Una D. McCann

(±)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced serotonin neurotoxicity: Studies in animals

The popular recreational drug, (±)3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) is a potent and selective brain serotonin (5-HT) neurotoxin in animals. MDMA-induced 5-HT neurotoxicity can be demonstrated using a variety of neurochemical, neuroanatomical and, more recently, functional measures of 5-HT neurons. Although the neurotoxic effects of MDMA in animals are widely accepted, the relevance of the animal data to human MDMA users has been questioned, largely because dosages of drugs used in animals are perceived as being much higher than those used by humans. In the present paper, we review the extensive body of data demonstrating that MDMA produced toxic effects on brain 5-HT neurons in animals and present new data indicating that levels of the type 2 vesicular monoamine transporter are reduced in MDMA-treated animals, providing further indication of MDMA’s 5-HT neurotoxic potential. Further, we demonstrate, using principles of interspecies scaling, that dosages of MDMA known to be neurotoxic in animals fall squarely in the range of dosages used typically by recreational MDMA users.

Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB

(±)3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMAs serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [11C]McN5652 and [11C]DASB, first- and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DVspec and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [11C] McN5652 and [11C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first- and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

Positron Emission Tomographic Studies of Brain Dopamine and Serotonin Transporters in Abstinent (±) 3,4-Methylenedioxymethamphetamine (“Ecstasy”) Users: Relationship to Cognitive Performance

Background(±)3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance.Materials and methodsSixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing.ResultsMDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship.ConclusionsUse of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.

Amphetamine neurotoxicity: Accomplishments and remaining challenges

In addition to the social, cultural and indirect medical complications of amphetamine analog abuse, this class of drugs is also known to have the potential to damage brain monoaminergic cells directly. Using methamphetamine as a prototype, this article provides a brief review of the history of amphetamine neurotoxicity research and the progress that has been made toward defining its characteristics. Remaining challenges for this line of investigation are outlined, and suggested avenues for addressing these challenges are provided.

Recognition and management of complications of new recreational drug use

Use of illicit drugs in clubs and large dance parties (so-called raves) is a burgeoning cultural trend. Such recreational drug use is associated with several medical complications, both acute and longlasting. Although few, if any, of the drugs currently used in recreational venues are truly new, their patterns and context of use have changed (a great deal in some instances). For some of these substances, this cultural repackaging of the drug experience has resulted in various medical disorders that have previously gone undocumented. This review aims to help treating physicians recognise and manage complications associated with the use of new drugs in clubs, including methylenedioxymethamfetamine, ephedrine, gamma-hydroxybutyrate; gamma-butyrolactone, 1,4-butanediol, flunitrazepam, ketamine, and nitrites. We also alert researchers to specific toxic effects of club-drugs on which more basic information is needed.

Can doctors and nurses recognize depression in patients hospitalized with an acute myocardial infarction in the absence of formal screening

Objective: The objective of this study was to determine the ability of cardiovascular healthcare workers to assess the presence or absence of symptoms of depression in patients hospitalized with acute myocardial infarction (AMI) in the absence of formal screening. Methods: Patients admitted with AMI underwent screening using the Beck Depression Inventory (BDI) administered by a research assistant. The cardiovascular nurse, medicine resident or intern, and attending cardiologist caring for the patient were then approached (blinded to the BDI results) and asked to assess, using a visual analog scale, whether the patient had symptoms that would warrant further evaluation for depression. Results: BDI screening and at least one provider assessment were completed for 60 patients with AMI. A total of 18 of 60 patients (30.0%) had a BDI score of ≥10. Symptoms of depression were considered not present in 24 of 32 patient assessments when the BDI was ≥10 (75% false-negatives). The mean BDI score of patients assessed as depressed by at least one provider (6.7 ± 6.3) was no different from the mean BDI score of patients assessed as not depressed (7.5 ± 7.2, p = .67). Overall, there was little correlation between BDI scores and provider assessments, and this was not influenced by provider type or provider gender. Conclusions: Cardiovascular nurses and medicine residents and interns underrecognize depression in patients with AMI in the absence of formal screening. Formal screening for symptoms of depression should be considered part of routine AMI care. AMI = acute myocardial infarction; BDI = Beck Depression Inventory; CPK = creatine phosphokinase; D-VAS = depression–visual analog scale; DIS = Diagnostic Interview Schedule.

