ABSTRACT
Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.
Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , Butyrophenones/toxicity , Chemical and Drug Induced Liver Injury/etiology , Methylamines/toxicity , Propiophenones/toxicity , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/toxicity , Animals , Autophagy/drug effects , Butyrophenones/administration & dosage , Cell Line, Tumor , Chemical and Drug Induced Liver Injury/pathology , Designer Drugs/administration & dosage , Designer Drugs/toxicity , Dose-Response Relationship, Drug , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/pathology , Humans , Male , Methylamines/administration & dosage , Oxidative Stress/drug effects , Propiophenones/administration & dosage , Rats , Rats, WistarABSTRACT
Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA, "molly", "ecstasy") appear to have unusual, potentially therapeutic, emotional effects. Understanding their mechanisms can benefit from clinical experiments with related drugs. Yet the first known drug with such properties, 3,4-Methylenedioxyamphetamine (MDA), remains poorly studied and its pharmacokinetics in humans are unknown. We conducted a within-subjects, double-blind, placebo-controlled study of 1.4 mg/kg oral racemic MDA and compared results to those from our prior similar studies with 1.5 mg/kg oral racemic MDMA. MDA was well-tolerated by participants. MDA induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA. MDA self-report effects shared features with MDMA as well as with classical psychedelics. MDA self-report effects lasted longer than those of MDMA, with MDA effects remaining elevated at 8 h while MDMA effects resolved by 6 h. Cmax and AUC0-∞ for MDA were 229 ± 39 (mean ± SD) and 3636 ± 958 µg/L for MDA and 92 ± 61 and 1544 ± 741 µg/L for the metabolite 4-hydroxy-3-methoxyamphetamine (HMA). There was considerable between-subject variation in MDA/HMA ratios. The similarity of MDA and MDMA pharmacokinetics suggests that the greater duration of MDA effects is due to pharmacodynamics rather than pharmacokinetics.
Subject(s)
3,4-Methylenedioxyamphetamine/administration & dosage , Hallucinogens/administration & dosage , 3,4-Methylenedioxyamphetamine/pharmacokinetics , 3,4-Methylenedioxyamphetamine/pharmacology , Adult , Area Under Curve , Cross-Over Studies , Double-Blind Method , Female , Hallucinogens/pharmacokinetics , Hallucinogens/pharmacology , Humans , Male , N-Methyl-3,4-methylenedioxyamphetamine/pharmacokinetics , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Young AdultABSTRACT
This article describes the context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes from the 1940s to the 1960s. Germans first tested mescaline as a "truth drug" in a military context. In the 1940s, the United States military started testing hallucinogenic substances as truth drugs for interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible "speech-inducing" effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4-Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the compounds delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/1954 revealed that some of the "mescaline derivatives" tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. In 1955, the military changed focus to lysergic acid diethylamide (LSD), but some interest in mescaline-like compounds remained for their ability to change mood and habit without interfering with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) whether any of the mescaline derivatives tested were being used operationally.
Subject(s)
3,4-Methylenedioxyamphetamine/administration & dosage , Designer Drugs/administration & dosage , Hallucinogens/administration & dosage , Mescaline/administration & dosage , Military Personnel/psychology , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Animals , Designer Drugs/chemistry , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/trends , Hallucinogens/chemistry , Humans , Mescaline/chemistry , N-Methyl-3,4-methylenedioxyamphetamine/chemistry , United States , World War IIABSTRACT
Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples from 16 healthy participants receiving 125 mg of MDMA orally in a controlled study were analyzed using liquid chromatography-tandem mass spectroscopy after chiral derivatization. Pharmacokinetic parameters of R- and S-stereoisomers were determined. Sulfates of 3,4-dihydroxymethamphetamine (DHMA), and sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA) were identified, whereas free phase I metabolites were not detected. Stereoselective differences in Cmax and AUC24 were observed with the following preferences: R>S for MDMA and DHMA 4-sulfate; S>R for 3,4-methylenedioxyamphetamine (MDA), DHMA 3-sulfate, and HMMA glucuronide; and no preference in Cmax for HMMA sulfate. R/S ratios were >1 for all analytes after 24 hours, independent of the initial chiral preference. These are the first data on chiral pharmacokinetics of MDMA phase II metabolites in human plasma in vivo after controlled administration. The main human MDMA metabolites were shown to be sulfate and glucuronide conjugates.
