Midomafetamine, or MDMA, is reported to undergo extensive CYP-mediated hepatic metabolism, with CYP2D6 playing a major role in humans. Other CYP enzymes contributing to MDMA metabolism are CYP3A4 and COMT. MDMA is metabolized via two primary metabolic pathways. It may undergo O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation. In contrast, it may also undergo N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Due to autoinhibition of CYP2D6 and CYP2D8, MDMA displays a complex, nonlinear pharmacokinetics profile, with the zeroth order kinetics occurring at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.
MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in the immortalized human liver epithelial cell line THLE-Neo lacking phase I metabolism and primary rat hepatocytes expressing both phase I and II metabolism. Furthermore, we evaluated the potential protective effects of two antioxidants, N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly decreased cell viability and depleted GSH levels, resulting in an increased expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat hepatocytes, cell viability or GSH levels were not significantly affected upon MDMA exposure. GCLC expression levels where not significantly altered either, although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced cytotoxicity and restored GSH levels. Phase II enzyme expression was also reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, while GCLC and GST expression were significantly induced. In addition, PXR expression decreased after HHMA and MDMA exposure, while co-exposure to SFN induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo cells and rat hepatocytes, respectively. Taken together, these data indicate that HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction with the glutathione system. The results of our study show that for MDMA intoxication the treatment with an antioxidant such as NAC may counteract the potentially hepatotoxicity. However, SFN supplementation should be considered with care because of the indications of possible drug-drug interactions.
3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 hr. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 hr followed by a 100 mg dose of caffeine 4 hr later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.
The R- and S-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) exhibit different dose-concentration curves. In plasma, S-MDMA was eliminated at a higher rate, most likely due to stereoselective metabolism. Similar data were shown in various in vitro experiments. The aim of the present study was the in vivo investigation of stereoselective elimination of MDMA's phase I and phase II metabolites in human urine following controlled oral MDMA administration. Urine samples from 10 participants receiving 1.0 and 1.6 mg/kg MDMA separated by at least one week were analyzed blind by liquid chromatography-high resolution-mass spectrometry and gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. R/S ratios at C(max) were comparable after low and high doses with ratios >1 for MDMA, free 3,4-dihydroxymeth-amphetamine (DHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) sulfate, and with ratios <1 for 3,4-methylendioxyamphetamine (MDA), free HMMA, DHMA sulfate and HMMA glucuronide. In the five days after the high MDMA dose, a median of 21% of all evaluated compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly greater MDMA, DHMA, and HMMA sulfate R-enantiomers and HMMA and HMMA glucuronide S-stereoisomers were excreted. No significant differences were observed for MDA and DHMA sulfate stereoisomers. Changes in R/S ratios could be observed over time for all analytes, with steady increases in the first 48 hr. R/S ratios could help to roughly estimate time of MDMA ingestion and therefore, improve interpretation of MDMA and metabolite urinary concentrations in clinical and forensic toxicology.
3,4-Methylenedioxy-amphetamine (MDA) and benzodioxolyl-butanamine (BDB) are chiral designer drugs distributed on the illicit drug market and they are also N-dealkyl metabolites of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy, Adam), 3,4-methylenedioxyethylamphetamine (MDEA, Eve), and N-methyl-benzodioxolyl-butanamine (MBDB, Eden), respectively. MDA and BDB are mainly metabolized via demethylenation to the corresponding catecholamines. The aim of the present work was to elucidate the contribution of the relevant human P450s in the demethylenation of the MDA and BDB enantiomers. They were incubated using heterologously expressed human P450s and the corresponding metabolites dihydroxyamphetamine and 1,2-dihydroxy-4-[2-amino-butyl]benzene were determined. Highest contributions to the demethylenation as calculated from the enzyme kinetic data were obtained for CYP2D6 (MDA and BDB) and additionally CYP3A4 in the case of BDB at substrate concentrations corresponding to plasma concentrations of recreational users. A preferred transformation of the S-enantiomer could be observed for the CYP2D6- and CYP3A4-catalyzed reactions.
IDENTIFICATION AND USE: 3,4-Methylenedioxymethamphetamine (MDMA) is a schedule I controlled substance. Ecstasy is the popular name for the illicit drug MDMA and is widely used at dance parties. It is usually consumed orally in tablet or capsule form. MDMA acts as both a stimulant and psychedelic, producing an energizing effect, as well as distortions in time and perception and enhanced enjoyment from tactile experiences. HUMAN STUDIES: Acute toxic effects of MDMA include hyperthermia, muscle rigidity, metabolic acidosis, disseminated intravascular coagulation, and rhabdomyolysis. These effects can lead to multiorgan failure and death. The level of hyperthermia predicts the potential for survival. MDMA produces cardiovascular effects similar to those seen with methamphetamine, including an increase in blood pressure and heart rate. Serious sequelae can occur from electrolyte abnormalities seen in MDMA abuse and overdose. Hyponatremia from inappropriate antidiuretic hormone production and increased free water intake has been described in several case reports of significant cerebral edema and subsequent death. Acute hepatotoxicity has been described as a consequence of MDMA use. An acute hepatitis pattern with lymphocytic infiltration of hepatic parenchyma is seen. Over the course of a week following moderate use of the drug, many MDMA users report feeling a range of emotions, including anxiety, restlessness, irritability, and sadness that in some individuals can be as severe as true clinical depression. Similarly, elevated anxiety, impulsiveness, and aggression, as well as sleep disturbances, lack of appetite, and reduced interest in and pleasure from sex have been observed in regular MDMA users. MDMA has been implicated as a cause of amnesic syndrome associated with severe ataxia. Chronic use of MDMA has been implicated in sleep disorders and mood changes. Cognitive deficits such as memory recall were also seen in users of MDMA even after 6 months of abstinence. Eye pathology, including retinal hemorrhage with blurred vision, has been described with the use of MDMA. Prospective follow up of 136 babies exposed to ecstasy in utero showed that the drug may be associated with a significantly increased risk of congenital defects. Cardiovascular anomalies and musculoskeletal anomalies were predominant. ANIMAL STUDIES: A variety of animal models have shown MDMA to be a selective serotonin neurotoxin. Acutely MDMA exposure elicits a classical serotonin syndrome. In the long-term, exposure results in serotonin neurotoxicity and a lasting cognitive impairment. Direct injection of MDMA into the brain fails to reproduce the serotonergic neurotoxicity seen following peripheral administration. The serotonergic neurotoxicity of MDMA therefore appears to be dependent upon the generation of a neurotoxic metabolite, or metabolites, the identity of which remains unclear. ECOTOXICITY STUDIES: Environmentally relevant MDMA concentrations did not induce deleterious effects to the zebra mussel (Dreissena polymorpha).
