Catechol-0-methyltransferase (COMT) is responsible for several methylation reactions in the metabolism of MDMA 37 and, perhaps not coincidently, this ubiquitous enzyme has also been reported to be less active in women 97. The effect of MDMA on core body temperature emerges gradually during ontogeny while a reduction in body weight is evident at all ages (Table 1). Mood swings, anxiety, depression – these are all potential long-term consequences. It’s as if the drug borrows happiness from your future self, leaving you to deal with the emotional debt. This cocktail approach can compound the risks, creating a perfect storm of neurotoxicity.
MDMA alters several physiological processes including reducing food 71 and, to a lesser extent, water intake 39,50. Elevated salivation has also been documented following MDMA 146 which, in combination with increased grooming, aids in thermoregulation. Further, rats increase their respiratory rate after MDMA which causes substantial evaporative water loss 56.
Is Ecstasy the Same as Meth? The Key Differences
Researchers have found a link between SERT density and the length of abstinence, a period where the drug is not being used. This means that, without MDMA, serotonin and 5-HT levels may be restored in the brain (Müller et al., 2019), which in turn could possibly lead to improved mood and memory. MDMA stimulates the release of neurotransmitters like dopamine and serotonin, which can produce euphoric feelings such as heightening of the five senses and increased empathy (Mustafa et al., 2018).
Similarly, the dynamic changes in postsynaptic monoamine receptor levels are also likely contributors to the differential sensitivity to the physiological and behavioral effects of MDMA. Interestingly, direct administration of MDMA, or amphetamine, to the chicken embryo five days prior to hatching induced an acute reduction in motility 13. Young rats (PD 28) also exhibit an acute elevation in motor-activity, particularly horizontal activity, following MDMA 16,17.
HUMAN STUDIES
Age-at-first ecstasy use predicted midbrain SERT binding in ecstasy users that started to use during adolescence but not in users that started during adulthood. In adolescent rats, MDMA administration resulted in a less pronounced loss of SERT binding in the frontal cortex. The differences between the effects of MDMA on the developing and matured brain most likely occur because of the differential maturational stage of the 5-HT projection fields at the time of first exposure in combination with 5-HT’s neurotrophic effects on the connective organisation of the developing brain. Darvesh et al. 151 demonstrated that the systemic administration of MDMA to rats significantly increased the formation of nitric oxide and the nitrotyrosine in the striatum. These results support the conclusion that nitrogen reactive species (formed by the reaction of NO with O2•− radicals) could also be involved in MDMA damage.
The Siren Song of Serotonin
- MDMA also inhibits serotonin reuptake by its binding to the transporter protein, thus prolonging signaling at the synapses.
- Positive events in your life (like falling in love, perhaps) cause greater serotonin release, increasing receptor binding.
- MDMA has also been shown to trigger neuroinflammation which seems to be linked with glial activation, in particular microglial activation (Costa et al. 2013, 2014; Frau et al. 2013; Lopez-Rodriguez et al. 2014).
- MDMA may also suppress nigral GABA release following 5-HT2A/2C receptor activation thus causing disinhibition of the striatal DA neurons (Gudelsky and Yamamoto 2008).
- However, MDMA dependence is still less understood, but it has been reported to be different from other drugs or alcohol (Degenhardt, Bruno, & Topp, 2010).
The picture on the right (B) is from a monkey that was injected with a very large dose of MDMA.1 As you can see, many of its serotonin axons have been lost. Neurotoxicity can manifest in many forms and severity levels and MDMA appears to be neurotoxic under certain circumstances. High doses or several doses throughout the period of ingestion, frequent use (e.g. weekly use at nightlife events), aduleration, and substance mixing all are implicated in the adverse event of MDMA neurotoxicity. Data from phase II trials of MDMA-AP do not support risks of clinically significant neurotoxicity from MDMA use as side effects were observed to be mild and limited to the week after use, while participants also saw profound improvements in clinical symptoms for PTSD. In summary, MDMA induced neurotoxicity is easy to avoid with moderate doses, adequate time between use, and pure substances without combination. The toxicity effects induced by MDMA made the researchers motivated to explore its potential treatments.
