Sub-acute effects of MDMA (±3,4-methylenedioxymethamphetamine, "ecstasy") on mood: evidence of gender differences

RATIONALE: Research with animals suggests that central 5-hydroxytryptamine (5-HT) function may be attenuated for a period following a single dose of +/-3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). If the same is true in humans, then functions thought to be modulated by 5-HT may differ in MDMA users compared with non-users a few days after the drug is taken. AIMS: The present study therefore investigated both acute and sub-acute effects of MDMA on mood of recreational users. A second aim was to determine whether these effects differ for females and males. DESIGN: A parallel group design was used to compare 40 participants who reported taking MDMA with 40 participants who reported using illicit substances excluding MDMA (polydrug controls). Participants were assessed on the night of drug use (day 0) and again 4 days later. RESULTS: Female MDMA users showed higher depression scores mid-week than male users or male or female controls. Mid-week depression in female users was correlated with the amount of MDMA taken on day 0. MDMA users rated lower levels of aggression than controls on the night of drug use but significantly higher levels of aggression mid-week, and in males change in aggression correlated with the amount of MDMA taken on the weekend. There was no association between mood and measures of long-term use of MDMA (e.g. years of use). CONCLUSION: Women are more susceptible than men to mid-week low mood following weekend use of MDMA; however, both men and women show increased self-rated aggression. These results are interpreted in terms of an attenuation of 5-HT function for a period following acute use of MDMA.     

Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration

RATIONALE: Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult. However, moderate success has been achieved when sensitive animal models and drug challenge have been used together. OBJECTIVE: The present study used a repeated-acquisition technique and dose-effect determinations before, during and after neurotoxic MDMA exposure to characterize the effects of serotonergic drugs on learning, and to determine if MDMA-induced serotonin (5-HT) neurotoxicity is associated with learning deficits as measured by changes in response rate or the percentage of errors. METHOD: The effects of various serotonergic drugs were characterized in six squirrel monkeys responding under a repeated-acquisition procedure before and after neurotoxic dose regimens of MDMA. Specifically, cumulative dose-effect curves for m-CPP (0.032-1 mg/kg), fenfluramine (0.1-3.2 mg/kg) and triazolam (0.0032-0.1 mg/kg) were obtained prior to MDMA administration, with the latter drug serving as a non-5-HT control. RESULTS: In general, all of the drugs tested decreased overall response rate as the cumulative dose increased, whereas only triazolam markedly increased the percentage of errors. MDMA treatment produced significant (80-99%) decreases in brain 5-HT and 5-HIAA axonal markers, but did not lead to changes in either dependent measure of responding or shifts in the dose-effect curves obtained during pharmacological challenges with m-CPP, fenfluramine or triazolam. CONCLUSIONS:Taken together, these results demonstrate that serotonergic drugs can disrupt learning in monkeys, but indicate that MDMA-induced 5-HT neurotoxicity does not lead to disruptions in this particular type of serial learning task.     

Transducing system operated by adenosine A(2A) receptors to facilitate acetylcholine release in the rat hippocampus

In spite of the increasing evidence concerning its neurotoxicity, young human individuals are often involved in the recreational use of amphetamine-type stimulants such as 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). A study aimed to investigate short- and long-term consequences of a repeated and intermittent MDMA administration (0, 5 or 10 mg/kg i.p., 3 days treatment history) was conducted in mice. Mice were injected at different phases in development, namely at early (28 days old), middle (38 days old) or late (52 days old) adolescence. When assessed for nociceptive response, a dose-dependent analgesia was found in middle and late adolescent mice. Carryover consequences of previous MDMA treatment were then investigated at adulthood (80 days old). In a social interaction test, levels of environment exploration and social behaviour resulted markedly increased in drug-free state as a function of drug exposure during development, whereas others behaviours were reduced. MDMA challenge (5-mg/kg dose) produced the expected hyperactivity, as well as a marked increment of hypothalamic serotonin (5-hydroxyhyptamine, 5-HT) levels. Mice treated chronically with MDMA during middle and late adolescence were associated with important reductions of the indoleamine. As a whole, these results indicate a differential long-term vulnerability to behavioural and neurotoxicant effects of MDMA as a function of the developmental stage of exposure.     

Preprotachykinin A gene expression after administration of 3,4-methylene dioxymethamphetamine (Ecstasy)

This study tested the effects of 8 days of subchronic administration of 3,4-methylene dioxymethamphetamine (MDMA) (5 mg/kg b.w.) on preprotachykinin A mRNA levels in discrete rat brain regions. In situ hybridization examined preprotachykinin A mRNA levels in the core and shell of the nucleus accumbens, the islands of Calleja, the olfactory tubercle, the dorsal and ventral caudate–putamen, the bed nucleus of the stria terminalis, the medial preoptic area, the medial habenular nucleus and in the postero-dorsal part of the medial amygdala. Higher levels of preprotachykinin A mRNA were found in the core and shell of the nucleus accumbens, in the islands of calleja, in the olfactory tubercle, in the bed nucleus of the stria terminalis, in the medial habenular nucleus and the postero-dorsal part of the medial amygdala, compared to control animals. Conversely, increased preprotachykinin A mRNA levels were observed in the dorsal and ventral caudate–putamen in MDMA treated when compared to control rats. In the social memory test, MDMA significantly impaired rats' short-term working memory. These results show that chronic exposure to MDMA strongly affects preprotachykinin A mRNA levels in discrete rat brain regions. These changes occur in experimental conditions in which working memory is markedly reduced, suggesting that changes in gene expression of tachykinin mechanisms may contribute to the effects of MDMA on memory function.     

Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals. Serotonin plays a role in numerous functional systems in the CNS. Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine, and cognitive disorders might be expected in humans following damage of the central serotonergic system. In recent years, the questions of possible functional disorders following ecstasy-induced neurotoxicity were addressed in several cross-sectional studies with drug users. In this review we summarize and evaluate the quality of design of these studies. Despite large methodological problems, evidence accumulates in favor of persisting brain damage in ecstasy users resulting in subtle cognitive deterioration. Findings of relatively low memory performance associated with heavy ecstasy use are highly consistent across different studies and user populations. In addition, low performance in tests of higher executive function were reported in some but not all studies. The important questions about progression, persistence, or reversibility of damage after long periods of abstinence have to be addressed in future studies with longitudinal design.     

The impact of regular ecstasy use on memory function

Aim  To assess memory impairment in a group of regular users of ecstasy compared with a group of regular users of cannabis, after accounting for possible confounding factors such as other drug use, premorbid intelligence and psychopathology.
METHOD  Comparative and regression analysis was used to determine the presence or absence of a difference in memory function between 40 regular ecstasy users and 37 regular users of cannabis, who were interviewed at the National Drug and Alcohol Research Centre in Sydney, Australia. Regression analysis was used to find associations between life-time exposure to ecstasy use and memory performance. Memory function was assessed using an age-standardized memory test. Other scales were used to assess premorbid intelligence, physical and psychological health, drug withdrawal and other drug use.
Results  Initial comparative analysis showed a trend towards a significantly poorer performance by the regular ecstasy-using group on the 'auditory immediate memory' and 'auditory delayed memory' indices. When regression analysis was performed an estimate of verbal intelligence was found to be the most predictive of most memory indices including 'auditory immediate memory' and 'auditory delayed memory'. Life-time exposure to ecstasy was not predictive of the memory indices. The current frequency of cannabis use was found to have some predictive effect for immediate and delayed visual memory.
Conclusion  This study does not show memory impairment in a group of ecstasy users relative to cannabis using controls. The previously reported association of life-time exposure to ecstasy and memory was not found. The findings may indicate a confounding role of cannabis use, as has been recently reported.     

Non-linear pharmacokinetics of MDMA ('ecstasy') in humans

AIMS: 3,4-Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers. METHODS: A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA). RESULTS: As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent. CONCLUSIONS: It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.     

乳果糖的制备与纯化

本文采用乳糖在硷性环境中,在特殊催化剂和保护剂存在下加热,使乳糖产生异构化而转变成乳果糖。乳果糖的反应混合液,经特殊处理,制得纯度高的乳果糖糖浆,再制得乳果糖结晶(国内尚没有结晶产品)。经鉴定该品与国外同类产品一致.     

生物液晶中马尔它十字成因初探

本文对生物液晶中马尔它十字的成因作了研究,作者认为:马尔它十字是通过生物液晶的线偏振光的干涉图样。由于生物液晶的光轴方向有随意性,故在正交偏光显微镜下观察时,将看到不同的干涉图样,呈现为不同形状的马尔它十字。     

Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

Rationale Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause fatal hyperthermia, few studies of the effects of MDMA on core body temperature in humans have been conducted demonstrating increased body temperature. In rats, MDMA causes hyperthermia at warm ambient temperatures but hypothermia at cold ones.Objectives In this study, the physiological and subjective effects of MDMA in humans were determined at cold (18°C) and warm (30°C) ambient temperatures in a temperature and humidity-controlled laboratory.Methods Ten healthy volunteers who were recreational users of MDMA were recruited. Four laboratory sessions were conducted in a 2×2 design [i.e., two sessions at 30°C and two at 18°C, two during MDMA (2 mg/kg, p.o.) and two during placebo, in double-blind fashion]. Core body temperature (ingested radiotelemetry pill), skin temperature (four weighted sites), heart rate, blood pressure, metabolic rate (indirect calorimetry), shivering (electromyogram levels), and sweat rate (capacitance hygrometry) were measured as well as subjective effects for several time periods following capsule ingestion.Results MDMA produced significant elevations in core body temperature and metabolic rate in both warm and cold conditions. MDMA also produced significant elevations in blood pressure and heart rate and significantly increased several ratings of subjective effects similar to those previously reported. There were no differences related to ambient temperature for any of the subjective effects, except that ratings of cold and warm were appropriate to the ambient temperature and were not influenced by MDMA.Conclusions Unlike findings in rats, MDMA increased core body temperature regardless of ambient temperature in humans. These increases appeared related to increases in metabolic rate, which were substantial. These findings warrant further investigations on the role of MDMA and other stimulants in altering metabolism and thermogenesis.