Subject(s)
3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/blood , Methamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/chemistry , Administration, Oral , Adult , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Methamphetamine/administration & dosage , Methamphetamine/blood , Methamphetamine/chemistry , Stereoisomerism , Young AdultABSTRACT
MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature.
Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , Hippocampus/metabolism , Neurotoxicity Syndromes/genetics , Protein Biosynthesis , Stress Disorders, Post-Traumatic/genetics , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/adverse effects , Animals , Gene Expression Regulation , Neurotoxicity Syndromes/pathology , Protein Folding/drug effects , Rats , Serotonin/genetics , Serotonin/metabolism , Serotonin Agents/administration & dosage , Serotonin Agents/adverse effects , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/pathologyABSTRACT
The popular synthetic drug of abuse 3,4-methylenedioxymethampetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) act mainly on the serotonergic system, though they also increase the amount of extracellular dopamine (DA) in the brain, presumably via reversal of the membrane dopamine transporter (DAT). As the involvement of exocytotic DA release is debated, we investigated if these drugs alter the intracellular calcium concentration ([Ca(2+)](i)) and subsequent DA exocytosis in single PC12 cells using respectively Fura-2 imaging and amperometry. MDMA and MDA did not change basal [Ca(2+)](i) or exocytosis, but inhibited depolarization-evoked increases in [Ca(2+)](i) and exocytosis following 15 min exposure to high concentrations of drugs (1 mM). Surprisingly, MDA was more potent in inhibiting exocytosis than MDMA and already inhibited exocytosis at concentrations that did not inhibit depolarization-evoked Ca(2+) influx (10-100 µM). Without 15 min pre-exposure, both drugs failed to inhibit depolarization-evoked Ca(2+) influx. These results indicate that at high concentrations both MDMA and MDA inhibit exocytosis via indirect inhibition of Ca(2+) influx, whereas at lower concentrations MDA may also reduce vesicle cycling. Our data suggest that the DAT-independent increase in extracellular DA in vivo is not due to direct stimulation of exocytosis, but rather to effects of these drugs on other neurotransmitter systems that innervate the dopaminergic system.
Subject(s)
3,4-Methylenedioxyamphetamine/administration & dosage , Calcium/antagonists & inhibitors , Calcium/metabolism , Dopamine/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Synaptic Vesicles/metabolism , 3,4-Methylenedioxyamphetamine/metabolism , Animals , Cell Survival/drug effects , Cell Survival/physiology , Exocytosis/drug effects , Exocytosis/physiology , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , PC12 Cells , Rats , Synaptic Vesicles/drug effectsABSTRACT
The aim of this study was to investigate the involvement of serotonin-1A (5-HT(1A)) receptors in the effects of 3,4-methylenedioxymetamphetamine (MDMA) on prepulse inhibition of acoustic startle (PPI) by comparing male and female wild-type (WT) mice and 5-HT(1A) receptor knockout (1AKO) mice. MDMA dose-dependently decreased PPI in male and female mice although female mice were more sensitive at the 100-ms inter-stimulus interval (ISI). In male mice, 10 mg/kg MDMA disrupted PPI in 1AKO but not in WT controls. There was no genotype difference at higher or lower doses of MDMA. In female mice, there was no difference between genotypes at any dose of MDMA. Average startle was reduced by 10 mg/kg and 20 mg/kg MDMA similarly in male and female mice and all genotypes. These results show an involvement of 5-HT(1A) receptors in the effect of MDMA on PPI in male, but not female mice.
