The data were obtained from a PubMed search for papers having titles that contained the search terms “3,4-methylenedioxymethamphetamine or MDMA” and “lysergic acid diethylamide or LSD” conducted on March 20, 2018. Another theory gaining wider acceptance among researchers is that MDMA causes the reuptake transporters work backwards, transporting serotonin from inside the axon directly into to the synapse, without involving the vesicles at all. According to this theory, once the MDMA enters the transporter, it falls off inside the axon terminal, leaving the transporter in such a state that a serotonin molecule now binds to the place where the MDMA fell off. The transporter then spins around and deposits the serotonin molecule into the synapse, where another MDMA molecule binds to where this serotonin molecule fell off. We’ve been neglecting this issue for a while because it would have been confusing to present in the beginning.

• For instance, it is well known that MDMA inhibits the activity 190 and abundance of tryptophan hydroxylase 191 at least two weeks after MDMA.
• Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine.
• Part of the motivation to look for toxic metabolites may have been a red herring; the localized injections into rat’s brains that failed to produce notable damage probably also failed to produce a significant increase in body temperature.
• Neurotoxicity studies can help us understand how common and severe these risks are in the long run.
• Depending on how much MDMA you took, you may end up depleting so much of your serotonin that fewer receptors are activated than before you took ecstasy, when you were in a normal brain state.

MDMA and Caffeine Effects on PDYN and PENK Gene Expressions and on Behavior

Your serotonin brain cells produce serotonin when an amino acid called 5-Hydroxy-Tryptophan (5-htp) enters the cell and comes into contact with an enzyme called decarboxylese. The decarboxylase strips off a piece of the 5-htp molecule, resulting in 5-ht (another name for serotonin). Some ecstasy users take 5-htp supplements to restore their depleted serotonin levels more quickly. L-tryptophan is another amino acid that will do the same thing, since it is a precursor of 5-htp. A diet high in tryptophan-containing proteins can also increase the amount of 5-htp in your brain, helping your brain build serotonin more quickly. Along with binding to receptors on the dendrite, serotonin molecules also bind to reuptake transporters on the axon.

MDMA (3,4-methylenedioxymethamphetamine) known as “ecstasy” is one of the most popular illicit drugs with empathogenic properties. MDMA acting at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) stimulates non-exocytotic release of DA and 5-HT (Baumann et al. 2005; Sulzer et al. 2005). In rodents, MDMA has a preferential affinity for SERT over DAT, so it exerts a more pronounced effect on 5-HT release (Rudnick and Wall 1992).

The neurotoxic effect of MDMA in mice seems to be related to dopaminergic and serotonergic systems. Our data showed a significant decrease in markers of neuronal terminals, DAT, and SERT in the mouse striatum and frontal cortex after chronic administration of MDMA. There was also depletion of tissue concentration of DOPAC and 5-HIAA, but not DA and 5-HT, in the striatum and the frontal cortex of mice. Neurotoxic effect seems to result from formation of ROS because we observed oxidative damage of neuronal DNA in the cortex 2 months after acute and chronic doses of MDMA.

David E Olson

Ecstasy (MDMA) and stimulant amphetamines (METH and AMPPI) are popular drugs of abuse and they are neurotoxic in animal studies. High and repeated doses of MDMA cause selective and long-lasting degeneration of 5-HT axon terminals in several brain regions, whereas METH and AMPH damage both serotonergic and dopaminergic neurons. Although the doses taken recreationally are considerably lower than the doses typically given in animal studies, some users exhibit compulsive binge use behaviors that may well correspond to the animal doses. In addition, polydrug use and the typical environment of use (hot, overcrowded, and noisy rooms, extensive physical exercise in the form of dancing) may well potentiate the neurotoxic effects of the drugs. The amphetamine-type stimulant drugs, such as MDMA or ecstasy become the choice of drug abuse among young people and adults besides opioids, which is due to a feeling of excitement experienced immediately after the administration.

Effects on Monoamines.

Caffeine potentiates MDMA effect on dopaminergic system and inhibits its effect on serotonergic neurons. Exacerbation of MDMA-evoked oxidative stress may cause damage of serotonergic terminals. In contrast to the lack of research on DA involvement in the acute effects of MDMA, a number of pharmacological studies using various transporter inhibitors and receptor antagonists have provided information regarding the role of the serotonergic and noradrenergic systems in the subjective and physiological effects of MDMA in humans.

