Drugs constituting psychopharmacological classes are of various types. Although their therapeutic potential has contributed to the treatment of mental illnesses, there is a risk of side effects. As such, their usage may need to be monitored. In certain instances, these drugs are subjected to misuse by many individuals who fall victims to the practice of addiction.
This would lead to serious consequences for the users and society as a whole. So, the present description is concerned with highlighting a psychoactive drug known as 3, 4-methylenedioxymethamphetamine (MMDA) in a similar context. This drug is a synthetic amphetamine analog and was believed to be recreationally used to obtain a psychological effect of increased affiliative emotional response on the name of ‘Ecstasy’ (El-Mallakh & Abraham, 2007).
This drug is reported to possess a complicated mechanism of action. It mainly exerts its effect by facilitating the release of serotonin from neuron terminals where it increases the activity of protein kinase C (PKC) (www.neurotransmitter.net). This protein kinase activity enables the efflux of serotonin from serotonin transporters at plasma membranes, decreases the influx of inward transport, and internalizes the cell-surface serotonin transporters. In higher doses, MDMA prevents the reuptake of serotonin and norepinephrine by binding directly to the transporters (www.neurotransmitter.net). MDMA-enabled serotonin increase was reported to result from presynaptic PKC activation and serotonin transporter inhibition. This serotonin increase may contribute to postsynaptic PKC activation via serotonin 5-HT2 type receptors (www.neurotransmitter.net). The activated PKC may play a mediator role in increasing extracellular dopamine and norepinephrine levels and could support the release of monoamines through mechanisms not involving monoaminergic transporters. Serotonin increased at postsynaptic serotonergic receptors may contribute to the release of other neurotransmitters. The monoamine efflux induced by MMDA is due to its vesicle-depleting effect.
Neurotransmitters such as dopamine and serotonin get redistributed by the MDMA inhibitory effect on vesicular monoamine transporter-2 (VMAT-2) that prevents monoamine uptake into vesicles and reduces the amine uptake concerned transmembrane pH difference. MDMA was also reported to exert its agonistic effect at TA1 considered as a trace amine receptor. Therefore, MDMA executes its vital function through these pathways.
The next aspect to focus on is its application. MDMA’s clinical usefulness in psychotherapy relies on its ability to treat PTSD (Post Traumatic Stress Disorder) and terminally ill cancer patients. It may induce increased feelings of empathy and acceptance, depersonalization-pleasurable loosening of ego boundaries, and decreases aggressiveness and defensiveness. As these feelings are commonly encountered in individuals with cognitive impairments, it can be assumed that MDMA may become a useful drug for correcting Psychological defects. MDMA was grouped under the class of stimulatory hallucinogenics and was reported to give off a mixture of psychomotor stimulant and hallucinogenic effects, depending on dose and other factors (www.addictionscience.net). This was further strengthened by another report that described that MDMA is a potent central nervous system (CNS) stimulant which affects several neurotransmitter systems and intensifies a range of psychobiological functions. MDMA executes very positively and life-enhancing acute mood effects (Parrott, 2007). As such it may be useful for treating mood disorders associated with a spectrum of CNS disorders.
It was described that psychostimulants are used for the management of attention deficit disorders (ADD and ADHD) and narcolepsy where the role of methamphetamines such as Desoxyn, Dexedrine, and DextroStat was indicated. As MDMA is also a psychostimulant, it may have better clinical implications for treating behavior disorders like ADHD.
Therefore, from the above information, the likely clinical applications of MDMA are for treating PSTD, cancer, mood, or behavior disorders of CNS. However, the clinical relevance of MDMA may need further confirmation.
The next important aspect is the side effects and problems related to the abuse of MDMA.
This drug was reported to induce depressed mood, persistent elevation of anxiety, sleep disorders, impulsiveness and hostility, and selective impairment of episodic memory, working memory, and attention in individuals who become long-term users.
The other side effects of MDMA include nausea chills, sweating, and faintness, muscle tension vertigo, dizziness, and the ‘come down’ which includes severe anxiety, paranoia, sleep problems, and vivid nightmares. These MDMA-initiated problems also cause loss of appetite, mild to intense trismus, mild to moderate post-session fatigue, nystagmus, agitation, restlessness, nervousness, and shivering or tremor. Its high doses were also described to cause a sharp rise in body temperature (hyperthermia) which leads to failure of the liver, kidney, and heart.. However, these problems or side effects are mainly associated with the practice of drug abuse. As this drug was considered to be a recreational drug, its abuse has made the availability more rampant with common street names E, XTC, X, beans, Adam, hug, clarity, love drug, and lover’s speed.
So, there is a need to further explore the underlying complications associated with the use or misuse of MDMA. Yamamoto and Raudensky (2008) described that amphetamine derivatives including MDMA cause damage to dopaminergic and serotonergic terminals facilitated by increased oxidative stress, metabolic compromise, and inflammation. It was further reported that chronic MDMA treatment increases the mesocorticolimbic dopaminergic neurons from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) (Nakagawa & Kaneko, 2008).
