History of the Drug
MDMA, also known as Ecstasy or Molly, has German roots as a medicine that was first introduced in a German laboratory in 1912 by a chemist who made it in preparation for a bleeding-controlling drug. However, this intensity did not attract much attention until the 1970s (NIDA, 2019). It became popular amongst the support groups because of the effects of empathogens. Thus, group members became emotionally open and comfortable with expression. At the beginning of the 1980s, MDMA was gaining popularity in discos and also was associated with rave culture and electronic music (García-Montes et al., 2020). This drug’s testimony as a “love drug” has its origin in situations of increased empathy and sociability among users (Price, 2022). This history indicates that the behavioral, brain, and physiological effects of MDMA are of a magnitude similar to the incremental popularity of the rave culture.
Despite its initial acclaim, MDMA’s history is also marked by concerns about its safety and long-term effects. Similarly, the growing use of it was accompanied by a spike in adverse reactions and deaths related to its consumption (Elkattawy et al., 2021). The risks of dehydration, hyperthermia, and serotonin syndrome as its effects were known about the classification of Morgan Stanley as a Schedule I controlled substance in the United States. Additionally, researchers found that long-term use of MDMA may impair neurons in the serotonin system and contribute to several mood disturbances and cognitive impairment in the long run (Costa & Gołembiowska, 2022). As such, MDMA’s history symbolizes not only it’s tempting nature as a rave drug and a serotonin releaser but also brings together the awareness of the dangers and long-term problems it may cause to brain function and mental health.
Pharmacokinetics
MDMA is a drug that works via absorption, distribution, metabolism, and elimination processes in the body. Usually, MDMA is ingested orally, and it can be found in tablets or capsules (Bisagno & Cadet, 2022). As soon as it enters the body, it gets absorbed through the gastrointestinal tract into the bloodstream. Then, the drug reaches maximum plasma concentration within the first two hours after the patient’s administration. Despite this, absorption may change by individual features, including the presence of food in the stomach and the dose taken.
As the MDMA enters the bloodstream, it quickly reaches all areas of the body, including the brain. With its lipophilic nature, this characteristic of the neurotransmitter gave it the ability to quickly pass the blood-brain barrier, thereby, its psychoactive feature (Mustafa & Mohamad, 2019). As it is distributed and absorbed relatively quickly, the medication can be a cause of its rapid onset of action and its high effect on mood and cognition.
MDMA metabolism mostly happens in the liver, where cytochrome P450 enzymes oxidize it through oxidative metabolism. The primary metabolites are 3,4-methylenedioxyamphetamine (MDA) and 3,4-dihydroxyamphetamine (DHA), which are then further metabolized and la finally excreted in the urine (Esteves et al., 2021). The half-life of MDMA elimination tends to fall into a range between 6 to 10 hours, but this can be differentiated depending on factors such as the age of an individual or liver functioning and dope abuse.
Although many components of MDMA’s pharmacokinetics have been discovered, some dimensions are still not fully elucidated. Therefore, the exact pathways responsible for MDMA distribution into specific brain regions or its interaction with many neurotransmitter systems are yet to be well characterized (Fonseca et al., 2021). In addition, individuals differ in the rate of metabolism and clearance. Therefore, individual variability in MDMA pharmacokinetics requires further examination to understand the factors involved.
Pharmacodynamics
MDMA modulates the central serotonin, dopamine, and norepinephrine neurotransmitter systems. It serves as a substrate for the serotonin transporters (SERT), allowing the serotonin release from presynaptic neurons into synapse cleft (Schenk & Highgate, 2021). The action of MDMA is also connected to the inhibition of serotonin reuptake and the prolongation of its presence in the synaptic space, as well as the enhancement of serotonergic neurotransmission (Islas & Scior, 2022). This higher serotonin emission is thought to be the main reason for the psychedelic’s empathogenic and mood-stimulatory effectiveness. In addition to these effects, MDMA also induces the release of dopamine and norepinephrine, but to a much lesser degree than serotonin (Kermanian et al., 2022). This dual action on several neurotransmitter systems is its complex, psychoactive influence, which induces euphoric sensations, socializing tendencies, and heightened cognitive activity.
MDMA functionally operates in the central nervous system, home in specific brain locations mainly involved with mood swings, reward processes, and social behavior. Serotonin is released in the synaptic cleft through binding to serotonin transporters SERT and is present in presynaptic neuron neurons. It is these enhanced levels of serotonin in the synapses that lead to the activation of post-synaptic receptors, especially the 5-HT2A and 5-HT2C receptors, which are critical in mood, cognition, and behavior modulation (Schenk & Highgate, 2021). Furthermore, it improves dopamine secretion, especially in the striatum, by increasing DAT turnover. This determines whether the drug can be used regularly, which may hinder its abuse potential. Additionally, the elevation of norepinephrine through the interaction of MDMA with NET results in an increase in sympathetic functioning and arousal.
