Explore the complex effects of MDMA on the brain, potential long-term consequences, and the confounding factors that may influence the outcome of studies.
Overview: MDMA, a psychoactive drug commonly known as ecstasy, produces euphoria and empathy but comes with health risks due to unstandardized dosing and adulteration; while it has shown potential in PTSD therapy, its long-term effects on the brain remain complex and debated; brain imaging studies suggest subtle changes in brain activity, but the interpretation of these changes is challenging due to confounding factors; future research is needed to understand the impact of concomitant drug use and genetic factors, and the dissemination of evidence-based drug science information and harm reduction strategies are crucial in minimizing potential harm.
MDMA, or “ecstasy” as it is often called when in tablet form, is a synthetic substance belonging to a class of psychoactive drugs known as entactogens. It was first synthesized by the German pharmaceutical company Merck in 1912.
MDMA is structurally similar to stimulants and psychedelics, and it produces feelings of euphoria, empathy, and boundless energy. It also intensifies sensory perception, making it a particularly popular drug among festival-goers and fans of electronic dance music.
MDMA became a popular recreational drug in the 60s and 70s and, after chemist Alexander Shulgin re-synthesized it in 1976, MDMA gained the attention of psychotherapists due to its apparent ability to soften emotional boundaries. However, MDMA’s production ramped up, and it began being detected increasingly in clandestine labs and street samples, leading to its eventual scheduling in 1985.
While MDMA has been shown to be a powerful aid to psychotherapy in clinical trials investigating the effects of MDMA-assisted psychotherapy on people with post-traumatic stress disorder (PTSD), recreational use does come with potential health risks associated with unstandardized dosing, purity variability, adulteration, hyperthermia (overheating), and hyponatremia (water intoxication).
To minimize these negative effects, it is crucial to spread evidence-based drug science information and encourage the employment of potentially life-saving harm reduction strategies.
The question of whether the use of MDMA has long-term effects on the brain is quite complex, and has been the subject of considerable scientific debate down through the years as a result. Below, we describe how MDMA works in the brain and provide a rundown of brain changes associated with recreational MDMA use.
MDMA stimulates the release of three neurotransmitters: serotonin, norepinephrine, and dopamine.
A 1986 study by chemist David Nichols found that MDMA binds to the serotonin transporter (SERT) and inhibits serotonin reuptake, allowing it to remain in the synapse and stimulate receptors in the striatum, hippocampus, and cortex. This is the primary mechanism by which MDMA produces its characteristic effects.
The inhibition of norepinephrine and dopamine reuptake is less important for the subjective effects of MDMA, but likely contributes to the drug's physical effects.
MDMA has also been shown to decrease activity in the amygdala, a brain region important for processing fear. Notably, the amygdala is often hyperactive in people with PTSD. Increased activity in the prefrontal cortex and hippocampus have also been observed in MDMA brain imaging studies, two areas of the brain that PTSD patients typically have reduced activity in.
MDMA also increases connectivity between the amygdala and hippocampus, which may play a role in the feeling of safety and reduced fear that PTSD patients experience when processing traumatic memories in MDMA-assisted psychotherapy sessions.
In 2002, a controversial study that aimed to investigate the effects of MDMA on the human brain concluded that a single recreational dose of MDMA could cause permanent damage to dopamine neurons in the brains of non-human primates, which raised concerns about the safety of MDMA use in humans.
However, it was later revealed that the findings of the study were based on a mistake made by the lead researcher, George A. Ricaurte. It turned out that the primates used in the study were mistakenly given a massive overdose of methamphetamine, not MDMA, which caused the brain damage. Additionally, it was discovered that Ricaurte had manipulated the data to support his conclusion. The study was retracted, and Ricaurte faced disciplinary action from the scientific community.
After this study was published, the public perception of MDMA was negatively impacted. Its publication led to increased media attention and government scrutiny of MDMA use, and some people became more cautious or even afraid of using the drug.
However, once the errors in the study were revealed, and the findings were retracted, the public perception of MDMA shifted again. Today, MDMA is considered a relatively safe drug. However, there are still risks associated with its use.
