Ecstasy (MDMA) is 3, 4-Methylenedioxymethamphetamine and is considered as one of the most recreational psycho-actives. It is an euphoric and stimulant drug. It is a serotonergic (5HT) drug where serotonin is well known to be associated with major depression and obsessive compulsive disorder. MDMA causes acute toxic effects and hundreds of cases are reported about these adverse effects. The risk of MDMA also includes the possible long-term brain damage which is more difficult to assess. Many studies in laboratory animals have shown that MDMA can produce long-lasting decreases in brain functions involving the neurotransmitter serotonin.
Ecstasy or 3, 4-methylenedioxymethamphetamine (MDMA) which is frequently used for its acute euphoric effects is considered as a serotonin releaser. However, recent investigations have revealed that MDMA users are at risk to develop persistent negative mood and personality disorders (1, 2). This drug has become popular in Europe and North America over the last 20 years. It is mainly consumed by young people during night parties, for a single night or along the weekend. Ecstasy produces pleasurable effects, including an enhanced sense of self-confidence and energy, the feelings of peacefulness and empathy. Some MDMA users mention that they experience feelings of closeness with others and also a desire to touch others. This means that this drug starts with desirable effects such as euphoria, emotional openness and ability to gain insights into self (3, 4). Dancing for extended periods is one of the stimulant effects of MDMA, which when combined with the hot crowded conditions usually found at raves can lead to severe dehydration and high increases in body temperature. This might result in some other disorders as muscle breakdown and kidney, liver and cardiovascular failure. Cardiovascular failure has been reported in some cases of MDMA-related fatalities. However, the undesired effects that might happen in Ecstasy user include dizziness, vertigo, muscle tension, trismus, bruxism, nausea, blurred vision, rapid eye movement and faintness (3, 4). In later stages “comedown” individuals could experience severe anxiety, paranoia, sleep problems, and nightmares which last for days or weeks (4).
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Long term drug abuse leads to neuro-adaptive processes which might result in drug tolerance and/or sensitization. Drug sensitization can mainly result in psychomotor activity which includes increased locomotion, exploratory rearing and sniffing, and repetitive stereotyped movements (5, 6, 7). There are some other effects of MDMA which include loss of inhibitions, seizures, transfixion on sights and sounds, chills and/or sweating, involuntary teeth clenching, nausea and blurred vision. Cardiovascular effects might also result from using MDMA such as increases in heart rate and blood pressure.
When the induced effects of the drug decrease, the drug users tend to increase the dose to retain these effects and this might result in drug tolerance. This tolerance can increase up to the level of doubling the dose 5-10 times as was described by an experienced user who was using MDMA pills in a single session (8). Tolerance to MDMA can develop to certain mediated responses after repeated administration of the drug as revealed from experimental study in lab animals. These responses include hormone secretion, heart rate and 5-HT responses (9). In addition many neuroadaptations can result from repeated administration of MDMA including anxiety, depression and sleep problems.
Ecstasy and brain Damage
When MDMA (3, 4-methylendioxymethamphetamine) is given in high doses, it causes selective and persistent lesions of central serotonergic nerve terminals. The neurotoxicity and the resulting functional errors have been inestigated in several studies in MDMA users. The results show that ecstasy has adverse effects on serotonergic transmission. A partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. Severe adverse effects also were recorded particularly with memory. Meanwhile, long term neurotoxic effects of stimulant use are relatively rare. In contrast using methamphetamine (METH) as a stimulant results in alterations of the dopaminergic system that might persist even after years of abstinence and can result in deficits in motor and cognitive performance (10).
A monograph published on chronic MDMA abuse revealed that the two patients developed movement disorders typical of the Parkinson's syndrome. It was noted that both men bought their drug (MDMA) from the same illicit source. In this study, the authors concluded that there was a possible contamination of the used drug by both patients. Also, they mentioned that potential risks including movement disorders might result from contaminants and using of nonpharmaceutical-grade MDMA (11).
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Another study was carried out for the first time in primates other than humans to identify the pattern of MDMA-induced brain activation and also the consequences of using MDMA even in recreational doses (12). They used functional magnetic resonance imaging (fMRI) to investigate the acute effects of a recreational dose (1 mg/kg p.o.) of MDMA on regional brain activity in awake, restrained marmoset monkeys. The authors carried out another study by using magnetic resonance spectroscopy (MRS) and postmortem measurements of serotonin transporter (SERT) binding and serotonin (5-HT) concentrations to determine the neurotoxic effects at two dose levels of MDMA, low dose (4 x 1 mg/kg p.o.) and a higher one (4 x 10 mg/kg i.m.). The results revealed that there were significant activation of several brain areas at the low dose level of the drug, including the midbrain raphe nuclei, hippocampus, hypothalamus, amygdala, and the corticostriatal circuit composed of the dorsal thalamus, sensory motor cortex, and basal ganglia. In addition there was an activation of visual cortical response to photic stimulation and also the primary visual cortex under baseline conditions. The brain activation correlated well with the increased concentrations of plasma MDMA measured in separate monkeys given the same drug treatment. Meanwhile, the study revealed that at higher dose level there was a prolonged hyperthermia and reductions in 5-HT and SERT in a number of brain areas. Results showed also that even lower doses are not safe because lower doses reduced hypothalamic N-acetylaspartate (a putative neuronal maker)/creatine ratio.
