Chemistry

    3, 4-methylenedioxy-methamphetamine (MDMA) also known as ecstasy is a highly neurotoxic chemical analog of methamphetamine. MDMA is a commonly used as a recreational drug among young people (Holland, 53). It is structurally related to mescaline, a natural hallucinogenic compound.  MDMA is a derivative of 3, 4-methylenedioxyamphetamine (MDA) with ring modifications at position 3 and 4. During aromatic ring modification of the methamphetamine molecule, a methylenedioxy (O-CH2-O) moiety is attached to position 3 and 4 of the ring.

Molecular and Biochemical Mechanism of MDMA
    The drug causes a rapid and acute synaptic release and inhibition of neuronal uptake of neurotransmitters serotonin (5-Hydroxytryptamine, 5-HT) and dopamine from the nerve endings of the brain. The MDMA molecule is rapidly transported through serotonin transporter, a membrane protein, into the terminals of the presynaptic serotonin axons (Stone, 95). At the terminals of the presynaptic axons, MDMA acts to inhibit serotonin reuptake.

    In the nerve cell, MDMA acts to alter the configuration of the transporter protein and easily binds to cytoplasmic serotonin. Due to changes in receptor binding, the membrane-based transporter protein can no longer bind to serotonin and therefore serotonin is released on the outside of the cytoplasm (Rattray, 78). As a result, the rate of transporter-mediated serotonin outflow is greatly increased by MDMA. Any additional serotonin release at the synapse causes an increased dopamine release particularly in the reward centers of the nucleus acumbens and the striatum. The release of oxytocin has also been suggested to surge due to the stimulation of serotonin receptor, 5-HT1A (Stone, 96).

    Administration of MDMA sharply increases the levels of synaptic 5-HT. This sharp increase in 5-HT is followed by a massive course of 5-HT depletion. The mechanism behind this interplay is that MDMA simultaneously promotes the release and blocking of any further 5-HT reuptake (Goodwin, 255). The serotonin dependent transporter mechanism of serotonin reuptake is suggested to be greatly inhibited.

    Similarly, dopamine synthesis is promoted while its reuptake is highly inhibited. The increased dopamine synaptic availability inhibits the glutamate-evoked firing in the accumbens of the nucleus. The inhibition of the firing of the GABAergic spiny projection neurons is caused by increased levels of dopamine that is released in the vesicles due to the serotonin receptor activation. The major serotonin receptors that are activated to increase dopamine release include 5-HT1B and 5-HT2A (Gerra, 127). The euphoric bliss is caused by the inhibition of excitability of the spiny projection neurons in the shell of the rostral in the accumbens of the nucleus.  

    MDMA acts predominantly on serotonergic neurons although other neurotransmitters such as dopamine have been found to be affected by MDMA. For instance, in rodents, MDMA causes a selective permanent loss of dopaminergic neurons in rats and mice. The neurotoxicity mechanism behind this selective damage in mice suggests the formation of free radicals which extensively damage the nerve tissues (Stone, 93). Further breakdown of MDMA metabolites can result to the increased production of the free radicals.

    A number of clinical and experimental studies of the pharmacology of MDMA have concentrated on the biochemical effects the drug elicits on 5-HT (serotonin). However, the release and reuptake of another important neurotransmitter, dopamine, is significantly affected by MDMA particularly in rodents (Greer, 24). For instance, MDMA causes a long-term effect on serotonergic neurons in most species including humans and also affects the dopamine system in mice. 

    Studies have also identified the effect of MDMA on the release of noradrenalin although the mechanisms are poorly understood. This implies that MDMA affect noradrenergic, dopaminergic and serotonergic systems. The effect on these major neurotransmitter systems causes an array of biochemical consequences such as oxidative stress, hallucinogenic and neurotoxic effects and hyperthermia (Rattray, 80)

    Users of MDMA have high chances of their brain cells being damaged by overproduction of free radicals (Stone, 94). MDMA has been found to have a weak affinity for 5-HT2A receptors and it acutely inhibits tryptophan hydroxylase (TPH) which is a rate limiting enzyme in the synthesis of serotonin. The observation that MDMA can promote the neuronal components oxidative changes came from the study of reversibility of the inhibition of TPH in reducing states (Gerra, 131). The structure and function of body macromolecules are affected by oxidative stress which results from highly unstable and energetic chemical species having unpaired electrons. These chemical species are called, the free radicals. The free radicals are persistently made in vivo although the body has protective machinery, antioxidants, which protect the cellular macromolecules from facing the risk of oxidation (Stone, 90). Unfortunately, the antioxidant capacity can not be overwhelmed which will often leads to cell death and cell damage. It has been observed in some studies that MDMA promotes oxidative stress that explains the mechanism of serotonergic neurotoxicity (Parrot, 108).

Psychiatric and Hallucinogenic Effects
    MDMA is not a potential hallucinogen as compared to MDA (amphetamine). Perhaps, the reason why its potential of hallucinogenic property seems to be reduced is because of the functional groups or moiety of methyl (O-CH2-O) attached to it. MDMA is typically classified as a hallucinogenic amphetamine because of its similarity to amphetamine and mescaline. However, MDMA per se rarely induces such hallucinatory effects nor does it act as a psychostimulant as amphetamine does. It has been observed that the administration of oral MDMA greatly induces a subjective experience of heightened mood, extroversion, increased self confidence and emotional excitability. In addition, depersonalization, moderate derealization and intensified sensory perception can result due to MDMA administration. Peak levels of MDMA effects are during 15 to 30 minutes following administration and can last up to 3 to 4 hours.

    Neurotoxic regimens in MDMA result into long-term serotonergic degeneration or sometimes leading into acutely depleted levels of serotonin. This consequence leads to increased chances of developing serotonergic-mediated psychopathology such as anxiety, depression, panic disorder and psychosis (Greer, 180). Other psychopathological complications caused by depletion of serotonin level include memory disturbances and dysphoria. However, these effects vary from heavy users and light users with heavy users presenting signs of somatization, psychoticism, elevated levels of paranoid ideation, hostility, obsession, anxiety, phobic, appetite disturbance, impulsiveness and restless sleep.

    MDMA greatly increases the body temperature (hyperthermia) which contributes to greater cause of death among the MDMA users. The body temperatures can rise to intolerable levels to abut 420C until major organs such as the liver and kidney shut down. MDMA-induced hyperthermia result due to serotonin syndrome where excess serotonin is released to the brain. MDMA-induced hyperthermia is encouraged by simultaneous administration of other serotonergic drugs. These drugs act in synergy with MDMA to make the effects of MDMA to last longer, a strategy utilized by MDMA drug users (Holland, 239). Hyperthyroidism has also been suggested to increase risks of MDMA-induce hyperthermia.

    The science of chemical analogs has for years resulted to the synthesis of novel drugs able to wipe human, veterinary and plant diseases. At the same time, this great science has led to the synthesis of substances of abuse. Analogs of amphetamine are highly required to solve problems such as anorexia. The challenge remains on the development of these analogs which will prove to be safe and suitable for human use. The study of various mechanisms and biochemical effects of MDMA is imperative to the development of non-neurotoxic entactogens and empathogens that are suitable for long-term human use.