In a microdialysis study, perfusion with caffeine caused an increase in DA release which was mimicked by the selective A1 receptor antagonist DPCPX, while A1 receptor agonists, but not adenosine A2A agonists, depressed DA levels (Okada et al. 1997). It is also suggested that adenosine A1 receptors present on glutamatergic neurons may be involved in striatal DA release (Borycz et al. 2007). Despite over 30 years of intensive research on MDMA both in humans and in animal models, there remain several major controversies that have yet to be resolved. Does repeated MDMA exposure cause long-lasting mood changes and/or cognitive deficits?
Similarly, neurotoxic METH regimens which are sufficient to produce neurotoxicity were shown to induce only moderate, if any, alterations in behaviour of laboratory animals. The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure.
When you are happy, it is likely that you have more serotonin receptors activated. Positive events in your life (like falling in love, perhaps) cause greater serotonin release, increasing receptor binding. Caffeine in high doses elevates messenger RNA (mRNA) coding for opioid neuropeptides deriving from prodynorphin (PDYN) and proenkephalin (PENK) (Svenningsson et al. 1997). Medium-sized spiny GABA neurons projecting to the substantia nigra express D1 receptor as well as neuropeptides derived from PDYN (Vincent et al. 1982). On the other hand, medium-sized spiny neurons projecting to the globus pallidus express D2 receptor (Gerfen et al. 1990) as well as PENK-derived peptides (Curan and Watson 1995). DA release increased by amphetamines activates neurons that express D1 receptors and PDYN, but not those that express D2 receptors and PENK (Granado et al. 2014; Johansson et al. 1994).
The Russian Roulette of Recreational Use
The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open-field (OF) test and novel object recognition (NOR) test.
Studies in ecstasy users
- 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.
- In general, such studies have found neither further deterioration in users nor recovery of function in subjects who discontinued ecstasy use76–78 (see Zakzanis and Campbell79 for an exception to these findings).
- The previously reported studies showing no loss of the SERT protein band after MDMA, is not the only argument some authors put forward to question the 5-HT neurotoxic potential of MDMA.
- It’s like looking at a before-and-after picture, but instead of a makeover, we’re seeing alterations in brain tissue and activity.
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.
- Dextromethorphan and its metabolite, dextrorphan, may have a protective effect against MDMA-induced serotonergic toxicity in the brain (Finnegan, Skratt, Irwin, & Langston, 1989; Ma et al., 2016).
- Main age, treatment and age-BY-treatment interactions effects were further analyzed using a Student t-test.
- Forebrain structures that are essential for cognitive function like the hippocampus and frontal cortex are highly sensitive to MDMA 58.
- While the drug was initially thought to cause immediate dependence and pose a high risk to public health, current studies no longer indicate for sure that MDMA can cause addiction.
Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice
The role of glutamatergic pathway damage by oxidative stress in the hippocampus and cognitive impairment was also shown in mice by Frenzilli et al. (2007). Anxiety-like behavior in rats was related to oxidative damage of DNA in the hippocampus by chronic caffeine (Noschang et al. 2009b). The alterations in the brain antioxidant system were suggested to affect the cognitive functions of rats after chronic caffeine ingestion (Abreu et al. 2011).
Neurotoxicity describes a given substance’s harmful effects on the brain and the rest of the nervous system. This can include damage to nerves and neurons, which are responsible for communicating signals (messages) in the brain. Neurotoxins can be found in a variety of substances such as heavy metals, pesticides, and drugs. There is a significant range in how these neurotoxins affect us, and how much they harm our bodies and functioning (Robertson, 2019).
Brain Serotonin Function in MDMA (Ecstasy) Users: Evidence for Persisting Neurotoxicity
Bi-directional effects were also observed following oral MDMA treatments to female rhesus monkeys 3. These findings of a high dose reduction and low dose increase in 5-HT are consistent with the predictions of a hormetic model 19 although further study with very low doses is necessary. Note that high 5-HT levels are not “good” as abnormal levels suggest a disruption in indoleamine homeostasis. Ecstasy users frequently lament the weight loss that accompanies chronic use 113. The rapid increase in body mass from birth through young-adulthood might be anticipated to influence the sensitivity of this measure to MDMA treatments. Although weight data is commonly obtained in animal studies, the simplicity of measurement belies the numerous factors that can change this index.
Cognitive changes in ecstasy users
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.
The MDMA may still be around trying to make your vesicles release more, but there isn’t enough there. In about four hours, ecstasy has used up most of your serotonin.You could take more ecstasy at this point, which a lot of people do. Because the ecstasy feeling is really a “serotonin feeling,” and you currently don’t have enough serotonin left. (It takes time for your brain to build up more, which we will be discussing soon.) Of course, if you took a lower-than-normal dose, you may not have released most of your serotonin, in which case you may feel the effects come on again if you take more. There will come a point (sooner rather mdma and the brain: is ecstasy neurotoxic than later) when you have depleted your serotonin levels so much that taking more ecstasy will not work.
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. Some investigators have attempted to deal with this confounding factor by statistically controlling for exposure to other substances of abuse.19 Another important approach, which is discussed below, is to perform experimental animal studies in which pure MDMA is administered to animal subjects with controlled dosing regimens. Laboratory studies have also permitted an analysis of the acute effects of MDMA in humans; however, simulation of heavy recreational ecstasy exposure cannot be performed for ethical reasons.
It is possible that these changes to the brain also have psychological consequences. Even though relatively few people require psychological treatment for their MDMA use, this does not necessarily represent a lack of impact on mental health. In a turn-of-the-millennium study on ecstasy users in the UK, researchers found that 83% reported midweek “low mood”, and 80% reported concentration or memory problems. These changes in mood and functioning could be linked to serotonin toxicity, as well as damage to brain regions involved in key tasks such as learning and memory. Interestingly, Potter and colleagues found that the average depression level (as measured by the Beck Depression Inventory) was 13.35 in people who used MDMA, 7 points higher than that of non-drug users (2013).