Otherwise classified as MDMA or ecstasy, Methylenedioxymethamphetamine is a psychomotor stimulant that is synthetically derived from the structure of amphetamines. MDMA is a chiral molecule, meaning that it exists in two forms, which are labeled as S(+) MDMA and R(-) MDMA. S(+) MDMA is thought to possess greater central pharmacological effects. The attachment of the methylenedioxy group to MDMA’s aromatic ring is where it differs from amphetamines and adopts a similar structure to the hallucinogen class. Due to the characteristic effects from this class, MDMA is often used for recreational purposes.
Though there are various ways of administering MDMA, the most prominent have been noted to be oral ingestion, injecting intravenously or subcutaneously, smoking, and intranasally. The most utilized method appears to be oral ingestion, which is done by swallowing the drug, usually sold in the form of an identifiably colored and imprinted tablet. Injecting the drug is not as commonly used, as there are various problems that have been associated with this method. Additionally, smoking MDMA often involves a mixture of cannabis (Parrot, 2002).
The optimal adult dose of MDMA is approximately 125mg although depending on body weight the optimal dosage can range from 75-250mg. Given their proportional differences in body mass, women are more sensitive to the sub-acute and longer-term effects than men so their optimal dosage may be lower.
As MDMA is a weak acid that becomes less ionized in an acidic environment, when the drug is taken orally, the lack of electrical charge makes the drug more lipid soluble and it is able to be readily absorbed from the gastrointestinal tract into the bloodstream. As a result, the onset of action is rapid, beginning within 30 minutes of administration, and its duration is often shorter with peak plasma levels occurring after one to three hours (Baker et al., 2004). MDMA is cleared through the process of first-order kinetics, with an elimination half-life of approximately seven hours, though alkaline urine can increase this to increase to 16-31 hours.
The main metabolic pathway for MDMA is oxidation of the methyldioxy-phenyl group, which is catalyzed in the liver by CYP2D6, a member of the cytochrome P450 family of enzymes (Parrott, 2002). MDMA is metabolized to the longer acting metabolite 3,4-methylenedioxyamphetamine (MDA) by N-demethylation (Pearce, 2014). MDMA’s two compounds are metabolized and eliminated at different rates, with S(+) MDMA, the more neurotoxic of the two, being metabolized faster than R(-) MDMA. A large increase in concentrations within the blood and brain may occur if more of the drug is taken when the high-affinity enzymes reach a saturation point between 120-150mg. A large quantity of the drug is excreted through urine, especially when taken at higher doses (Pearce, 2014).
The extended stimulation of serotonin as well as the harmful effects on the body caused by repeated use of MDMA was explained based on the energy metabolism within the presynaptic terminal. It was comprehended that acute MDMA causes the active carrier systems to remain at a permanently activated state, which is worsened by hyperthermia induced by the drug. This then leads to impaired ATP cell metabolism, exhausting the normal metabolic process of recovery and repair. This causes cellular damage within the presynaptic region along with the loss of axon terminals and neural pruning (Parrott, 2002).
MDMA is characterized as an indirect serotonergic agonist, as its primary action is to inhibit the reuptake of serotonin (5-HT) and increase its release from presynaptic vesicles. This is then followed by a decrease in brain levels of 5-HT and 5-hydroxyindolaecetic acid (5-HIAA), as well as a decrease in the activity of tryptophan hydroxylase. It has been observed that the most severe reductions of 5-HT and 5-HIAA are found in the striatum, hippocampus and prefrontal cortex, with smaller reductions in the brain stem and hypothalamus (Cole & Sumnall, 2003). The membrane-bound serotonin transporter then transports MDMA to the presynaptic serotonin axon terminals where it reverses the normal direction of the 5-HT reuptake pump (Pearce, 2014). Within the terminal of this nerve cell, MDMA causes the transporter protein to instead bind to cytoplasmic serotonin. Due to its excess, 5-HT then gets dumped outside of the cell, causing an increase in the outward release of serotonin and its amount available at the synapse. This MDMA-induced flood of serotonin in the synapse also activates the 5-HT2A receptor and causes the release of dopamine, especially in the reward centers of the striatum and the nucleus accumbens (Cole & Sumnall, 2003).
As the drug approaches its peak, serotonin is released into the synaptic cleft and activates multiple receptor subtypes. Along with the induced flood serotonin, taking MDMA indirectly causes a release of extra dopamine in the mesolimbic reward centers. Activation of the serotonin 5-HT1B and 5-HT2A receptors leads to an increase of dopamine in the vesicles. Dopamine levels are also increased by reuptake inhibition. In addition, dopamine synthesis is increased and turnover reduced. Increased synaptic availability of dopamine in turn inhibits glutamate-evoked firing in the nucleus accumbens. Dopamine released in the shell of the nucleus accumbens inhibits the firing of GABA neurons. The inhibited excitability of these neurons in the nucleus accumbens is where the sense of euphoria is generated (Pearce, 2014).
