Because animal studies of MDMA neurotoxicity have typically used large and/or repeated drug doses, we may ask whether one or a few modest doses of ecstasy are capable of exerting neurotoxic effects in users. This question has been addressed by several prospective studies of new ecstasy users participating in the Netherlands XTC Toxicity (NeXT) study. The results thus far have failed to show any serotonergic deficits in these low-dose users; however, other abnormalities were found related to brain vasculature and white matter structure.
- If Ricaurte et al have additional information about this case that was unavailable to the doctors treating the patient, they have made no mention of it.
- Caffeine given repeatedly increased the basal extracellular level of DA and increased MDMA effect on DA release.
- Perhaps the true potential of MDMA lies in its use as a lead structure for the development of safer and more efficacious alternatives.
- Perinatal MDMA exposure (PD 1-4) resulted in significant SERT labeling reductions in the neocortex but an elevation in the striatum in middle aged (9 month old) rats 101.
- It has also been shown that repeated MDMA induces behavioral sensitization and cross-sensitization to cocaine, MDMA substitutes for cocaine in a drug discrimination task, and that MDMA pre-exposure facilitates cocaine conditioned place preference and intravenous self-administration 37-41.
The Russian Roulette of Recreational Use
However, MDMA is also a highly divisive compound having the potential to swing public opinion against general use of psychedelics in medicine. When an electrical charge comes down the axon, these vesicles merge with the outer membrane of the axon terminal and release serotonin into the synapse. Soon we will look at the synapse up close and see what happens when MDMA causes large amounts of serotonin to be released there. But first, let’s look at how serotonin cells are distributed throughout your brain.
Cognitive changes in ecstasy users
In this post we’ll give some background information on what neurotoxicity is, how MDMA may act as a neurotoxin, summarize research findings on MDMA-induced neurotoxicity, and explain use parameters that are likely to prevent development of significant neurotoxic effects. Data reported by the United Nations on Drugs and Crime on the total number of drug addicts worldwide shows the increasing number of drug users every year. Global trends in the estimated number of drug users (15–64 years old) increased from 208 million to 255 million people from 2006 to 2015, while people with drug user disorders increased from 26 million to 29.5 million cases (UNODC, 2017). While other psychedelic compounds such as LSD, psilocybin, and ibogaine have been more extensively studied than MDMA with respect to their abilities to treat SUDs, the minimal perceptual disturbances caused by MDMA may offer a distinct advantage over the classical hallucinogens. An effective dosing paradigm was established by Oehen and co-workers utilizing low dose MDMA as an active placebo.221 The use of an active placebo is an important part of the experimental design implemented by Oehen and co-workers.
Rationale and Objective
Additional study using a more moderate MDMA dose (20 mg/kg/day) at intermediate ambient temperatures showed that adolescents are less sensitive than adults to pyrexia 120,121. Twenty mg/kg was administered twice per day to pregnant rats on gestational day (GD) 14 to 17. The first MDMA treatment caused hyperthermia but the dams rapidly developed tolerance to this response 28. A gradually diminishing temperature dysregulation in rat dams was also seen by 76. The development of thermal tolerance is not unique to females or to pregnancy as a blunted temperature dysregulation also occurs in adolescents 118 and adults 25,142. The mechanism(s) responsible for tolerance, especially at different ages, is presently unclear as, in addition to the activation of uncoupling proteins by norepinephrine and thyroid hormones 103, dopamine, serotonin, and several cytokines mediate the core temperature response to MDMA 58.
At the end of the day….
The additive effect of increased urination and defecation is evident by examining the large short-term weight reduction that occurs immediately following adult exposure 8,121. Similarly, adolescent rats lost over ten grams, 8% of pre-drug weight, only hours after MDMA treatments 121. The molecular mechanisms of MDMA induced weight loss are incompletely understood but are quite likely to involve systemic norepinephrine release by this sympathomimetic and binding to alpha1 or beta3 adrenergic receptors followed by activation of uncoupling proteins.