Long-term MDMA use has been connected with cellular changes and alterations of neural activity in different brain areas. Long-term MDMA administration has been proven to elicit neuroadaptation along the SERT density and serotonin receptor expression pathway, represented by the prefrontal cortex, the amygdala, and the hippocampus (Schenk & Highgate, 2021). This alteration may consequently bring about a persistent disruption in mood regulation, memory, and emotional processing. Moreover, neurotoxicity induced by MDMA, in the kind of oxidative stress and excitotoxicity, can cause neurons to degenerate and become dysfunctional, particularly in serotoninergic neurons. These neurotoxic effects could worsen the cognitive impairment and emotional disturbances that are found to be interrelated with long-term MDMA usage.
Drug Effects
The effects of MDMA as a drug on the brain and body are intimately associated with its pharmacodynamics. A prominent effect of MDMA is on the serotonin, dopamine, and norepinephrine systems within the central nervous system. Attachment to serotonin transporters (SERT) and inhibition of serotonin reuptake is the mechanism through which MDMA causes a rise in serotonin levels in the synaptic cleft, thus producing enhanced serotonin activity (Schenk & Highgate, 2021). Such a scenario leads to a rising mood, greater sociality, and altered sensory experience. The addiction to the drug is generated by dopaminergic and noradrenergic effects, which are responsible for reinforcing the drug’s properties and heightened arousal.
Cellularly, neurotoxicity can harm highly vulnerable regions like serotoninergic neurons involved in mood and thinking. Long-term MDMA abuse may cause neuroplastic changes, including reduced density of SERT and changes in serotonin receptor expression, which underlie the developmental distortions of mood and memory capability (Costa & Gołembiowska, 2022). In the case of behavior, one of MDMA’s effects on brain parts associated with reward and reinforcement, e.g., nucleus accumbens and prefrontal cortex, is to promote drug-searching behavior and addiction (Ibrahim et al., 2024). The drug’s pharmacodynamic effects, particularly its ability to amplify dopamine neurotransmission, may involve the emergence of tolerance and sensitization, thereby producing higher drug consumption.
Psychologically and physically, dysregulation of the serotoninergic neurotransmission leading to withdrawal symptoms can result from intake of MDMA. These are among the symptoms which might involve depression, anxiety, fatigue, and a decrease in appetite. This results from the change in mood and arousal intensities (Stone, 2022). The relationship between MDMA’s specific pharmacodynamics and its effects on neurotransmission, together with various withdrawal symptoms, serve as key ingredients in the formation of dependence and addiction associated with chronic use.
References
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Costa, G., & Gołembiowska, K. (2022). Neurotoxicity of MDMA: Main effects and mechanisms. Experimental Neurology, 347(1), 113894. https://doi.org/10.1016/j.expneurol.2021.113894
Elkattawy, S., Mowafy, A., Younes, I., Tucktuck, M., & Agresti, J. (2021). Methylenedioxymethamphetamine (MDMA)-Induced Hyponatremia: Case Report and Literature Review. Cureus. https://doi.org/10.7759/cureus.15223
Esteves, F., Rueff, J., & Kranendonk, M. (2021). The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family. Journal of Xenobiotics, 11(3), 94–114. https://doi.org/10.3390/jox11030007
Fonseca, D. A., Ribeiro, D. M., Tapadas, M., & Cotrim, M. D. (2021). Ecstasy (3,4-methylenedioxymethamphetamine): Cardiovascular effects and mechanisms. European Journal of Pharmacology, 903, 174156. https://doi.org/10.1016/j.ejphar.2021.174156
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Islas, Á. A., & Scior, T. (2022). Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with ΔG Calculations, Induced Fit Docking and Monte Carlo Simulations. Molecules, 27(9), 2977. https://doi.org/10.3390/molecules27092977
Kermanian, F., Seghatoleslam, M., & Mahakizadeh, S. (2022). MDMA related neuro-inflammation and adenosine receptors. Neurochemistry International, 153, 105275. https://doi.org/10.1016/j.neuint.2021.105275
Mustafa, N. S., & Mohamad, N. (2019). MDMA and the Brain: A Short Review on the Role of Neurotransmitters in the Cause of Neurotoxicity. Basic and Clinical Neuroscience Journal, 11(4). https://doi.org/10.32598/bcn.9.10.485
NIDA. (2019, September). What is the history of MDMA? National Institute on Drug Abuse. https://nida.nih.gov/publications/research-reports/mdma-ecstasy-abuse/what-is-the-history-of-mdma
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Price, S. (2022, February 14). MDMA: the love drug? Psychedelic Health. https://psychedelichealth.co.uk/2022/02/14/mdma-love-drug/
Schenk, S., & Highgate, Q. (2021). Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse. Journal of Neurochemistry, 157(5), 1714–1724. https://doi.org/10.1111/jnc.15348
Stone, S. (2022, October 27). MDMA (Ecstasy) Withdrawal: Symptoms, Timeline, and Detox. Northridge Addiction Treatment Center. https://www.northridgeaddiction.com/recovery-blog/mdma/mdma-withdrawal-symptoms-side-effects/
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