MDMA as a substitute of amphetamines has been associated with loss of multiple markers serotonergic terminals in the brain. It might also lead to oxidative stress, excitotoxicity and mitochondrial dysfunction which are linked to neurotoxicity. More recently it was revealed that the METH or MDMA-induced oxidative stress, excitotoxicity, and mitochondrial dysfunction are described in relation to the classical markers of METH-induced damage to dopamine terminals (13).
Although MDMA damaging effects on brain serotonin (5-HT) neurons in animals and possibly humans are well studied, the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved are not well defined yet (14). The authors investigated the effects of moderate and heavy MDMA use on cognitive function together with the effects of long-term abstention from MDMA, in subjects genotyped for 5-HTTLPR. Their results indicated that there was no significant effect of MDMA on 5-HTTLPR. In another study they tried to determine if there is a difference in the effects between males and females and they concluded that there was no significant difference in MDMA adverse effects between genders. Also, they postulated that there was no significant impairment in memory in moderate MDMA users while there was sever impairment in heavy users.
Ecstasy can cross the blood placental barriers and this was proved by a follow up study in 136 babies who were born to mothers with a history of using Ecstasy i.e. (prenatal exposure). The authors concluded that prenatal exposure to Ecstasy alone causes musculoskeletal malformations where prenatal exposure to Ecstasy combined with amphetamines, g-hydroxybutyric acid, or alcohol results in cardiovascular malformations mainly (15).
Two studies were carried out in two different cases on the adverse effects of Ecstasy (16, 17), the authors reported that there were hyponatremia-induced cerebral edema and syndrome of inappropriate antidiuretic hormone, respectively that were linked to over-hydration. Meanwhile, they mentioned that acute adverse effects of a single dose of long term use of Ecstasy results in decreased quality of life and functional incapacity due to development of memory problems, cognitive impairment and psychiatric disturbances such as palinopsia (abnormal recurring visual hallucinations), paranoid, depression, anxiety, anorexia psychosis and panic attacks. In addition, it was reported that patients who have first degree relatives with psychiatric conditions are in a greater risk for the adverse effects of ecstasy than others (18). The psychiatric disturbances can appear within few weeks from the last administered dose of MDMA and can persist even in the abstinence period and for as long as six month.
It was stated that the level of cerebrospinal fluid 5-hydroxyindoleacetic acid (a metabolite of serotonin), which was considered as a marker for serotonin terminal degeneration (19) has decreased in Ecstasy uses. In this study the authors tried to determine the cognitive impairment in individuals with repeated use of Ecstasy. The participants in this study have taken Ecstasy on at least 25 occasions but had abstained from it for at least 3 weeks before the study. Walter Reed Army Institute of Research Performance Assessment Battery was used to measure cognitive performance in study subjects. The results showed that Ecstasy users suffered from impairment of a short-term memory task, task requiring visual discrimination and working memory, sustained attention task and a task of semantic recognition and verbal reasoning than other users who were taking many other substances and have never taken Ecstasy. They attributed these effects in those who repeatedly took Ecstasy to the alterations in serotonin and catecholamine.
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Ecstasy becomes increasingly popular in Europe and North America over the past 20 years. It is mainly consumed by young people pleasurable effects such as euphoria, emotional openness. Because the drug is given usually in an environment of overcrowding such as in parties, MDMA is normally associated with vigorous physical activity for extended periods. This effect can lead to a marked rise in body temperature (hyperthermia). Treatment of hyperthermia requires prompt medical attention to avoid muscle breakdown, which can in turn result in kidney failure. The adverse effects of Ecstasy can range from nausea, chills, sweating, involuntary teeth clenching, muscle cramping, and blurred vision to high blood pressure, faintness and panic attacks if over dose is taken. The adverse effects can also include some other disorders as muscle breakdown, kidney, liver and cardiovascular failure. It might lead to reduction of the pumping efficiency of the heart which can lead to many complications in case of periods of increased physical activity. MDMA leads to significant reductions in mental abilities, anxiety, depression, impulsiveness, and aggression, as well as sleep disturbances and lack of appetite in regular users. Also, it is dangerous to perform complex or even skilled activities, such as driving a car if the user is under the influence of this drug. Some of these side effects might not be attributed to MDMA alone but it could be related to some other drugs when combined with MDMA such as cocaine, marijuana or some impurities found in MDMA tablets.
There are a number of treatment options for MDMA dependence. One of the most important regimes is the abstinence which is considered as a suitable management plan especially for short term users of this drug. However, it is not a suitable option for long term users because of the fear of severe withdrawal symptoms. The treatment programs include behaviour modification and detoxification and using of sedatives.
Certain tools must be applied as preventive measures to explain the severe side effects of this drug especially among adolescents and young people in high schools and colleges. This includes education and providing accurate scientific information regarding to the adverse and damaging effects of MDMA abuse.
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