The consensus on: MDMA

MDMA, or 3,4-Methylenedioxymethamphetamine is a common psychoactive stimulant that is illegal in most parts of the world. It causes sensations of euphoria and elation, but also a sense of well-being and inner awareness much like psychedelics. This gives rise to its use at festivals and clubs, as well as its use in a more relaxed setting for self-therapy purposes and an enhanced interpersonal connection with partners and friends . Notably, there is also a perception that MDMA is ‘safer’ than many alternative drugs, but the true extent of its potential danger is still up for debate among the scientific community.

The basics:

MDMA is most commonly taken in pill form and stimulates many positive effects including: euphoria, increased empathy, sense of well-being, talkativeness and music enhancement with effects lasting up to three hours. However, side effects such jaw clenching, dry mouth, sweating, anxiety or panic can occur in some individuals.

The drug acts by binding to serotonin transporters, this reverses the flow of the transporters flooding the synapses with serotonin. This excess serotonin is the primary force behind the desired effects but is eventually metabolised and removed from the body. However, this removal process is often too effective, leading to low serotonin levels the following day resulting in feelings of depression, fatigue and altered sleep. For this reason MDMA is said to ‘borrow’ happiness from the following day.^[1] It also can take time for serotonin levels to return fully, such that there is a three month ‘rule’ that some users swear by as if the drug is taken too frequently, the positive effects are reduced and the ‘come downs’ start to increase in severity.

MDMA also acts on dopamine and norepinephrine transporters in the same way, but to a lesser extent. This is one of the reasons why the drug is less addictive than others, as there is limited activation of the reward system of the brain (the dopaminergic pathway).

Negative side effects:

Short term:

Unlike drugs such as marijuana, MDMA poses a very present and real threat of overdose. The main issue sarise due to three main processes: hyperthermia, hyponatremia and cardiovascular complications. Hyperthermia is caused by the drug’s pro-hyperthermic qualities combined with the very active, crowded setting it is often taken in, hypernatremia is the condition of dangerously low sodium levels sometimes caused by excessive water consumption and cardiovascular issues are caused by the drug increasing heart rate and blood pressure. All three of these issues are incredibly dangerous at their extremes and are the causes of many of the deaths from overdoses, but cause few problems when each of them is managed properly, and a regular (<150mg) dose is taken.

Long term:

The research on extended MDMA use is highly disputed and controversial and is an incomplete and active area of scientific literature. Firstly, MDMA is likely to cause neurotoxicity due its metabolism leading to the formation of Reactive Oxidative Species (ROS) that damage serotonergic neurons ^{[2] [3]}. This can lead to lasting serotonin decline and impaired cognitive function after extended use ^[4].

Taking MDMA in an uncontrolled environment can exacerbate issues, hyperthermia can increase the production of more ROS, causing further damage to serotonergic neurons^[5]. Furthermore, combining MDMA with other stimulants like caffeine can intensify the dangers ^[6].

While some studies show that serotonin levels can recover after extended use^[7], the recovery of serotonin levels is not guaranteed ^[8]. Memory also can be affected by extended use ^[9].

However, much of this evidence looks at MDMA use in long term, high dose users who have also used other, more dangerous drugs. There is little evidence to support the claim that infrequent common doses, with ambient temperature controlled, cause significant damage to serotonin transporters.

Takeaways:

With this taken into account, here are the main takeaways:

1. MDMA poses an acute risk of overdose from overheating, low sodium levels and cardiovascular issues, which need to be controlled for safer use.  
2. MDMA can cause lasting damage to serotonergic neurons, this damage increases with polydrug use and hyperthermia.
3. The risk of damage is low with a small lifetime dosage, but increases substantially if taken regularly.

Given the threat that MDMA can pose to brain function, there seems to be no reasonable level of consumption that can be considered truly ‘safe’. The principle of fewer doses is better and even fewer is even better should be applied. However if use of the drug is unavoidable, then taking a regular dose in a controlled setting with friends at a frequency of less than once every three months is the safest option. If the drug is chosen for use at festivals, clubs or in other active environments, extreme caution must be taken when managing the effects of hyperthermia, hyponatremia and cardiac issues, and ensuring that a common dose is taken.

For a more detail, the drug classroom has several in depth articles on the risks and how to manage them.

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[1] MDMA (Ecstasy) | Mechanism of Action & Metabolism: https://www.youtube.com/watch?v=9uu3uKAtd80

[2] Jones, D. C., Duvauchelle, C., Ikegami, A., Olsen, C. M., Lau, S. S., De La Torre, R., & Monks, T. J. (2005). Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. Journal of Pharmacology and Experimental Therapeutics, 313(1), 422-431.

[3] Esteban, B., O’Shea, E., Camarero, J., Sanchez, V., Green, A. R., & Colado, M. I. (2001). 3, 4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose. Psychopharmacology, 154(3), 251-260.

[4] Erritzoe, D., Frokjaer, V. G., Holst, K. K., Christoffersen, M., Johansen, S. S., Svarer, C., … & Knudsen, G. M. (2011). In vivo imaging of cerebral serotonin transporter and serotonin2A receptor binding in 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) and hallucinogen users. Archives of general psychiatry, 68(6), 562-576.

[5] Capela, J. P., Meisel, A., Abreu, A. R., Branco, P. S., Ferreira, L. M., Lobo, A. M., … & Carvalho, F. (2006). Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. Journal of Pharmacology and Experimental Therapeutics, 316(1), 53-61.

[6] Khairnar, A., Plumitallo, A., Frau, L., Schintu, N., & Morelli, M. (2010). Caffeine enhances astroglia and microglia reactivity induced by 3, 4-methylenedioxymethamphetamine (‘ecstasy’) in mouse brain. Neurotoxicity research, 17(4), 435-439.

[7] Reneman, L., Booij, J., de Bruin, K., Reitsma, J. B., de Wolff, F. A., Gunning, W. B., … & van den Brink, W. (2001). Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. The Lancet, 358(9296), 1864-1869.

[8] Taurah, L., Chandler, C., & Sanders, G. (2014). Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy). Psychopharmacology, 231(4), 737-751.

[9] Bhattachary, S., & Powell, J. H. (2001). Recreational use of 3, 4 methylenedioxymethamphetamine (MDMA) or ‘ecstasy’: evidence for cognitive impairment. Psychological Medicine, 31(4), 647-658.