This is certainly a reasonable starting point as mdma and the brain: is ecstasy neurotoxic this tactic has determined that the immature organism is less vulnerable to MDMA induced reductions in 5-HT and SERT because, in part, the neuroplasticity that is evident in the adult brain 6 may be even more pronounced in the developing organism. Age differences in temperature regulation 10, antioxidant enzymes 28, dopamine innervation 2, and, possibly, drug metabolism 165 could protect the immature organism from the indoleamine consequences of MDMA. Recent studies have moved beyond measuring only 5-HT and SERT and have targeted indices that may be even more relevant to the many ongoing neurodevelopmental events 75,76,101. This approach will continue to be useful in determining how age modulates the physiological, neurobehavioral, and biochemical sequelae of MDMA.
In 2011, the first completed clinical trial evaluating the potential of MDMA-assisted psychotherapy for alleviating treatment-resistant PTSD was published.220 The results were positive, and in 2017, MDMA was granted “breakthrough therapy” status by the FDA. This designation helps to expedite the review and potential approval process for promising therapeutics. Phase III clinical trials are currently being planned, and if the results of those trials warrant approval by the FDA, a bona fide accepted medical use for MDMA will have been established. This would necessitate the removal of MDMA from the Schedule I list, a regulatory change that could have profound implications for the field of psychedelic medicine. Schedule I status has severely hampered access to psychedelics for research purposes. In sum, this trajectory is perhaps why MDMA is the most influential compound for the future of psychedelic research.
Acute effects and aftereffects of MDMA/ecstasy use
In addition to studies using cultured neurons, in vivo animal models are frequently used to test the neurotoxic potential of MDMA. While findings dating back to 1987 suggest that MDMA has neurotoxic effects in animals,188 the relevance of these models to human neurotoxicity is highly debated. Another reason you can become depressed after using MDMA frequently has to do with the down-regulation of serotonin receptors.
- 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.
- However, MDMA is also a highly divisive compound having the potential to swing public opinion against general use of psychedelics in medicine.
- The honest answer is you can’t, although you can at least try not to promote a bias.
This study is one of the largest, most sophisticated pieces of research of its type to date. They gathered precise brain scans measuring SERT density from no less than 54 current and former ‘ecstasy’ users, which they divided into “current moderate”, “current heavy”, and “former” user groups of men and women. The male users didn’t show even temporary reductions in SERT this time, even among the “heavy” user group (which had an average lifetime use of 530 pills.)14 The female “current heavy user” group, however, did have lower SERT density…but once more, women who where no longer current users had normal SERT densities. Frequency of use is also probably consequential as dosing on a weekly basis (as some may be if frequenting raves often) is not enough time to allow for recovery from prior use, even in some taking doses in clinical environments. This is rather simple in that your serotonin neuron simply has a capacity for how high the concentrations can be without damage and how fast it can return to balance after use. The two may go hand in hand as frequent use can produce tolerance and result in increased doses when used 3.
Human Subjects
In this regard, any pharmacological or non-pharmacological manipulations capable of preventing the acute hyperthermic response caused by MDMA also attenuate or reverse the serotonergic deficits induced by the drug. MDMA use can lead to temporary yet prolonged periods of depression, for a few pharmacological reasons. Perpetually low serotonin levels resulting from weekly MDMA use is one of these reasons. If you take ecstasy on a regular basis, you may be releasing and depleting your serotonin before it has a chance to fully replenish itself. This means you will be operating on lower-than-normal serotonin levels most of the time, and this can lead to depression.
Thus, the described mechanism of adenosine receptor involvement in the control of 5-HT release and their blockade by caffeine may be responsible for the diminished 5-HT release in response to MDMA and caffeine co-administration. Caffeine and MDMA given acutely or chronically produced oxidative damage of DNA in nuclei from the mouse cortex as measured 2 months after cessation of treatment (Fig. 3a, b). The damage of DNA was stronger after combination of both drugs administered acutely or chronically (Fig. 3a, b). The extent of DNA damage was smaller after all treatments when it was measured 24 h after termination of drug administration (data not shown). Table 1 shows the comparison of the total effect expressed as an AUC in DA and 5-HT release induced by acute and chronic administrations of MDMA and caffeine. It is clear that the effect of the challenging doses of both psychostimulant drugs on DA release was weaker in groups pretreated chronically with caffeine and MDMA vs. their acute doses.