MDMA (“Ecstasy”) and panic disorder: Induction by a single dose

( +_ )3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine analogue used recreationally by humans in the United States (Pcroutka 1987) and Western Europe (Anon 1992), and is thought by some to have potential utility as a psychotherapoutic adjunct (Grinspoon and Bakalar 1986). It is generally believed that MDMA acts via central monoamines, primariJy by inducing transmitter release and interfering with monoamine reuptake inactivation (Johnson et al 1991; McKenna and Peroutka 1990). In animals, MDMA has been shown to damage brain serotonin neurons, and in the monkey the neurotoxic dose closely approximates the dose typically ingested by humans (Ricaurte et al 1988). Concern that MDMA may damage serotonin neurons in the human brain is largely responsible for MDMAs Schedule I status in the United States, and consequently, the dearth of controlled studies comparing the risks of MDMA to its possible benefit as a therapeutic adjunct. There have been several recent reports of lasting adverse neuropsychiatric sequelae in humans who have taken repeated (usually high) doses of MDMA (Crcighton et al 1991; Benazzi and Mazzoli 1991; McGuir¢ and Fahy 1991; Schifano 1991; McCann and Ricaurte 1991). These reports suggest that individuals with prior psychiatric histories may have an increased susceptibility to MDMAs adverse effects. Lingering psychiatric syndromes associated with MDMA ingestion have included chronic paranoid psychosis (Schifano 1991; McGuir¢ and Fahy 1991), recurrent acute paranoid psychosis (Crcighton et al 1991), depression with suicidality (Benazzi and Mazzoli 1991), and panic disorder with secondary depression (McCann and Ricaurte 1991). Although untoward effects of high neurotoxic doses of MDMA might be anticipated, particularly in vulnerable individuals, enduring psychiatric illness following a single moderate dose of MDMA in a healthy individual has not been reported. We describe an individual with no prior psychiatric history who developed panic disorder after ingesting a single typical dose of MDMA.

Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity

The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)‐induced dopaminergic neurotoxicity while controlling for temperature‐related neuroprotective effects of the test compounds, reserpine and α‐methyl‐p‐tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH‐induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24–26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long‐term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28°C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33°C (to eliminate AMPTs hypothermic effect in METH‐treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (< 0.05%). When core temperature differences were eliminated by raising ambient temperature, METH‐induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH‐induced DA neurotoxicity.

Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal

BACKGROUND Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal. METHODS Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABA(A) receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day. RESULTS During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next-day cognitive performance impairments. CONCLUSIONS These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders.

Effects of (±) 3,4- Methylenedioxymethamphetamine (MDMA) on Sleep and Circadian Rhythms

Abuse of stimulant drugs invariably leads to a disruption in sleep-wake patterns by virtue of the arousing and sleep-preventing effects of these drugs. Certain stimulants, such as 3,4-methylenedioxymethamphetamine (MDMA), may also have the potential to produce persistent alterations in circadian regulation and sleep because they can be neurotoxic toward brain monoaminergic neurons involved in normal sleep regulation. In particular, MDMA has been found to damage brain serotonin (5-HT) neurons in a variety of animal species, including nonhuman primates, with growing evidence that humans are also susceptible to MDMA-induced brain 5-HT neurotoxicity. 5-HT is an important modulator of sleep and circadian rhythms and, therefore, individuals who sustain MDMA-induced 5-HT neurotoxicity may be at risk for developing chronic abnormalities in sleep and circadian patterns. In turn, such abnormalities could play a significant role in other alterations reported in abstinent in MDMA users (e.g., memory disturbance). This paper will review preclinical and clinical studies that have explored the effects of prior MDMA exposure on sleep, circadian activity, and the circadian pacemaker, and will highlight current gaps in knowledge and suggest areas for future research.