Long-Term Effects of MDMA on Cognition

Overview: MDMA, also known as ecstasy or Molly, is a popular recreational drug with potential therapeutic benefits for mental health disorders. Clinical trials support MDMA-assisted psychotherapy for PTSD, but concerns about long-term cognitive effects exist. Recent research examines MDMA's impact on cognition, including declarative memory, prospective memory, executive function, spatial working memory, memory updating, and semantic memory. Findings suggest impairments in various cognitive domains, but confounding factors like polydrug use and adulterated ecstasy complicate interpretations. Challenges in studying MDMA's effects include its illegal status, adulteration, and polydrug use. Further research is needed to better understand MDMA's cognitive effects.

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Introduction to MDMA: Therapeutic and Long-term Concerns 

MDMA, also known as “ecstasy” or “Molly,” is a popular recreational drug of the “entactogen”or “empathogen” class that has been used for decades for its euphoric, prosocial, and empathy-promoting properties. 

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However, in recent years, there has been growing interest in the therapeutic potential of MDMA for treating mental health disorders such as post-traumatic stress disorder (PTSD). Several clinical trials conducted by the Multidisciplinary Association for Psychedelic Studies (MAPS) have demonstrated the efficacy of MDMA-assisted psychotherapy for reducing symptoms of PTSD, leading to its recent designation as a breakthrough therapy by the Food and Drug Administration (FDA).

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Despite its apparent therapeutic benefits, concerns have been raised about the potential long-term cognitive side effects of MDMA, including potential impairments in memory and executive function — the set of mental skills that enables people to plan, organize, focus attention, remember details, and manage time and space effectively in order to achieve a specific goal.

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Recently, researchers Catherine Montgomery and Carl Roberts from University of Liverpool and John Moores University, respectively, conducted a detailed examination of the impact of MDMA use on human cognition. Their analysis sheds light on the potential long-term cognitive effects of the drug and emphasizes the necessity for additional research to be conducted in this area.

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In this blog, we will explore the findings regarding the effects of MDMA on cognition, examining the latest research on this topic and discussing how confounding factors such as polydrug use and adulterated street ecstasy can influence the outcome of studies.

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Long-term Effects of MDMA in Recreational Users 

A variety of research domains have evaluated the long-term impacts of MDMA administration in laboratory animals. According to a recent systematic review of animal studies investigating the effects of MDMA on cognitive function, it was concluded that there was no long-term effect on cognitive function from doses less than 3 mg/kg, and only limited evidence of impairment in studies using larger doses.

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However, while the evidence from animal studies for cognitive deficits is weak, the authors caution that factors such as drug purity, environmental conditions, and concomitant use of other substances (polydrug use) in human recreational users may result in a different type of impairment than that those observed in preclinical animal studies.

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Studies examining cognitive impairments in individuals who use ecstasy in combination with other drugs originate from earlier psychopharmacological animal studies that demonstrated the critical role of serotonin receptors in the prefrontal cortex for carrying out numerous higher-order cognitive tasks.

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Long-term Effects of MDMA on Declarative Memory 

Studies show that recreational MDMA polydrug users commonly experience problems with declarative memory, which roughly refers to the ability to consciously recollect facts, events, and knowledge that can be expressed verbally, such as remembering the capital city of a country or recalling a childhood memory.

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Notably, these deficits are more severe in people who use MDMA frequently and in higher doses. However, some studies have shown that even infrequent users of MDMA can experience deficits in immediate and delayed recall of words and prose.

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The cause of these impairments is believed to be depleted serotonin, but some studies show that the deficits occur only during MDMA use and do not persist beyond the drug’s action. Interestingly, there is also some evidence to suggest that these deficits don't improve with prolonged abstinence, meaning they may be long-lasting.

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Long-term Effects of MDMA on Prospective Memory 

Mongomery and Roberts also found that recreational MDMA polydrug use can cause problems with prospective memory, which is the ability to remember to perform a planned action or intention at a future point in time, such as remembering to take medication at a specific time or remembering to meet a friend for lunch. Prospective memory involves forming and retaining an intention, monitoring the environment for appropriate cues, and initiating the intended action at the appropriate time.

