dobutamine, 20 and 40 microg/kg per minute. Inotropism, measured by using meridional wall stress corrected for ejection fraction, decreased after administration of dobutamine, 40 microg/kg per minute, but did not change after either dose of MDMA. CONCLUSIONS: Modest oral doses of MDMA increase heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to dobutamine, 20 to 40 microg/kg per minute. In contrast to dobutamine, MDMA has no measurable inotropic effects.     

Use of club drugs by HIV-seropositive and HIV-seronegative gay and bisexual men

Club drugs such as methylenedioxymethamphetamine (MDMA, ecstasy), gamma hydroxybutyrate (GHB), and ketamine are among the fastest-growing drugs of abuse in the United States. Reports have shown that some gay and bisexual men are likely to engage in club-drug use in a myriad of venues. This is concerning given that the use of club drugs has been linked to high-risk sexual behaviors. Further, the use of club drugs by HIV-seropositive individuals may have detrimental outcomes on disease progression by either influencing adherence, resulting in drug-drug interactions with antiretrovirals, or potentially compounding immune suppression. Clinicians caring for HIV-seropositive and -seronegative individuals should be aware of the clinical effects and management guidelines associated with these chemicals. This article reviews the available literature with regard to the use of club drugs by HIV-seropositive and -seronegative gay and bisexual men. Although club-drug use may be associated with many risk behaviors for HIV infection, this review focuses on risk behavior among gay and bisexual men since this is the group for which the most data have been reported. The clinical effects and management guidelines associated with these agents are described, and the potential detrimental effects of these substances on HIV disease are discussed.     

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans

(±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”), a ring-substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDMA produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDMA has been demonstrated in a variety of experimental animals (including non-human primates). In monkeys, the neurotoxic dose of MDMA closely approaches that used by humans. While the possibility that MDMA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDMA use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDMA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDMA, with the hope that improved recognition of MDMA-related syndromes will provide insight into the function of serotonin in the human brain, in health as well as disease.     

Mood and cognitive effects of 6 3,4-methylenedioxymethamphetamine (MDMA, ''ecstasy''): week-end ''high'' followed by mid-week low

Aims. Recreational use of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') is widespread. The present study aimed to examine both the acute and residual effects of this drug on users' mood and cognitive function. Design and participants. A parallel group design was used to compare 12 participants who reported having taken MDMA with 12 participants who reported having consumed only alcohol, on the relevant night (day 1). These same participants were then re-assessed the following day (day 2) and again mid-week (day 5). Findings. Acute effects of MDMA broadly replicated previous findings. MDMA users rated elevated mood on day 1 but significantly low mood on day 5, at which point some participants scored within the range for clinical depression. In contrast, the alcohol group showed less pronounced changes, which followed a U-shaped curve over days with the lowest point being day 2. The MDMA group also showed significant impairments on an attentional/working memory task, compared with alcohol users. Conclusions. Weekend use of MDMA may lead to depressed mood mid-week. Possible mechanisms underlying the findings are discussed in terms of temporary depletion of serotonin, serotonergic neurotoxity and psychological aspects of mood change.     

Diffusion Tensor Imaging in MDMA Users and Controls: Association with Decision Making

Diffusion Tensor Imaging (DTI) may provide information regarding effects of 3,4-methylenedioxymethamphetamine (MDMA) use on brain structure. Twelve MDMA users and 20 healthy controls underwent whole brain DTI data acquisition. Fractional anisotropy (FA), mean diffusivity (D_av), and longitudinal (λ₁) and transverse (λ_T) diffusivities were compared between MDMA users and controls in 6 regions of the corpus callosum. MDMA users also completed the Barratt Impulsiveness Scale (BIS), and a subset of subjects completed the Iowa Gambling Task (IGT). Results showed significantly smaller λ₁ in the rostral body of the corpus callosum in MDMA users, with no differences between groups on λ_T, FA, or D_av. MDMA users also had a significantly higher BIS nonplanning score and greater preference for disadvantageous choices on the IGT. There was a significant positive correlation between λ₁ in the rostral body of the corpus callosum and advantageous choices on the IGT. Further research on the etiology of these findings is warranted.