◈ What is MDMA?
3,4 methylenedioxymethamphetamine (MDMA) is a drug that can cause an altered state of mind (hallucinations / delusions). Other names for MDMA include Molly, ecstasy, E, X, XTC, and Mandy. MDMA can be taken by mouth as a pill or capsule or snorted / inhaled as a powder.If you have been using MDMA, please seek help right away. Treatment is available to help you stop using MDMA. Talk with your healthcare providers; they are there to help you.
◈ I am taking MDMA, but I would like to stop taking it before getting pregnant. How long does the drug stay in my body?
People eliminate drugs at different rates. In healthy adults, it takes up to 4 days, on average, for most of the MDMA to be gone from the body.
◈ I take MDMA. Can it make it harder for me to get pregnant?
It is not known if MDMA can make it harder to get pregnant.
◈ Does taking MDMA increase the chance for miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if MDMA increases the chance for miscarriage.
◈ Does taking MDMA increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, it is not known if MDMA increases the chance for birth defects above the background risk. One small study reported an increase in heart defects and / or club foot (foot points downward and inward). However, it is not known if the MDMA or other factors caused the increase in birth defects.
◈ Does taking MDMA in pregnancy increase the chance of other pregnancy-related problems?
Based on the studies reviewed, it is not known if MDMA can cause other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking MDMA in pregnancy affect future behavior or learning for the child?
Based on the studies reviewed, it is not known if MDMA increases the chance for behavior or learning issues. A study of twenty-eight pregnancies exposed to MDMA reported infants showed a delay in development at four months old. Another study followed a small group of children exposed 1 month before pregnancy and in the first and second trimesters. The study suggested that babies exposed to MDMA might be delayed in their motor development up to 2 years of age. However, the people who were pregnant also reported exposure to alcohol and other drugs. This makes it hard to know if the MDMA, other exposures, or other factors caused these delays.
◈ Breastfeeding while taking MDMA:
Breastfeeding while using MDMA is not recommended. MDMA passes into breast milk. Amphetamine drugs (like MDMA) are found at higher levels in breastmilk than in the blood stream. If MDMA has already been taken, it has been recommended to express and discard breast milk for 48 hours. If you suspect the baby has any symptoms (fever, seizures, rapid heartbeat, eyes rolling, looking upwards for a period of time), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes MDMA, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if MDMA could affect male fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.
The effects of injection of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDEA) (all 20 mg/kg) on blood pressure, heart rate, core body temperature and locomotor activity in conscious rats were investigated using radiotelemetry. MDMA and MDA produced a prolonged increase in both systolic and diastolic pressures, with MDA causing the most marked rise. MDEA produced a transient but nonsignificant fall in diastolic pressure. The pressor response produced by MDA was accompanied by bradycardia. All three amphetamine derivatives caused an initial hypothermic response; however, MDA also produced a subsequent hyperthermia, and the speed of recovery from hypothermia was MDA>MDMA>MDEA. The alpha-2A-adrenoceptor antagonist 2-((4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3-dihydro-1-methyl-1H-isoindole (BRL 44408) (1 mg/kg) prolonged the hypothermic response to MDMA. Only MDA induced locomotor activity when given alone, but in the presence of BRL 44408, MDMA produced increased locomotor activity. The order of potency for producing isometric contractions of rat aorta (alpha1D) and vas deferens (alpha1A) was MDA>MDMA>MDEA, with MDEA acting as an alpha1-adrenoceptor antagonist with a pKB of 4.79 +/- 0.12 (n=4) in aorta. The order of potency for prejunctional inhibition of stimulation-evoked contractions in rat vas deferens (alpha2A-adrenoceptor mediated) was MDA>MDMA>MDEA. Blood pressure actions of the three amphetamine derivatives may be at least partly due to alpha1-adrenoceptor agonism or antagonism. The reversal of the hypothermic actions are at least partly due to alpha2A-adrenoceptor agonism since the hypothermic response was more prolonged with MDEA which exhibits low alpha2A-adrenoceptor potency, and effects of MDMA after alpha2A-adrenoceptor antagonism were similar to those of MDEA.
Ethanol and 3, 4-Methylenedioxymethamphetamine (MDMA) are popular recreational drugs widely abused by adolescents that may induce neurotoxic processes associated with behavioral alterations. Adolescent CD1 mice were subjected to ethanol intake using the drinking in the dark (DID) procedure, acute MDMA or a combination. Considering that both drugs of abuse cause oxidative stress in the brain, protein oxidative damage in different brain areas was analyzed 72 hr after treatment using a proteomic approach. Damage to specific proteins in treated animals was significant in the hippocampus but not in the prefrontal cortex. The damaged hippocampus proteins were then identified by mass spectrometry, revealing their involvement in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. Mice treated with MDMA displayed higher oxidative damage t