Subject(s)
3,4-Methylenedioxyamphetamine/toxicity , Hallucinogens/toxicity , Neural Inhibition/drug effects , Receptor, Serotonin, 5-HT1A/physiology , 3,4-Methylenedioxyamphetamine/administration & dosage , Acoustic Stimulation , Adrenergic Uptake Inhibitors/administration & dosage , Adrenergic Uptake Inhibitors/toxicity , Animals , Dose-Response Relationship, Drug , Female , Hallucinogens/administration & dosage , Heterozygote , Illicit Drugs/toxicity , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, Serotonin, 5-HT1A/genetics , Reflex, Startle/drug effects , Sex CharacteristicsABSTRACT
The amphetamine-derived designer drugs have been illegally used worldwide as recreational drugs, some of which are known to be hepatotoxic in humans. To compare their cytotoxic effects, 3,4-methylenedioxy-N-methamphetamine (MDMA) and its related analogues, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-(methylenedioxyphenyl)-2-butanamine (BDB) and 2-methylamino-1-(3,4-methylenedioxyphenyl)-propane-1-one (methylone) were studied in freshly isolated rat hepatocytes. MBDB caused not only concentration (0-4.0 mM)- and time (0-2 h)-dependent cell death accompanied by the formation of cell blebs, and the loss of cellular ATP and adenine nucleotide pools, and reduced glutathione levels, but also the accumulation of oxidized glutathione. Of the other analogues examined, the cytotoxicity of MBDB and BDB was greater than that of MDMA and methylone, suggesting that hepatotoxicity is generally induced by these drugs. In addition, DNA damage and the induction of reactive oxygen species were greater after the incubation of hepatocytes with MBDB (2 and 4 mM) than after that with MDMA. In isolated liver mitochondria, MBDB/BDB resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA/methylone, indicating an uncoupling effect and a decrease in the rate of state 3 oxygen consumption in a concentration dependent manner. Furthermore, MBDB resulted in mitochondrial swelling dependent on the mitochondrial permeability transition (MPT); the effect of MDMA was less than that of MBDB. Taken collectively, these results suggest that (1) the onset of cytotoxicity caused by designer drugs such as MBDB and MDMA is linked to mitochondrial failure dependent upon the induction of the MPT accompanied by mitochondrial depolarization and depletion of ATP through uncoupling of oxidative phosphorylation in rat hepatocytes, and (2) MBDB and MDMA elicit DNA damage, suggesting that nuclei as well as mitochondria are target sites of these compounds.
Subject(s)
Hepatocytes/drug effects , Mitochondria, Liver/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/toxicity , Adenosine Triphosphate/metabolism , Animals , Cell Death/drug effects , DNA Damage/drug effects , Hallucinogens/administration & dosage , Hallucinogens/toxicity , Hepatocytes/metabolism , Male , Methamphetamine/administration & dosage , Methamphetamine/analogs & derivatives , Methamphetamine/toxicity , Mitochondria, Liver/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Oxidative Phosphorylation/drug effects , Rats , Rats, Inbred F344 , Time FactorsABSTRACT
RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans. OBJECTIVES: The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR). MATERIALS AND METHODS: Sprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation. RESULTS: HOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (P<0.001). HR responses to MDMA over 6 weeks at both TAs progressively decreased with repeated dosing (P<0.05). TC was significantly higher in both 6-week groups compared to the 1-week groups (P<0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P<0.05) and 5-hydroxyindole acetic acid (5-HIAA; P<0.001) decreased significantly irrespective of TA, while concentrations of dopamine and 5-HT did not change. CONCLUSION: Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.
Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , Body Temperature Regulation/drug effects , Heart Rate/drug effects , 3,4-Dihydroxyphenylacetic Acid/antagonists & inhibitors , 3,4-Dihydroxyphenylacetic Acid/chemistry , 3,4-Dihydroxyphenylacetic Acid/metabolism , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/adverse effects , Animals , Behavior, Animal/drug effects , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dopamine/analysis , Dopamine/chemistry , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Hot Temperature , Humans , Hydroxyindoleacetic Acid/antagonists & inhibitors , Hydroxyindoleacetic Acid/chemistry , Hydroxyindoleacetic Acid/metabolism , Hyperthermia, Induced/instrumentation , Hyperthermia, Induced/methods , Injections, Intraperitoneal , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Serotonin/analysis , Serotonin/chemistry , Serotonin/metabolism , Telemetry , Time FactorsABSTRACT
AIM: The mechanism of MDMA (3,4-methylenedioxymethamphetamine)-induced toxicity is believed to be, in part, due to enhanced oxidative stress. As MDMA is eliminated via the kidney, the aim of this study was to investigate whether MDMA created conditions of oxidative stress within rat kidney. METHODS: Adult male Wistar rats were divided into three groups, control treatment (water), acute MDMA administration (single oral dose: 5, 10, 20 or 40 mg/kg body weight) and subacute MDMA administration (5, 10, or 20 mg/kg body weight per day during 14 days). Animals were sacrificed 8 h after the single oral MDMA administration in the acute MDMA administration group and after the last MDMA administration in the subacute MDMA administration group. Rectal temperature measurements, oxidative stress status parameters and histological examinations were performed. RESULTS: In all MDMA-administered rats, rectal temperature markedly increased peaking approximately 1 h after MDMA ingestion. Superoxide dismutase activity and thiobarbituric acid reactive substances increased after MDMA administration. Histological examinations of the kidney revealed dose-dependent disruption of tissue structure in subacute MDMA-administered rats. The latter was not observed in acute MDMA-administered rats.
Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , Kidney Diseases/metabolism , Oxidative Stress/physiology , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/toxicity , Administration, Oral , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Kidney/metabolism , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Male , Oxidative Stress/drug effects , Rats , Severity of Illness Index , Spectrophotometry , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
A sensitive and reliable LC-ESI-MS procedure for the simultaneous determination of MDMA and its five metabolites including 4-hydroxy-3-methoxymethamphetamine (HMMA) conjugates has been established following the synthesis of two HMMA conjugates, 4-hydroxy-3-methoxymethamphetamine-glucuronide (HMMA-Glu) and 4-hydroxy-3-methoxymethamphetamine-sulfate (HMMA-Sul). Pretreatment of urine samples with methanol and LC-MS employing a C(18) semi-micro column with a gradient elution program provided the successful separations and MS determinations of these analytes within 20 min. Upon applying the method to MDMA users' urine specimens, HMMA-Glu and HMMA-Sul have been directly determined, suggesting the superiority of sulfation to glucuronidation in the HMMA phase II metabolism.
Subject(s)
Glucuronides/urine , Hallucinogens/metabolism , Methamphetamine/analogs & derivatives , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , Substance Abuse Detection/methods , Sulfates/urine , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/urine , Amphetamine-Related Disorders/urine , Calibration , Designer Drugs/administration & dosage , Designer Drugs/analysis , Gas Chromatography-Mass Spectrometry/methods , Glucuronides/chemical synthesis , Glucuronides/metabolism , Hallucinogens/administration & dosage , Hallucinogens/urine , Humans , Methamphetamine/chemical synthesis , Methamphetamine/metabolism , Methamphetamine/urine , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/analogs & derivatives , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Sulfates/chemical synthesis , Sulfates/metabolismABSTRACT
3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, alpha-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-alpha-MeDA and alpha-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity.