Affecting several neurotransmitters, MDMA also has an impact on norepinephrine as it induces the release and inhibits its reuptake. MDMA also triggers the receptor mechanisms of 5-HT4 and dopamine D(1) to release acetylcholine in the striatum and prefrontal cortex. Activation of the norepinephrine system causes an acute elevation of blood pressure. Also, MDMA induces hormonal effects by increasing plasma cortisol, prolactin, dehydroepiandrosterone (DHEA), and aldosterone secretion. MDMA use alters the expression of several proteins involved in GABA transmission. Furthermore, MDMA triggers the release of hypothalamic arginine-vasopressin to regulate the amount of water in the blood, and oxytocin. These hormonal changes may influence some of MDMA\’s psychological effects (Pearce, 2014).
With the metabolism of dopamine by monoamine oxidase-B producing hydrogen peroxide, which could lead to the deterioration of lipids and oxidative stress (the inability to balance the production and detoxification of free radicals), the reuptake of dopamine into the serotonin terminal has been reported to cause neurotoxicity. Following the administration of MDMA, these levels can be reduced with a 5-HT2A receptor agonist such as the SSRI Prozac (Parrott, 2002). This is done by lessening the severity of the oxidative stress and the risk of axon damage caused by reactive products of dopamine. Prozac and its longer acting metabolite, norfluoxetine, prevent the uptake of dopamine into the nerve terminals by binding to the serotonin reuptake transporter with a higher affinity than MDMA or serotonin (Pearce, 2014).
Psychologically, MDMA generates feelings of arousal, elation, emotional closeness and sensory pleasure. It has been concluded that the positive moods are related to the increase of serotonin and the euphoric effects appeared to be a result of dopamine levels (Parrot, 2002). Additionally, MDMA can produce wakefulness, increased energy, alleviation of fatigue, and hallucinations have occasionally been reported. Repeated use of MDMA over a short time frame may reduce the effect of the drug or cause an individual to develop a tolerance (Baker et al., 2004). With steady use, this tolerance may develop rapidly. Taken chronically, the effect of MDMA ceases to be rewarding. With consecutive use, effects of dysphoria also begin to predominate. At this time, serotonin becomes depleted from the axon terminals. At the same time, there is an inactivation of tryptophan hydroxylase, which inhibits the synthesis of serotonin and re-regulates the nerve cell receptors (Pearce, 2014).
In addition to these psychological effects, MDMA often induces a crash effect during the days following its use. Parrott (2002) conducted a study on the mood states of individuals before, during and after taking the drug at a nightclub. The users reported “feeling significantly more depressed, unpleasant, sad, abnormal, and unsociable than the nonuser controls; 7 days later the mood states of all groups had returned to baseline” (Parrot, 2002). Instances of energy loss, irritability, muscle aches and trouble sleeping following the drug use was acknowledged to be a result of the monoaminergic depletion.
Common adverse effects reported during the drug experience and shortly afterwards include dry mouth, ataxia, stiffness and pain in the back and limbs, headache, nausea, loss of appetite, blurred vision, insomnia and increased muscle tension, experienced as jaw clenching, tooth grinding and restless leg (Baker et al., 2004). There is also a high prominence of hyperthermia, which increases the lethality of MDMA and enhances serotonergic neurotoxicity (Cole & Sumnall, 2003). In addition, acute cardiovascular effects of MDMA include increases in heart rate, blood pressure and cardiac output (Baker et al., 2004).
The use of MDMA can have various affects that lead to toxicity, some of them being hyperthermia, formation of toxic metabolites, inhibition of serotonin synthesis, dopamine release and glutamate and nitric oxide pathways. At high ambient temperatures, MDMA induces hyperthermia and is often associated with neurotoxicity. Cardiovascular effects include hypertension, which results from the widening of blood vessels due to monoamines. Hypotension resulting from depletion of these chemicals may also occur. Use of MDMA may lead to various electrolyte disturbances including hypoglycaemia, a depletion or hyponatraemia, excess water ingestion. While the use of MDMA is typically associated with club dancing environments, users need to maintain a steady fluid intake to reverse the fluid loss from sweat. That being said, when an individual on MDMA consumes too many fluids, there is the potential of this causing hyponatraemia, a dilution of electrolytes such as sodium and potassium (Cole & Sumnall, 2003). In animal studies, administration of high dose MDMA leads to long-term depletion of serotonin, accompanied by reductions in other markers of serotonergic function including serotonin metabolites, transporters and serotonin-specific enzymes, degeneration of serotonergic axons and axon terminals and increased numbers of glial cells (Baker et al., 2004).
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