Data Analysis
The effects of single, large doses (up to 40 mg/kg) of MDMA on thermal homeostasis were compared in neonatal (PD 10), adolescent (PD 40), and young-adult (PD 70) rats by 10. It is important to note that a single 50 mg/kg dose is lethal for fifty percent of adult rats 62. MDMA treatment in a hot environment (33 °C) did not significantly alter rectal temperature in neonates but evoked an intense, prolonged, and potentially life-threatening, hyperthermia among adolescents and adults.
2. Effects of MDMA on memory and learning
This motor response has yet to be thoroughly characterized after perinatal exposure. Rat pups that received MDMA on PD 1–4 show a general increase in limb movements, but at this age, these do not result in locomotion (unpublished observations). Although the syndrome has been documented following prepubescent MDMA exposure 48,118, direct comparisons using the same treatment regimen at different ages has yet to be conducted.
- The binding in the cerebellum, which is presumed to be low in SERT, was used as a reference for background radioactivity (non-specific binding + free ligand).
- Bi-directional dose dependent 5-HT and 5-HIAA levels alterations were identified two-weeks after MDMA treatments to male pubescent rats 74.
- Because tryptophan hydroxylase is the rate-limiting enzyme for 5-HT synthesis, it is likely that decreases in this enzyme restrict the extent of 5-HT production, thus reducing the levels of this neurotransmitter regardless of whether or not axonal damage has occurred.
- Second, even if forebrain serotonergic fibers are not physically damaged, as postulated by the downregulation hypothesis, long-lasting deficits in 5-HT levels and in SERT expression would still cause severe dysfunction of the serotonergic system.
Cognitive changes in ecstasy users
Similarly, the damage in serotonergic system was also observed in non-human primates and in the human brain (Green et al. 2003; Ricuarte et al. 1988). Historical evidence showed that the mechanism of MDMA upon its administration is through its binding affinity to the serotonin receptors (Liechti, Saur, Gamma, Hell, & Vollenweider, 2000). The activation of these receptors triggers a massive release of neurotransmitters. MDMA also inhibits serotonin reuptake by its binding to the transporter protein, thus prolonging signaling at the synapses.
However, these changes went away after the ‘ecstasy’ users had stopped using drugs for a few months. Neuroadaptation (such as the brain scan research amply demonstrates the existence of) will not be considered. Ricaurte claims the drug manufacturer switched the labels on two vials (one of methamphetamine, one of MDMA) causing the error. The manufacturer (RTI) has vigorously disputed the claim that a switch occurred at their facilities (which are very tightly run under D.E.A. oversight.) The study reportedly cost the American taxpayers $1.3 million.
This was demonstrated in a study in which researchers first injected all the animals with MDMA, and, on every hour, they have some of the animals an injection of Prozac. Only those animals that got the Prozac during the first six hours exhibited no neurotoxic damage. Those that were injected with Prozac on the seventh, eighth, ninth and tenth hours, etc., sustained damage, with the ones that received Prozac injections later sustaining more damage than the others. Forebrain structures that are essential for cognitive function like the hippocampus and frontal cortex are highly sensitive to MDMA 58. The serotonin system in these regions undergoes dynamic 23,51,115 and protracted development 104.
Thus, initial studies showed that MDMA and its main metabolite 3,4-methylenedioxyamphetamine stimulate efflux of 3H5-hydroxytryptamine (5-HT) 28 (Figure 1) and 3Hdopamine from preloaded synaptosomes 29,30. Subsequent reports, using in vivo microdialysis, demonstrated that MDMA increases extracellular 5-HT, dopamine and noradrenaline levels in multiple brain regions with effects on 5-HT being greater in magnitude 31-34. MDMA also enhances the release of acetylcholine, an effect that appears to be secondary to the activation of serotonergic, dopaminergic and/or histaminergic receptors 35. The evaluation of monoamine release after MDMA intake has not been studied in humans or non-human primates, but mdma and the brain: is ecstasy neurotoxic several studies suggest that the interaction of MDMA with the 5-HT carrier and a subsequent release of 5-HT could be responsible for most of the physiological and psychological responses to MDMA in humans 5-8,36.