Subject(s)
Hallucinogens/metabolism , Hallucinogens/toxicity , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Neurons/drug effects , 3,4-Methylenedioxyamphetamine/administration & dosage , Acetylcysteine/pharmacology , Adenosine Triphosphate/metabolism , Animals , Caspase 3/metabolism , Cell Death/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Deoxyepinephrine/administration & dosage , Deoxyepinephrine/analogs & derivatives , Dose-Response Relationship, Drug , Drug Interactions , Embryo, Mammalian , Free Radical Scavengers/pharmacology , Glutathione/metabolism , Hallucinogens/chemistry , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/chemistry , Rats , Rats, Wistar , Temperature , Time FactorsABSTRACT
In the last decade, a global trend of escalating ecstasy (MDMA, MDA, MDEA, MBDB) use was observed. Mentions on medical death certificates, last year's ecstasy use, number of drug offenders, seizures, prices and dosage levels figures were used for this descriptive and correlational study. Figures (1994-2003) were taken from the UK General Mortality Registers, from the Home Office Statistical Bulletins, from the British Crime Survey and from those reported to both the National Crime Intelligence and Forensic Science Services. A total of 394 ecstasy deaths mentions were here identified from the UK; in 42% of cases ecstasy was the sole drug mentioned. Overall, number of fatalities showed a year-per-year increase and positively correlated with: prevalence of last year's use (p < 0.01); number of offenders (p < 0.01) and number of seizures (p < 0.01) but negatively correlated with ecstasy price (p < 0.05). Price negatively correlated with: prevalence of last year's use (p < 0.001) and number of seizures (p < 0.01); but positively correlated with average MDMA dosage per tablet (p < 0.01). MDA, MDEA and MBDB accounted for a significant proportion of tablets only up to 1997, but not afterwards. Increasing production with a concomitant decrease in ecstasy price may have facilitated an increase in consumption levels and this, in turn, may have determined an increase in number of ecstasy deaths mentions. Only medical death certificates and not coroners' reports at the end of their inquests were here analysed; no data were available in respect of other drugs use and toxicology results.
Subject(s)
Amphetamine-Related Disorders/complications , Crime/legislation & jurisprudence , Drug and Narcotic Control/legislation & jurisprudence , Illicit Drugs/adverse effects , N-Methyl-3,4-methylenedioxyamphetamine/adverse effects , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/adverse effects , 3,4-Methylenedioxyamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/economics , Amphetamine-Related Disorders/economics , Amphetamine-Related Disorders/epidemiology , Amphetamine-Related Disorders/mortality , Cause of Death , Crime/statistics & numerical data , Cross-Sectional Studies , Dose-Response Relationship, Drug , Drug and Narcotic Control/statistics & numerical data , Humans , Illicit Drugs/economics , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/economics , Statistics as Topic , United KingdomABSTRACT
3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are ring-substituted amphetamine derivatives with stimulant and hallucinogenic properties. The recreational use of these amphetamines, especially MDMA, is prevalent despite warnings of irreversible damage to the central nervous system. MDA and MDMA are primarily serotonergic neurotoxicants. Because (1) neither MDA nor MDMA produces neurotoxicity when injected directly into brain, (2) intracerebroventricular (i.c.v.) administration of some major metabolites of MDA and MDMA fails to reproduce their neurotoxicity, (3) alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-MeDA are metabolites of both MDA and MDMA, (4) alpha-MeDA and N-methyl-alpha-MeDA are readily oxidized to the corresponding ortho-quinones, which can undergo conjugation with glutathione (GSH), and (5) quinone thioethers exhibit a variety of toxicologic activities, we initiated studies on the potential role of thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA in the neurotoxicity of MDA and MDMA. Our studies have revealed that the thioether conjugates stimulate the acute release of serotonin, dopamine, and norepinephrine and produce a behavioral response commensurate with the "serotonin syndrome." Direct injection of the conjugates into rat brain also produces long-term depletions in serotonin (5-HT) concentrations, elevations in GFAP expression, and activation of microglial cells. The data are consistent with the view that thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA contribute to the neurotoxicity of the parent amphetamines.