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

Even sophisticated mathematical techniques to approximate dose equivalencies across species 22 do not address developmental factors. Further study using the same MDMA dose and route of administration across a range of ages in both sexes and measuring the neurotoxic MDMA metabolite levels in plasma, brain, and, if feasible, urine, would greatly enhance our understanding of how different development periods differ in their susceptibility to the consequences of MDMA. Images of single wavelengths were obtained with an epifluorescence microscope (Axio Scope A1, Zeiss, Oberkochen, Germany) connected with a digital camera (1.4 MPixels, Infinity 3–1, Lumenera, Nepean, Canada).

The girl’s brain scan may actually be abnormal, but there is no way to know what caused it (depression can also reduce brain activity, as can fatigue), or if her brain was ever like the “healthy brain” example they showed, or if what changes were seen were merely temporary. Looking back at the first pair of images, you’ll notice two blobs floating on one side of the ‘healthy’ image. The eyes do not appear in the other image, suggesting that different settings have been used–settings that would hide more of the scan’s data. In fact, those two images could possibly have been generated from the same scan of the same person, merely rendered differently. (Antioxidant use is actually good advice for any drug user, including smokers and drinkers.) Visit Preloading for more information on antioxidants.

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

MDMA was a chemical intermediate in the synthesis of hydrastinin, an astringent to control bleeding. (A popular, although inaccurate, misconception is that MDMA was developed as an appetite suppressant 77). The U.S. Army Chemical Center conducted toxicological studies in the 1950’s which were declassified and published two-decades later 62.

Neuropsychological deficits

Moreover, amphetamines and MDMA have been shown to be neurotoxic in animal studies, particularly when given at high and repeated doses. In the following sections we review the evidence for neurotoxicity in animal studies and in human populations. As MDMA is colloquially known as ecstasy, it may not be surprising that adult humans report that the drug modifies the sexual experience 42,175.

The pills typically contain 70 to 120 mg of MDMA, although the concentration may sometimes be higher or lower. Occasionally ecstasy tablets will contain similarly acting analogues (3,4-methylenedioxy-Nethylamphetamine MDE, 3,4-methylenedioxyamphetamine MDA, or 3,4-methylenedioxy-alpha-ethylN-methylphenethylamine MBDB, Figure 1) or amphetamines, and more rarely they may also contain substances from different classes. Amphetamines are mostly sold as powder which can be inhaled, smoked, ingested, or injected, although intranasal use (“snorting”) is now particularly common. Serotonin blocking antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs e.g. Prozac or fluoxetine) can diminish neurotoxic potential of MDMA 18. However, this is a poor strategy overall because serotonin blocking antidepressants also greatly diminish the subjective experience of MDMA 19-22.

MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions.

• The entactogen ±3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug among college, high school, and, occasionally, middle school students.
• Once MDMA was given a Schedule I designation, it was no longer legally possible to administer the substance for therapeutic purposes, although Greer and Tolbert141 later published a description of the methods they developed for using MDMA in a therapeutic setting.
• There have been findings of an increase 60,106, decrease 96, or no appreciable change 17,65 in anxiety-like behavior in adult rats.
• As mentioned in the “Introduction” section, caffeine increases the activity of both types of neurons (Johansson et al. 1994).

Neurotoxicity of ecstasy (MDMA): an overview

Although self-reported substance use is an imperfect measure, the conclusion that ecstasy use is prevalent is generally supported by other indices of drug use including arrests 123, drug seizures 143, hair analyses 69, emergency room records 53,98,114, and coroner’s reports 138. Serotonin isn’t just about feeling good – it plays a role in regulating mood, sleep, appetite, and even cognitive function. MDMA’s intense effect on this system can lead to long-term changes in how your brain processes serotonin, potentially setting the stage for mood disorders and other mental health issues. These initial findings provide hope that the addition of mdma and the brain: is ecstasy neurotoxic a few low doses of MDMA (ie, around 2 mg/kg or less) to established psychotherapeutic approaches may be beneficial to patients with chronic treatment-resistant PTSD. Indeed, Johansen and Krebs145 have offered a summary of potential neurobiological mechanisms that could underlie such an effect of MDMA. Virtually all medications involve some degree of risk, as a result of which, standard medical practice requires that the benefit obtained from a drug significantly outweighs the risk to the patient.