This causes abnormal glutamatergic function from the mPFC to the NAc and VTA (Nakagawa & Kaneko, 2008). The role of oxidative stress was also proved experimentally in rats when it was observed with left ventricular dilation and dysfunction (Shenouda et al., 2008). These are reported to result from the redox modification of proteins involved in the excitation-contraction coupling and/or mitochondrial energy production (Shenouda et al., 2008). Hence, MDMA may contribute to heart problems through this oxidation mechanism. Individuals using MDMA may be prone to adverse oral effects. These are xerostomia, bruxism, and dental erosion in addition to mucosal changes (Brand et al., 2008). It was described in the studies that recreational drugs like MDMA affect both working memory and everyday aspects of memory (Montgomery & Fisk, 2007). This was revealed when the Cognitive Failures Questionnaire (CFQ) and Everyday Memory Questionnaire (EMQ) were conducted on ecstasy-polydrug users (Montgomery & Fisk, 2007).
The popularity of MDMA has spread to college, high school, and, occasionally, middle school students. Its acute and long-term responses have also been studied in utero. It was revealed that MDMA is influential in gradually changing the body temperature during ontogeny and reducing the body weight in all ages. In contrast, the alterations in the learning and working memory were reported to occur independently. This has indicated that MDMA responses are diverse and complicated in inducing physiological, behavioral, and neurochemical effects, regardless of age and sex (Piper, 2007).
This was further strengthened by another report that described the potential role of MDMA in causing febrile status epilepticus in children and multiorgan injury in young adults. However, the adverse effects of MDMA-induced multi-organ injury were also diagnosed in a toddler. This may indicate the widespread usage of MMDA by individuals who rely on simply augmenting the euphoric experience of “raves” (Feldman & Mazor, 2007).
MDMA may also induce a state of euphoria which was considered as a secondary activity after its psychostimulant property (Marasco & Lim, 2007). This was revealed from the clinical profile of patients with pneumomediastinum and who have previously used MDMA for hours.
Depressive symptoms associated with long-term mood disturbances are more prominent in recreational MDMA users (Guillot, 2007). The reason for this specific problem could be polydrug use in general, MDMA-induced serotonergic deficits, individual effects of illicit drugs besides MDMA, combined effects of MDMA and other illicit drugs, and preexisting differences in the levels of depressive symptoms in MDMA users (Guillot, 2007).
This may indicate that individuals who use MDMA with other drugs may develop more severe illnesses. This assumption could support an earlier report. It was described that patients who used MDMA and other substances like alcohol and illicit drugs like cocaine and opiates were found with panic reactions and deep coma (Liechti, Kunz & Kupferschmidt, 2005).
The serious complications were cardiac arrest, hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, renal insufficiency and liver failure, seizures, and one fatal outcome (Liechti, Kunz & Kupferschmidt, 2005). Therefore, this report has indicated the complexity of MDMA-associated problems in patients with multiple drug ingestion (Liechti, Kunz & Kupferschmidt, 2005). However, MDMA was reported to induce a neurotoxic effect which could be due to the nitrergic system where nitric oxide (NO) released from neuronal nitric oxide synthase (nNOS) plays important role in the nonsynaptic interneuronal communication and excitotoxic neuronal injury. (Itzhak & Ali, 2006). This has provided further evidence that there is a cross-talk between dopamine, glutamate, and NO. This aspect strengthened the role of NO as a vital neuronal messenger and a neurotoxicant after exposure to amphetamine-like psychostimulants. Hence, understanding the involvement of NO may furnish better insights into the neurotoxic insults caused by MDMA (Itzhak, & Ali, 2006). Hence, this part of the description has indicated a connection between MDMA use and the associated adverse clinical complications.
Finally, there has been a controversy for many years regarding the efficacy of MDMA.
This may be because MDMA has proven to induce selective and persistent neurotoxic damage of central serotonergic neurons in laboratory animals (Gouzoulis-Mayfrank & Daumann, 2006). This prompted anticipation that MDMA may induce neurotoxic brain damage in humans and could lead to psychiatric, vegetative, neuroendocrine, and cognitive disorders (Gouzoulis-Mayfrank & Daumann, 2006). Further, it was also revealed that previous efforts on the evaluation of MDMA neurotoxicity in humans often contained flaws in the methodology as well as interpretation (www.flashback.info). The other possible reasons were the lack of baseline measures as well as inadequate screening for other psychotropic drugs that affect serotonergic function (www.flashback.info). So, this may indicate poor research support.
Although the acute and possible long-term adverse effects of MDMA and other party drugs were studied, there were no concrete results of neurotoxicity because of the interference of confounding factors and its contrasting effect on social behavior enhancement. Similarly, the adverse effects produced by MDMA in combination with methamphetamine (METH) were found to be greater than the independent drug usage (Clemens et al., 2007).
These findings may enhance the difficulties while anticipating the therapeutic efficacy of MDMA alone and its side effects. Therefore, this particular controversial aspect may suggest further clinical data.
Given the above information, MDMA continues to raise concerns about its recreational use. Due to its strong psychostimulant properties, it has made a silent invasion into the lives of people regardless of age and sex through a carrier “abuse”. This practice appears more sounding than the feebly supported therapeutic potential of MDMA, especially for PSTD.
Although its neurotoxic effects have provided clues in the context of its safety, many investigations may be required to address the dilemmas and controversies.
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