Subject(s)
3,4-Methylenedioxyamphetamine/metabolism , Hallucinogens/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , Neurotoxicity Syndromes/etiology , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/adverse effects , Animals , Blood-Brain Barrier/metabolism , Catechols/metabolism , Hallucinogens/administration & dosage , Hallucinogens/adverse effects , Humans , Illicit Drugs/adverse effects , Illicit Drugs/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/adverse effects , Neurotoxicity Syndromes/metabolism , Reactive Oxygen Species/metabolism , Sulfides/metabolismABSTRACT
Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed. Males, but not females, exposed to MDMA had longer latencies and more errors in the Cincinnati water maze compared to males of the other treatments. In the Morris water maze (210 cm pool, 10x10 cm platform), the MDMA animals were impaired relative to all other treatments during acquisition. Only the MDMA females showed deficits when the platform was shifted to a new location, however, both MDMA males and females were impaired when the location of the platform was again shifted and a reduced platform (5x5 cm) used. No differences were observed in the ability to swim a straight channel, locate a platform with a cue, or the endocrine response to forced swim among the treatment groups. No differences were seen between animals injected with saline and those only weighed. The data suggest that factors, such as growth retardation, multiple injections, or the composition of the litter, do not affect the development of learning and memory impairments resulting from P11 to 20 MDMA exposure. The large litter approach offers a novel method to control for undernutrition during the preweaning period in rodents.
Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/adverse effects , Excitatory Amino Acid Agonists/adverse effects , Learning Disabilities/etiology , Litter Size/drug effects , Serial Learning/drug effects , Spatial Behavior/drug effects , 3,4-Methylenedioxyamphetamine/administration & dosage , Adrenocorticotropic Hormone/blood , Aging , Animals , Animals, Newborn/growth & development , Behavior, Animal , Body Constitution , Body Weight , Case-Control Studies , Corticosterone/blood , Cues , Excitatory Amino Acid Agonists/administration & dosage , Female , Litter Size/physiology , Male , Maze Learning/drug effects , Parity , Random Allocation , Rats , Rats, Sprague-Dawley , Reaction Time , Sex Factors , Stress, Physiological , Swimming/physiology , Time FactorsABSTRACT
Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT) suggesting competition between intact 5-GSyl-alpha-MeDA and GSH for the putative GSH transporter. gamma-GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma-GT at the blood-brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis-(glutathion-S-yl)-alpha-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.
Subject(s)
3,4-Methylenedioxyamphetamine/toxicity , Brain/drug effects , Isoxazoles/pharmacology , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Serotonin Agents/toxicity , gamma-Glutamyltransferase/antagonists & inhibitors , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/antagonists & inhibitors , Administration, Cutaneous , Animals , Brain/metabolism , Endothelium/metabolism , Enzyme Inhibitors/pharmacology , Humans , Male , Models, Molecular , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/antagonists & inhibitors , Neurotoxicity Syndromes , Neurotransmitter Agents/analysis , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Serotonin Agents/administration & dosage , gamma-Glutamyltransferase/metabolismABSTRACT
Illicit drug use by young people has changed in the last decade, with the increasing use of "designer" or "club" drugs such as ecstasy. Keeping abreast of current trends in illicit drug use prepares the primary care clinician to recognize the clinical effects of drug use, to manage drug emergencies, and to detect addictive behavior. Today's widely used drugs, their street names, their effects, and how to manage overdoses are reviewed.
Subject(s)
Illicit Drugs/adverse effects , Substance-Related Disorders/therapy , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/adverse effects , 3,4-Methylenedioxyamphetamine/pharmacology , Adolescent , Ephedrine/administration & dosage , Ephedrine/adverse effects , Ephedrine/pharmacology , Flunitrazepam/administration & dosage , Flunitrazepam/adverse effects , Flunitrazepam/pharmacology , Humans , Ketamine/administration & dosage , Ketamine/adverse effects , Ketamine/pharmacology , Methamphetamine/administration & dosage , Methamphetamine/adverse effects , Methamphetamine/pharmacology , Sodium Oxybate/administration & dosage , Sodium Oxybate/adverse effects , Sodium Oxybate/pharmacologyABSTRACT
Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.