For example, there is some evidence to suggest that repeated use of MDMA can cause damage to the serotonin system, which may lead to a range of neurological and cognitive changes. The results of some studies suggest that MDMA administration may have long-lasting neurotoxic effects on serotonin neurons in animals.
However, identifying serotonergic neurotoxicity in humans is more challenging due to confounding factors such as polysubstance use, genetic and environmental factors, and reliance on self-reported drug use. As a result, determining whether MDMA use may be harmful is quite a complex endeavor.
Current scientific research indicates that taking MDMA in a responsible way is generally safe, but taking it in high or repeated doses can lead to neurotoxicity in some way.
Catharine Montgomery and Carl Roberts, researchers from John Moores University, have written an eloquent review on the neurological changes associated with MDMA use in humans. Their study provides insights into the potential long-term brain effects of the drug, highlighting the need for further research in this area.
In a 2003 functional magnetic resonance imaging (fMRI) study, Daumann and colleagues sought to investigate brain activity in MDMA users.
fMRI is a non-invasive neuroimaging technique that uses a magnetic field and radio waves to detect changes in blood oxygenation and flow that occur in response to neural activity in the brain. By measuring changes in blood flow, fMRI can identify which areas of the brain are active during specific tasks or stimuli, providing insight into brain function and cognitive processes.
In the study, the authors observed no differences in brain activation between heavy MDMA users, moderate MDMA users, and non-users during a memory updating task, a cognitive task that assesses an individual's ability to update or modify previously learned information with new information), and no differences in performance.
However, when the researchers applied a less conservative significance level (a threshold value used to determine if the results of an experiment are statistically significant), differences were observed in the right parietal cortex, where heavy and moderate MDMA users groups showed greater activation than non-users. Heavy MDMA users had weaker activation in frontal and temporal areas of the brain than moderate users, also, suggesting that heavy MDMA use may be associated with subtle changes to brain function.
The frontal and temporal areas are two of the four main lobes of the brain. The frontal lobes are located at the front of the brain and are responsible for a range of cognitive functions, including planning, decision-making, problem-solving, and motor control. The temporal lobes are located on the sides of the brain, near the temples, and are involved in processing sensory information. The temporal lobes also play a role in memory formation and retrieval, and are involved in language comprehension and production.
In a follow up study that attempted to control for the effects of concomitant drug use (the use of two or more drugs or substances at the same time or within a close time frame), the same set of researchers compared the memory task performance of a group that uses ecstasy, a group that uses ecstasy, methamphetamine, and cannabis, and a group that doesn’t use any drugs.
Here, the researchers observed reduced activity in the temporal and angular gyri (two specific parts of the brain's cerebral cortex involved in a variety of complex functions) in ecstasy users compared to the other two groups, but no differences in performance. These results indicate that alterations in brain structure could be apparent in MDMA users even if there are no apparent changes in behavior.
Interestingly, there are also several fMRI studies that report no differences between MDMA users and non-users. For example, a 2008 study conducted by Jager and colleagues showed no effects of ecstasy use on brain activation.
fNIRS is a non-invasive brain imaging technique that uses light to measure changes in blood flow in the brain. It is similar to fMRI but uses infrared light instead of magnetic fields to monitor brain activity. fNIRS is often used to study cognitive processes such as attention, memory, and language, as well as neurological conditions like stroke and brain injury.
fNIRS studies show that ecstasy users display changes in their brain activity, namely, differences in blood oxygenation in certain parts of the brain, but that this does not impact performance on cognitive tasks.
Most studies show increases in blood oxygenation in the brain that may be a consequence of ecstasy users increasing their cognitive effort to compensate for possible brain damage, with some researchers suggesting that such increases reflect a neurobiological change that manifests prior to any performance deficit.
Other studies show reduced blood oxygenation in ecstasy users which may be indicative of reduced cognitive effort. Alternatively, reduced oxygenation could be explained by MDMA-induced vasoconstriction — a narrowing of the blood vessels that reduces blood flow altogether — which has been observed in people when under the influence of MDMA and also in people who had been abstinent for prolonged periods.
