We will be looking at what happens in the brain during the various stages of an ecstasy experience as well as some changes that may occur in the brain after long-term, frequent use. But now, let’s take a look at the “reuptake transporters” (those yellow “H” looking things). To understand how ecstasy works over time in the brain, it is important to know what these things do. When a serotonin molecule attaches to a receptor, which is called receptor binding, the receptor sends chemical information down the dendrite to the cell body of the neuron. The cell body then decides, based on the information from all its receptors put together, whether or not to fire an electrical impulse down its own axon. If a critical amount of receptor binding occurs, then the axon will fire, causing the release of other neurotransmitters into other synapses.

• The effect of MDMA on DA and 5-HT systems may be due to modulation of different receptors.
• Noteworthy this neuroprotective effect was independent of any alteration in MDMA pharmacokinetics or MDMA-induced hyperthermia.
• This can contribute to negative psychological aftereffects such as depression, anxiety, and fatigue, which you may experience for a few days after MDMA use.
• Using the same species and dose as in 47, large age dependent differences were identified in rats at Postnatal Day (PD) 1 and PD 10 with half-lives of 2.8 and 4.0 hours, respectively 165.
• The first MDMA treatment caused hyperthermia but the dams rapidly developed tolerance to this response 28.

Can We Prevent the Long-Term 5-HT Deficits Caused by MDMA in Rats?

Studies of amphetamines have identified critical periods during ontogeny that are more easily disrupted relative to adult exposure 122,159. This can result from age dependent modulation of pharmacodynamics (e.g. lower number of neurotransmitter receptors at earlier ages). The tremendous plasticity of the developing nervous system could mask the long-term effects of a drug.

Serotonin-related functions

As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science—having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field. In 1987, researchers discovered that MDMA releases dopamine (Schmidt et al., 1987, Steele et al., 1987).

Additionally, we will attempt to highlight why this is such a contentious area and why the controversy is not likely to be resolved soon. To re-cap, we have (1) serotonin depletion causing the reuptake transporters to become empty. Then (2) dopamine, which exists in higher levels in the synapse now, enters the reuptake transporter. (4) Both the hydrogen peroxide and the remaining dopamine are toxic to the cell, producing oxidative stress. Prozac has a greater affinity for the reuptake transporter than both MDMA and serotonin. Most people on Prozac don’t feel MDMA when they take it because the MDMA cannot get into the serotonin axon terminal in order to release the serotonin.

HUMAN STUDIES

• Overheating, often of life-threatening proportions, is important for neurotoxicity to occur.

Keeping animals at low ambient temperatures during MDMA administrations 123,126 or surgical treatments such as hypophysectomy or thyrophysectomy 127 prevent both the acute hyperthermia and the long-term deficits observed in the serotonergic system after its administration. Despite its retraction, the Ricaurte study had dealt a serious blow to the credibility of MDMA as a safe therapeutic. Heated public debate ensued about the potential dangers of the drug and its government regulation. Since the retraction of the Ricaurte study, there have been multiple clinical trials investigating the effects of MDMA, and thus far, all data suggest that MDMA can be administered safely under these conditions. Despite its relatively simple structure, MDMA elicits robust behavioral responses by binding with high affinity to a number of neuroreceptors and transporters. Below, we discuss the synthesis of MDMA and its pharmacology, metabolism, and adverse effects.

Animals

Shortly thereafter, members of the mental health community began to explore the use of MDMA, known to therapists as “Adam”, as an adjunct to psychotherapy. Hundreds of sessions were conducted with Adam and the drug subsequently gained recognition among some clinicians for the treatment of depression, physical and psychological pain, and relationship problems 42,59. Proponents of MDMA for psychotherapeutic purposes have made some advances recently and studies are ongoing to determine whether MDMA is beneficial for veterans with post-traumatic stress disorder and for terminally ill cancer patients with anxiety 41,163. Mice received repeated doses of MDMA (4 × 10 mg/kg every 2 h) for 2 days ip and CAF (2 × 5 mg/kg every 4 h) for 2 days ip. After 5 days free of MDMA treatment, the animals received the next series of “binge” injections. Between binge injections, animals received caffeine (2 × 5 mg/kg) or saline for 5 days.