Subject(s)
3,4-Methylenedioxyamphetamine/administration & dosage , Hallucinogens/administration & dosage , Learning Disabilities/chemically induced , Memory Disorders/chemically induced , Age Factors , Animals , Animals, Newborn , Behavior, Animal/drug effects , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Escape Reaction/drug effects , Female , Injections, Subcutaneous , Learning Disabilities/diagnosis , Learning Disabilities/physiopathology , Male , Maze Learning/drug effects , Memory Disorders/diagnosis , Memory Disorders/physiopathology , Norepinephrine/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Survival RateSubject(s)
3,4-Methylenedioxyamphetamine/metabolism , Deoxyepinephrine/analogs & derivatives , Glutathione/analogs & derivatives , Hallucinogens/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , Serotonin Agents/metabolism , 3,4-Methylenedioxyamphetamine/administration & dosage , 3,4-Methylenedioxyamphetamine/pharmacology , Acetylcysteine/administration & dosage , Acetylcysteine/analogs & derivatives , Acetylcysteine/metabolism , Acetylcysteine/pharmacology , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Deoxyepinephrine/administration & dosage , Deoxyepinephrine/metabolism , Deoxyepinephrine/pharmacology , Glutathione/administration & dosage , Glutathione/metabolism , Glutathione/pharmacology , Hallucinogens/administration & dosage , Hallucinogens/pharmacology , Humans , Molecular Structure , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Neurotransmitter Agents/metabolism , Rats , Serotonin Agents/administration & dosage , Serotonin Agents/pharmacologyABSTRACT
Identification of the optical activity and simultaneous analysis of racemates (+/-) of three hallucinogens, 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA), and the urinary excretion of their optical isomers in rats was performed by high-performance liquid chromatographic analysis. Analysis of optical enantiomers of three N-alkyl MDA derivatives was performed within 50 min using two different detectors, polarimetry (OR) and ultraviolet spectroscopy (UV). The OR detector proved suitable for identification of the optically active forms, whereas the UV detector was suitable for simultaneous analysis of the enantiomers in urine. After the administration of each of the three N-alkylated derivatives, rat urine specimens were collected over four intervals, 0-4, 4-12, 12-20, and 20-24 h. After the administration of 30 mg/kg of racemic MDA and MDMA, somewhat less of the S(+)-forms of unchanged MDA and MDMA than of the R(-)-forms in each urine specimen were detected, which gave R/S ratios greater than 1.00 (p < 0.01). Conversely, after the administration of 30 mg/kg of racemic MDEA, more of the S(+)-form than the R(-)-form was found in the urine, thus giving R/S ratios less than 1.00 (p < 0.01). The percentage of the dose excreted up to 24 h was approximately 29.4% of the administered dose for MDA [S(+) 13.40% and R(-) 15.98%], 5.8% for MDMA [S(+) 1.96% and R(-) 3.79%], and 7.3% for MDEA [S(+) 3.89% and R(-) 3.43%]. Urinary excretion of optical isomers of N-dealkylated MDA from MDMA and MDEA origin were the opposite of those of the unchanged forms, and their R/S ratios up to 24 h were 0.48 to 0.72 (p < 0.01) and 1.31 to 1.50 (p < 0.01), respectively. The urinary excretion rates up to 24 h were approximately 4.3% for N-dealkylated MDA from MDMA origin [S(+) 2.72% and R(-) 1.63%] and 0.8% for N-dealkylated MDA from MDEA origin [S(+) 0.36% and R(-) 0.47%]. The total percent of unchanged forms and N-dealkylated MDA was approximately 10.1% for MDMA [S(+) 4.68% and R(-) 5.42%] and 8.2% for MDEA [S(+) 4.25% and R(-) 3.91%]. The total R/S ratio of MDMA was found to be 1.95 (p < 0.01), whereas that of MDEA was 0.88 (p < 0.01). The total R/S ratio of MDA was 1.20 (p < 0.01 ), which was comparable with that of MDMA. These three R/S ratios did not conform to the theoretical values for three N-alkyl derivatives used and neither did the R/S ratios of urine specimens collected at the four interval. These results suggested the stereoselective disposition of three N-alkyl MDA analogues in rat. The method would be suitable for the forensic chemistry and toxicology analysis of specimens obtained from hallucinogen abusers.