The results of fNIRS studies indicate that there are changes in the neurobiology of individuals who use ecstasy. However, while most studies interpret these changes as an increase in effortful cognition that serves as a compensatory mechanism for underlying brain damage, there are other studies that show effects in the opposite direction (reduced blood oxygenation), which may be a consequence of reduced blood flow to certain areas of the brain due to vasoconstriction.
Furthermore, fNIRS studies cannot yet predict whether ecstasy users with increased brain activation will develop cognitive problems in the future. Therefore, suggestions of MDMA-induced neurological impairment must be interpreted with caution.
Scientists have used molecular imaging techniques, such as Single-Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET) scans, to study the impact of MDMA use on the brain's serotonin system.
PET and SPECT are imaging techniques that involve injecting a small amount of a radioactive substance into the body, which travels to the brain. The radioactive substance then emits particles that are detected by a scanner, creating images of the brain that can show metabolic activity, blood flow, and other functions. PET uses positrons, while SPECT uses gamma rays, to create the images.
By injecting participants with a radioactive tracer, researchers can measure the availability of serotonin transporter terminals (SERTs), which are proteins that transports serotonin back into the presynaptic neuron thus regulating serotonin signaling in the brain, and serotonin receptors, which are proteins located on the surface of neurons that binds to serotonin, leading to various cellular responses and modulating brain function and behavior.
A 2016 meta-analysis of multiple studies found that current MDMA users showed reduced SERTs in many brain regions, including the frontal cortex, hippocampus, and amygdala. Several earlier studies suggest that this SERT damage may be reversible after abstinence, with some evidence of recovery in former users. However, negative cognitive effects potentially attributable to MDMA neurotoxicity, such as impaired verbal memory, may persist, even if SERTs recover.
Studying the effects of MDMA on the brain presents a significant challenge to researchers for several reasons.
Principal among these is MDMA’s illegal status, which makes it more difficult for scientists to conduct clinical trials, and is one of the main reasons why very few studies investigating the effects of MDMA on the brain have ever been conducted.
Furthermore, ecstasy consumed by recreational users contains varying amounts of MDMA, and often contains adulterants which can lead to neurological harms. Additionally, recreational users often engage in polydrug use. In such cases, observed changes in brain activity may be attributed to other substances used by the participants or unrelated factors rather than MDMA.
Physiological and environmental factors can worsen the harmful effects of MDMA, too. For example, females may be more prone to negative effects due to the impact of hormones on pharmacokinetics, while specific genetic variations can impact the metabolism of MDMA and serotonin, resulting in neurological changes.
Moreover, the environmental conditions under which ecstasy is used, such as high temperatures and increased physical activity, can contribute to the severity of adverse effects.
These confounding factors make it challenging to draw definitive conclusions about MDMA’s effects on the brain.
Inadequate control for confounding factors in research can lead to inaccurate findings. To minimize the influence of extraneous variables, researchers need to carefully design their studies to account for as many confounding factors as possible. They must also select suitable participants and use strict methodologies to gather and analyze data. By doing this, researchers enhance the validity and reliability of their results, thus building confidence in their conclusions about how drugs affect the brain.
Future long-term studies with prospective MDMA users, including toxicological testing to identify recent use and adulterants and genotyping techniques to identify individual vulnerabilities, could better detect the magnitude of MDMA-related effects and understand their impact at the individual level.
The literature on the effects of MDMA suggests that taking ecstasy can lead to changes in brain structure and function. However, not many studies have been conducted, and most studies have small sample sizes and inconsistent definitions of ecstasy users. Additionally, the purity and quantity of the ecstasy used is often unknown, and further research is necessary to understand the impact of concomitant drug use and genetic factors on the changes in brain activity observed in ecstasy users.
The changes produced by repeated ecstasy use seem to be subtle and potentially reversible over time. Additional research is crucial to fully comprehend the effects of MDMA on the brain.
The dissemination of evidence-based drug science information and employment of harm reduction strategies can help to minimize the potential negative health effects of MDMA.
Due to the high variability of ecstasy and potential for the presence of dangerous adulterants, users are recommended to test their drugs using reagent test kits, which are chemical test kits used to identify the contents of unknown substances and detect the presence of adulterants or other contaminants, or, where possible, to have the substance analyzed by a laboratory.
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