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Some studies have shown that long-term MDMA polydrug users have trouble with prospective memory, particularly those who use MDMA frequently or those who use other drugs like cannabis. Other studies have found that higher doses of MDMA in a single session are more harmful than lifetime use, while some found no negative effects of MDMA polydrug use on prospective memory at all. 

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Interestingly, improvements in prospective memory have been seen with abstinence from MDMA.

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Upon review of the available evidence, it seems that individuals who consume MDMA experience cognitive impairments in prospective memory. However, further research is necessary to account for the influence of other substances on these outcomes.

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Long-Term Effects of MDMA on Executive Function

Recreational ecstasy use is associated with impairments in executive function, which refers to a set of cognitive processes that enable people to plan, organize, initiate, and execute complex behaviors and goal-directed actions. These processes involve the ability to monitor and control one's own behavior and thought processes, adapt to changing situations, and maintain attention and focus.

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Executive function involves complex cognitive processes controlled by the prefrontal cortex (PFC), a part of the frontal lobe of the brain that is located at the front of the cerebral cortex, just behind the forehead. The PFC contains 5-HT2A serotonin receptors, which are important for executive function and can be damaged by chronic ecstasy use. Damage caused to these receptors by chronic use may contribute to executive dysfunction. 

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Some recreational ecstasy users show deficits in executive function tasks, but others do not. For example, inhibitory control (the ability to stop oneself from acting impulsively and to resist distractions) does not seem to be affected by MDMA use.

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Furthermore, studies using the Stroop task, Random Letter Generation, and Go/NoGo paradigms —cognitive tasks commonly used in psychology research to assess different aspects of cognitive functioning — do not report MDMA-group differences relative to controls.

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Likewise, studies on task switching (the ability to switch between two or more different tasks or mental activities), show mixed results, with some studies reporting lower scores for recreational ecstasy users but not all.

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Although group differences were not consistently observed in the different studies, a recent meta-analysis that combined and analyzed all of the data found that recreational ecstasy users exhibited significant impairment in set switching — the ability to switch between different mental sets or rules, such as switching from categorizing objects by shape to categorizing them by color — compared to nonusers. 

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Long-term Effects of MDMA on Spatial Working Memory 

Spatial working memory refers to the ability of an individual to remember and navigate through physical spaces or environments. It is the mental representation of the physical layout of objects in space and the relationships between them. Spatial working memory is an essential component of our daily lives, as it enables us to find our way around, remember the location of objects, and navigate through familiar or unfamiliar environments

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Early studies found that recreational MDMA use may impair spatial working memory, and that the degree of impairment is linked to the dose and frequency of use. However, a systematic review published in 2021 found contradictory evidence regarding the effect of ecstasy on visuospatial working memory, and emphasized the need for further research in this area. 

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Better controlled studies are needed to better understand the relationship between recreational MDMA use and spatial memory.

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Long-term Effects of MDMA on Memory Updating

Memory updating is a cognitive process that involves the ability to modify, replace, or remove information in working memory. It is crucial for tasks that require flexible thinking and adapting to changing demands, such as problem-solving, decision-making, and planning. It involves the coordination of various brain regions, including the prefrontal cortex. 

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Recreational ecstasy users show consistent impairments in letter updating, a task used to assess working memory and cognitive flexibility that involves the presentation of a sequence of letters, followed by a target letter, and the individual is required to indicate whether the target letter is the same or different from the last letter presented in the sequence. Higher levels of use are related to poorer performances on such tasks. 

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Recreational MDMA users have also been observed to perform worse than control participants on computation span, which is the process of holding a sequence of items in memory while simultaneously performing some type of cognitive operation or manipulation on that information. As with letter updating, the impairments seem to increase with higher levels and frequency of recreational MDMA use.