The lack of A2A receptors on the striatal monoaminergic neuronal terminals suggests that their role in the control of DA and 5-HT release may be secondary and related to the changes in the activity of striatal output pathways elicited by postsynaptic A2A receptors. In support of this concept, there are studies showing that the administration of A2A adenosine receptor antagonists increased DA release and 5-HT release in the striatum of rats and mice (Gołembiowska et al. 2009, Górska and Gołembiowska 2015; Okada et al. 1996). Such subtle residual changes could be functionally important, and might contribute to clinical or subclinical alterations of psychological well-being and behavior of ecstasy users.

Evidence of neurotoxicity

Newborn mammals are very sensitive to decreases in the ambient temperature but can engage in nonshivering thermogensis to produce some heat from brown adipose tissue. Uncoupling proteins found in the inner mitochondrial membrane produce heat by separating ATP synthesis from oxidation 5. Adult mice lacking uncoupling protein-3 exhibited a substantially blunted hyperthermic response to MDMA 102. Some investigators argue that because the new born rat is more immature than the new born human, the neonatal rat is equivalent neurodevelopmentally to a third trimester human fetus. Although this justification for postnatal rodent dosing certainly has some merit, MDMA disposition following in utero exposure and direct rat pup administration are likely to be quite different which is likely a substantial consideration for extensively metabolized drugs.

Ecstasy does not cause uni-directional temperature changes as MDMA is a poikilothermic substance that elicits temperature dysregulation that is dependent on the ambient temperature. More specifically, MDMA administration in a cool environment causes hypothermia while dosing at warmer temperatures induces hyperthermia 56,86. The core temperature response at intermediate temperatures (20–23 °C) is bidirectional in rats 14,118,121. In contrast, recent evidence suggests that MDMA induces unidirectional temperature changes (hyperthermia) in rhesus monkeys 158 and possibly also humans 49.

• As an in-depth examination of the preclinical pharmacology of MDMA is beyond the scope of this mini-review, only a brief summary will be detailed here (for more in-depth reviews, see 24-27).
• 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).
• SERT binding was lower in brain regions where the serotonin-2A receptors were elevated, a finding consistent with reduced serotonin and consequent upregulation of the serotonin-2A receptor.
• Perhaps counter-intuitively, newborn rat offspring from mothers that received MDMA during pregnancy performed better on an olfactory discrimination task.

The government of course hailed this as proof that the demon-drug ecstasy was destroying poor young minds. The author (Ricaurte) failed to control for disruptions of sleep patterns (long known to affect cognitive function, and likely to be an issue among stimulant users.) His ‘non-users’ were also younger, better educated, and had higher vocabulary scores than his ‘ecstasy user’ group. The ‘ecstasy’ users also took considerably more of all sorts of drugs than the non-ecstasy users did. They used more opiates, they used more amphetamines…and they smoked considerably more pot, long known to cause (non-permanent) memory problems. Indeed, there were numerous possible explanations for the modest differences in memory, including neuroadaptive responses to recent MDMA exposure.

Table 2. Specific β-CIT SERT binding ratios in saline and MDMA-treated rats.

The supernatant was discarded while the pellet was resuspended in the same volume of homogenization medium without Triton and centrifuged at 850×g for 10 min. The sediment was washed once more in the same way and centrifuged at 600×g for 8 min. The pellet was resuspended in 0.8 ml of homogenization solution without Triton, mixed with 4.2 ml of purification medium, and centrifuged at 19,000×g for 45 min. The pellet was resuspended in 0.5 ml of 2.0 M sucrose and was layered over a sucrose gradient (2.6 and 2.4 M bottom to top). As we wrap up our journey through the MDMA-affected brain, it’s clear that this is a complex issue with no easy answers.

However, serotonergic deficits have been reported following single doses at lower levels. A recent example comes from Mueller et al,85 who reported that single oral doses as low as 5.7 mg/kg given to squirrel monkeys produced statistically significant reductions in mdma and the brain: is ecstasy neurotoxic 5-HT concentrations and SERT binding in many forebrain areas when measured 1 week after drug administration. Do and Schenk86 also found that intravenous self-administration of a relatively low dose of MDMA (0.5–1.0 mg/kg per infusion) by rats eventually led to 30%–35% reductions in forebrain 5-HT, though the cumulative amount of drug taken by the animals over time was 315 mg/kg. Third, ambient temperature can modulate the extent of MDMA-induced neurotoxicity. As mentioned earlier, at the typical temperatures found in a laboratory animal colony room, a human residence, or a dance club, MDMA elevates core body (and brain) temperature. In mice, MDMA tends to produce dopaminergic, but not serotonergic, neurotoxicity.189,190,191 This is in sharp contrast to rats, for which the opposite seems to be true.