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.     

Glucocorticoids and 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity

The present study was carried out in order to explore the role of glucocorticoids in 3,4-methylenedio-xymethamphetamine (MDMA)-induced neurotoxicity of the central serotonergic system. The activity of tryptophan hydroxylase (TPH) was used as an index of this drug-induced neuronal degeneration. One week after a single high dose of MDMA (20 mg/kg), a significant decrease in the enzyme activity was measured in both the frontal cortex and hippocampus. Adrenalectomy (ADX) attenuated or blocked this decrease in TPH activity in the hippocampus but not in the frontal cortex. This protective effect of ADX on hippocampal serotonergic neurons disappeared with concurrent administration of corticosterone (CORT) and MDMA administration. The long-term MDMA-induced decreases in hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similarly affected by CORT replacement. However, ADX did not alter the short-term decline in hippocampal TPH activity and 5-HT concentrations measured 3 h after a single dose of MDMA (10 mg/kg s.c.). This study suggests that CORT play a role in the development of neurotoxicity induced by MDMA in the hippocampal serotonergic system, but may be less important in other brain structures.     

Acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA) in Sprague-Dawley and Dark Agouti rats.

Ingestion of MDMA ("ecstasy") by humans can cause acute toxicity manifested by hyperthermia and death. Demethylenation of MDMA is catalyzed by cytochrome P-450 2D6 (CYP2D6) and cytochrome P-450 2D1 (CYP2D1) in humans and rats, respectively, and is polymorphically expressed. It has been proposed that CYP2D6 deficiency may account for the unexplained toxicity of MDMA. The female Dark Agouti rat is deficient in CYP2D1, and serves as a model for the human poor metabolizer. We investigated thermogenic and locomotor actions of MDMA in adult female Sprague-Dawley (CYP2D1 replete) and Dark Agouti rats. MDMA (2, 5, and 10 mg/kg) and saline were injected subcutaneously at ambient temperatures of 22 and 31 degrees C. There was no difference in core temperature responses between the two rat strains. Hypothermia occurred in the first 30 min and temperature elevation thereafter. MDMA increased locomotor activity in Sprague-Dawley but not in Dark Agouti rats. However, MDMA had pronounced lethal effects at 31 degrees C ambient in the Dark Agouti rats only. We conclude that the poor metaboliser phenotype may predispose to lethality, but the mechanism is as yet unknown.     

Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

The effect of optical isomers of 3,4-methylenedioxymethamphetamine (MDMA) on stereotyped behavior in rats

The relative potencies of S(+)-, R(-)-3,4-methylenedioxymethamphetamine (MDMA) and S(+)-methylene-dioxyamphetamine (MDA) in inducing stereotyped behavior were determined in comparison with p-chloroamphetamine. S(+)-MDMA was more potent than R(-)-MDMA in eliciting stereotyped behaviors such as sniffing, head-weaving, backpedalling and turning and wet-dog shakes. These results are consistent with the actions of the drug on release of neurotransmitters in which the S(+) enantiomer is more potent. The desmethyl derivative of (+)MDMA, (+)MDA, was more potent than (+)MDMA in eliciting stereotyped behaviors, and produced wet-dog shake behavior.     

Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans

Rationale: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak prepulse stimulus. This phenomenon provides an operational measure of sensorimotor gating that has been found to be reduced in patients with schizophrenia and rats treated with serotonin agonists or serotonin releasers. Objective: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. Methods: Rats were tested after placebo and MDMA in a counterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test day, rats were first tested after no injections and retested 2 h later, 10 min after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI measures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. Results: As expected, MDMA decreased prepulse inhibition in a dose-related fashion in rats. In contrast, a typical recreational dose of MDMA (1.7 mg/kg, orally) increased prepulse inhibition in subjects experiencing robust psychological effects. Conclusions: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific difference in the mechanism of action of MDMA or in the behavioral expression of a similar pharmacological effect, or both. Received: 3 April 1998/Final version: 5 November 1998     

The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat

The antinociceptive effects of MDMA and morphine were examined in rats using the tail-flick and hot-plate analgesiometric tests. MDMA, in the dose range of 1.5-6.0 mg/kg IP, produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. In contrast, morphine (2-8 mg/kg, IP) produced analgesia on both the tail-flick and hot-plate tests in a dose-dependent manner. Neither the opiate antagonist naltrexone nor the adrenoceptor antagonist phentolamine effectively attenuated MDMA-induced analgesia. Conversely, the serotonin antagonist methysergide significantly reversed the analgesic effects of MDMA on the hot-plate test. These findings suggest that the antinociceptive effects of MDMA are serotonergically mediated. Furthermore, the results verify earlier findings describing the test-specific effects of serotonin-induced pain modulation.     

Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used phenethylamine. Reports have described the effects of MDMA in a controlled laboratory setting, but the full range of effects of MDMA in humans is still not completely characterized. OBJECTIVES: To describe the physiological, subjective, and hormonal changes after single doses of MDMA in a laboratory setting and examine relationships between these effects. METHODS: Eight MDMA-experienced volunteers each received placebo, 0.5 mg/kg, and 1.5 mg/kg oral doses of MDMA in a double-blind crossover study. RESULTS: The 1.5 mg/kg dose (comparable to that typically used by most participants) produced significant subjective effects, peaking at about 2 h after dosing, including some effects commonly associated with stimulant drugs, hallucinogens, and entactogens. MDMA significantly increased plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA) levels. Increase in plasma cortisol after the 1.5 mg/kg dose correlated with increased heart rate, rate-pressure product, and drug liking. Rise in DHEA correlated with euphoria. CONCLUSIONS: A typically used dose of MDMA produced effects commonly associated with stimulants and hallucinogens. Subjects liked MDMA. Correlations between cortisol and DHEA levels and some physiological and psychological effects are consistent with animal data suggesting that hormones modulate some responses to drugs of abuse.     

Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy

This review of chronic tolerance to MDMA (3,4-methylenedioxymetamphetamine) covers the empirical data on dosage escalation, reduced subjective efficacy and bingeing in recreational Ecstasy users. Novice users generally take a single Ecstasy tablet, regular users typically take 2-3 tablets, whereas the most experienced users may take 10-25 tablets in a single session. Reduced subjective efficacy following repeated usage is typically described, with many users subjectively reporting the development of tolerance. Intensive self-administration or bingeing is often noted by experienced users. This can comprise 'stacking' on several tablets together, and 'boosting' on successive doses over an extended period. Some experienced users snort Ecstasy powder nasally, whereas a small minority inject MDMA. Chronic tolerance and bingeing are statistically linked to higher rates of drug-related psychobiological problems. In terms of underlying mechanisms, neuroadaptive processes are certainly involved, but there is a paucity of evidence on hepatic and behavioural mechanisms. Further studies specifically designed to investigate chronic tolerance, involving low intermittent dose regimens, are required. Most animal research has involved intensive MDMA dosing regimens designed to engender serotonergic neurotoxicity, and this may comprise another underlying mechanism. If distal serotonin axon terminal loss was also developing in recreational users, it may help to explain why reducing subjective efficacy, dosage escalation and increasing psychobiological problems often develop in parallel. In conclusion, there is extensive evidence for chronic pharmacodynamic tolerance to recreational Ecstasy/MDMA, but the underlying mechanisms are currently unclear. Several traditional processes are probably involved, but one of the possible causes is a novel mechanism largely unique to the ring substituted amphetamine derivatives, namely serotonergic neurotoxicity.     

Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) increases locomotor activity when administered to rats. Although the published pharmacology of MDMA has focused almost exclusively on the roles of serotonin and dopamine, in vitro studies indicate that MDMA induces serotonin and norepinephrine release with equal potency. The present experiments tested the hypothesis that blockade of alpha(1)-adrenoceptors with systemic or local administration of the antagonist prazosin would attenuate the locomotor response to systemic administration of (+/-)-MDMA. Pretreatment with systemic prazosin (0.5 mg/kg) or microinjections into either the prefrontal cortex or ventral tegmental area completely blocked the locomotor stimulant effects of 5 mg/kg (+/-)-MDMA, assessed using a computerized Behavioral Pattern Monitor. Prazosin was more potent in blocking the locomotor stimulant effects of (+/-)-MDMA than a 2 mg/kg dose of (+)-amphetamine that produced a similar locomotor activity increase. These results indicate that activation of alpha(1)-adrenoceptors in both the prefrontal cortex and ventral tegmental areas modulates the locomotor response to MDMA.     

Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats

BACKGROUND AND PURPOSE

The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.

EXPERIMENTAL APPROACH

Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats.

KEY RESULTS

MDMA (1–20 mg·kg⁻¹) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1–10 mg·kg⁻¹) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β-adrenoceptor antagonist propranolol.

CONCLUSIONS AND IMPLICATIONS

Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.     

Amphetamine analogs methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) differentially affect speech

Rationale  

Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).     

Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats

We examined the involvement of tetrodotoxin (TTX)-resistant sodium channels in the peripheral mechanisms of the cough reflex in mice. We also examined the possibility of using ambroxol as an effective antitussive agent, and found that it produced antitussive effects through the inhibition of TTX-resistant sodium channels. The inhalation of fenvalerate, at concentrations of 0.3, 1 and 3μg/ml, for 5min produced coughs in a concentration-dependent manner. Pretreatment with tetrodotoxin, at a dose of 1μg/kg, s.c., slightly but significantly reduced the number of fenvalerate (3μg/ml)-induced coughs. However, the number of fenvalerate-induced coughs in tetorodotoxin-treated mice was still significantly greater than those in vehicle (0.4% DMSO) alone inhaled mice. On the other hand, pretreatment with tetrodotoxin, at a dose of 1μg/kg, s.c., almost completely reduced the number of citric acid (0.25M)-induced coughs to the level in vehicle (saline) alone inhaled mice. Pretreatment with ambroxol, at doses of 10, 30, 100 and 300mg/kg, p.o., dose-dependently and significantly reduced the number of fenvalerate (3μg/ml)-induced coughs. The present findings indicate that TTX-resistant sodium channels may play an important role in the enhancement of C-fiber-mediated cough pathways. Furthermore, ambroxol may prove to be a useful cough suppressant.     

3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans

There is evidence that some heavy users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) show signs of neurotoxicity (a cognitive dysfunction, a larger incidence of psychopathology). It has been postulated that the catechol intermediates of methylenedioxyamphetamines such as 3,4-dihydroxymethamphetamine (HHMA), a metabolite of MDMA, may play a role in their neurotoxicity by formation of thioether adducts. This study describes the first validated method for HHMA determination in plasma and urine by strong cation-exchange solid-phase extraction high-performance liquid chromatography/electrochemical detection (HPLC/ED) analysis. The method has been applied for the determination of HHMA in plasma and urine samples from a clinical study in healthy volunteers of MDMA and provides preliminary kinetic data on this metabolite. HHMA appeared to be a major MDMA metabolite with plasma concentrations as high as the parent compound. Thus, HHMA C(max) (154.5 microg/L) and AUC(0-24h)(1990.9 microg/L h) were similar to those obtained in previously published reports for MDMA (181.6 microg/L and 1465.9 microg/L h, respectively). The 24-h urinary recovery of HHMA accounted for 17.7% of the MDMA dose administered and increases the total 24 h recovery of MDMA and metabolites to 58% of the 100 mg dose administered. The determination of HHMA in plasma and urine samples is of interest in order to establish its relevance in MDMA metabolism and its possible contribution to MDMA neurotoxicity in humans. Its validation showed appropriate accuracy and precision for its use in pharmacokinetic studies.     

3,4-methylenedioxymethamphetamine (MDMA) intoxication in an infant chronically exposed to cocaine

Accidental ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) was detected in an infant admitted at the Pediatric Emergency Department by drug testing in urine. Concentrations of MDMA and its principal metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) in the infant's hydrolyzed urine were 11.7 mg/L and 34.4 mg/L, respectively. Apparent febrile convulsions and cardiovascular side effects resolved within 1 day after treatment with benzodiazepines. Chronic exposure to cocaine was evidenced by segmental hair analysis. Continuous maternal denial of the presence of any drug in the household made diagnosis of accidental ingestion of MDMA and chronic exposure to cocaine problematic. Periodic clinical and laboratory follow-ups were requested to check eventual long-term effects of exposure to illicit drugs and discontinuation of the child from exposure to dangerous environments.     

Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)

The use of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been associated with unexplained deaths. Male humans and rodents are more sensitive to acute toxicity than are females, including a potentially lethal hyperthermia. MDMA is highly metabolized to five main metabolites, by the enzymes CYP1A2 and CYP2D. The major metabolite in rats, 3,4-methylenedioxyamphetamine (MDA), also causes hyperthermia. We postulated that the reported sex difference in rats is due to a sexual dimorphism(s). We therefore determined (1) the LD50 of MDMA and MDA, (2) their hyperthermic effects, (3) the activities of liver CYP1A2 and CYP2D, (4) the liver microsomal metabolism of MDMA and MDA, (5) and the plasma concentrations of MDMA and its metabolites 3 h after giving male and female Sprague-Dawley (SD) rats MDMA (5 mg.kg(-1) sc). The LD50 of MDMA was 2.4-times lower in males than in females. MDMA induced greater hyperthermia (0.9 degrees C) in males. The plasma MDA concentration was 1.3-fold higher in males, as were CYP1A2 activity (twice) and N-demethylation to MDA (3.3-fold), but the plasma MDMA concentration (1.4-fold) and CYP2D activity (1.3-fold) were higher in females. These results suggest that male SD rats are more sensitive to MDMA acute toxicity than are females, probably because their CYP1A2 is more active, leading to higher N-demethylation and plasma MDA concentration. This metabolic pathway could be responsible for the lethality of MDMA, as the LD50 of MDA is the same in both sexes. These data strongly suggest that the toxicity of amphetamine-related drugs largely depends on metabolic differences.