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However, less demanding updating tasks such as the digit span backwards task —  a cognitive task in which a participant is presented with a sequence of digits, one at a time, and is instructed to recall them in reverse order immediately after presentation — show no differences between ecstasy users and non-users.

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Additionally, a study involving complex memory-updating tasks did not find any differences between ecstasy users and non-users. However, oxygenated and deoxygenated hemoglobin in areas of the prefrontal cortex did significantly change in the ecstasy group, leading the authors to hypothesize that this may be because they were working harder than the non-ecstasy group. 

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Long-term Effects of MDMA on Semantic Memory 

Semantic memory is a type of long-term memory that contains our general knowledge and understanding of the world, including concepts, facts, and meanings of words and symbols. It is the memory system that allows us to recognize and understand the meanings of words, objects, and concepts and to retrieve information about the world that is not tied to specific events or experiences.

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Studies using written word fluency tests to assess access to semantic memory have shown that ecstasy users perform worse than non-users, especially as task difficulty increases. The severity of the impairment appears to increase with the level of ecstasy.

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However, oral versions of the test show less impairment, possibly due to lower demands on the brain's prefrontal cortex. Many studies that employed simpler oral versions of this test have found no impairment, but other studies have shown deficits in heavy or problematic ecstasy users.

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To sum up, the ability to retrieve information from semantic memory seems to be impacted under conditions of high task complexity, as well as in situations where other variables like chronic use of MDMA may be present.

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Challenges to Researching the Effects of MDMA 

Researchers studying the effects of MDMA face challenges due to the drug’s illegal status, which makes it more difficult for researchers to obtain the drug to perform controlled trials and investigate its effects on cognition. At this stage, there are limited studies on the long-term cognitive effects of MDMA use despite the relatively high number of global recreational MDMA users.

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In addition, street ecstasy is often adulterated with other drugs or substances, such as caffeine, methamphetamine, or paramethoxymethamphetamine (PMMA), making it difficult to determine the specific effects of MDMA on cognition. Adulteration of the drug can also lead to unpredictable variations in the dosage, purity, and composition of the substance, which can further complicate research efforts.

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Furthermore, polydrug use is common among recreational MDMA users and can worsen cognitive impairments. Only a few studies investigating the effects of ecstasy on ecstasy-only users have been conducted to date, and, as a result, the observed cognitive alterations in human users are likely to be a product of polydrug use, and some combinations of drugs are believed to be more toxic than others. 

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Several other factors physiological and environmental factors can worsen the harmful effects of MDMA, including individual differences in pharmacokinetics, the impact of hormones on pharmacokinetics, specific genetic variations, and the environmental conditions under which ecstasy is used may contribute to the severity of cognitive effects, with high temperatures and increased physical activity being particularly significant factors.

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Montgomery and Roberts argue that in the future, it would be helpful to conduct more long-term studies in order to better understand the cognitive changes that occur over time. These studies could include toxicological testing to confirm recent use and identify the presence of adulterants and polydrug use, the researchers suggest, as well as genotyping techniques that could help identify individual vulnerabilities to MDMA-related cognitive changes. By doing so, researchers can better detect the magnitude of MDMA-related effects and understand the effects of ecstasy/MDMA use at the individual level.

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Closing Insights: MDMA's Influence on Memory and More

In summary, understanding the long-term effects of MDMA on cognition is a complex issue.

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While animal studies hint at minimal impact at lower doses, human users—especially frequent and high-dose consumers—might encounter challenges in various cognitive domains. These include declarative memory, prospective memory, executive function, spatial working memory, memory updating, and semantic memory. The complexity of these effects is compounded by factors like polydrug use, environmental conditions, and the uncertainty of street ecstasy composition.

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Despite the FDA acknowledging MDMA's therapeutic potential, a comprehensive understanding of its nuanced cognitive effects requires ongoing, controlled, and long-term research. Researchers stress the need to consider confounding factors, conduct toxicological testing, and explore genotyping techniques for a deeper understanding at both group and individual levels.

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As MDMA gains recognition for therapeutic use, ongoing research becomes crucial for assessing and managing potential cognitive consequences.