MDMA and the “Ecstasy Paradigm”

This review (2014) examines the lack of evidence to support the notion that MDMA causes widespread cognitive deficits among its users and critiques a prevalent ‘ecstasy paradigm’ which exaggerates the negative effects of this substance, sustains publication bias by ignoring methodological shortcomings of their study design, and disregarding its therapeutic potential. Although MDMA poses risks to its users, there is no wide-scale evidence to suggest that its users have been damaged, a matter of fact according to the author, which requires no further empiric investigation but a more critical analysis of the already existing evidence.

Abstract

“For nearly 30 years, there has been a steady flow of research papers highlighting the dangers of MDMA and the implications for ecstasy users. After such a long time, it would be reasonable to expect that these dangers would be obvious due to the large number of ecstasy users. The available evidence does not indicate that there are millions of ecstasy users experiencing any problems linked to their ecstasy use. The “precautionary principle” suggests that, in the absence of knowing for certain, “experts” should argue that MDMA be avoided. However, this may have been taken too far, as the dire warnings do not seem to be reducing with the lack of epidemiological evidence of clinically relevant problems. The “ecstasy paradigm” is one way of articulating this situation, in that the needs of research funders and publication bias lead to a specific set of subcultural norms around what information is acceptable in the public domain. By digging a little deeper, it is easy to find problems with the evidence base that informs the public debate around MDMA. The key question is whether it is acceptable to maintain this status quo given the therapeutic potential of MDMA.”

Author: Jon C. Cole

Summary

INTRODUCTION

Research into controlled drugs is not conducted from a neutral standpoint, and the media have a fascination with ecstasy. A journalist misread a discussion piece about ecstasy and created a media storm, which was widely repeated around the world. After the media circus had left town, a study was published that claimed that MDMA “caused” Parkinson’s disease in primates. It was later discovered that the primates had actually received methamphetamine.

Two events occurred after the release of MDMA, and they are important for our understanding of the risk posed by MDMA.

Most people believe that in order to obtain research council funding, you have to focus on the danger posed by MDMA/ecstasy use. However, it is important to understand that the human use of ecstasy is not as straightforward as young people popping pills in nightclubs.

The short- and long-term risks posed by the use of MDMA need to be identified. The research evidence on MDMA is not fit for purpose.

Publication Bias

The publication of studies examining MDMA/ecstasy is free of systematic bias, because researchers often do not attempt to publish studies that show negative results, and because anonymous peer review prevents the publication of negative results.

Lack of Replication

Studies on the long-term effects of ecstasy in humans are non-existent. To replicate findings, you need to compare at the level of individual tests of psychological functioning, but this may not be a simple comparison given the methodological problems discussed below.

Investigating the failure to replicate findings is difficult because many research articles do not report the failure to replicate results.

Methodological Problems

Methodological weaknesses in studies of long-term effects of ecstasy use in humans include intoxication at the time of testing, the after-effects of drug use at time of testing, sleep deprivation, circadian disruption, nutritional deficiencies, pre-morbid psychiatric problems, and polysubstance misuse.

PRE-CLINICAL PHARMACOLOGY

MDMA can produce long-term changes in the structure and function of the brain in a variety of species, but the term “neurotoxic” is rarely defined with any precision, and there are very few studies that have looked at the effects of MDMA beyond a few weeks after administration.

PRE-CLINICAL BEHAVIORAL PHARMACOLOGY

The literature on the pre-clinical behavioral pharmacology of MDMA indicates that serotonergic changes observed after MDMA administration are not large enough to reliably produce changes in behavior.

INTERSPECIES DOSE SCALING

Interspecies dose scaling has been debated, with some authors arguing that “neurotoxic” doses used in animal work are comparable to those ingested by human users, while others have argued that a dose that produces distinct behavioral effects is a more suitable dose for interspecies dose scaling.

To my knowledge, there is no established LD50 for MDMA administered orally to humans. However, doses of 125 mg and 1.7 mg/kg have been administered to volunteers without reporting adverse reactions.

ECSTASY TABLET COMPOSITION

Ecstasy tablets are typically sold with identifiable features, such as colors and imprinted designs. Although the contents of these tablets vary dramatically, even within tablets that have the same brand name, this suggests that tablets from different sources are being sold under the same brand name.

Researchers often equate the number of ecstasy tablets taken with an exact dose of MDMA, but this is flawed and likely to be misleading.

ECSTASY TABLET PURCHASING PATTERNS

Winstock and colleagues (2001) found that the average number of ecstasy tablets purchased by 1,106 ecstasy users was eight, and that 76.3% purchased less than five at once, 17.5% bought between five and 10, 3.1% bought between 10 and 15, 1% bought between 20 and 25, and 1% bought over 50 tablets.

Almost all ecstasy users have sold drugs in the past, and most have purchased ecstasy for a friend. Almost all have also sold ecstasy themselves.

Ecstasy users are not purchasing large amounts of ecstasy for their own use, and those purchasing large amounts are most likely to be selling ecstasy, regardless of their own ecstasy use.

ECSTASY TABLET CONSUMPTION

Ecstasy users typically consume between two and three tablets over a 24-hour period (usually Friday or Saturday night), and one participant used 15 and one used 10 tablets regularly.

Ecstasy users typically use ecstasy every weekend, but a few individuals use it more frequently. Scholey and colleagues (2004) found that only 9% of ecstasy users had used a maximum of 10 or more tablets in a week, and Fox and colleagues (2001a) found that the average intake was less than four tablets.

Winstock and colleagues (2001) found that the overwhelming majority of ecstasy users took four or less tablets during a session, with a minority reporting taking 10 or more tablets.

Hammersley and colleagues (1999) interviewed 229 ecstasy users and found that erratic users used more ecstasy than stable users, but that bingeing on ecstasy for extended periods of time is rare and the number of tablets consumed per day is similar to that used in discrete use episodes.

An individual with severe psychiatric and psychological problems self-reported using 25 tablets a day for a number of years. However, this self-reported data is likely to be exaggerated.

A small number of ecstasy users occasionally ingest large numbers of tablets per week, and this may be explained by the high variability of quality in the ecstasy market.

Every study published to date has relied on participant self-report to quantify ecstasy use. However, self-report is subject to both over- and under-reporting bias, particularly in a criminal justice context, and MDMA and other controlled drugs are associated with memory problems. Thomasius and colleagues (2003) found a 95% concordance between self-reported ecstasy use and the results of hair testing in 30 ecstasy users, whereas Semple and colleagues (1999) found no traces of MDMA or related drugs present in two of their 10 users.

Taken together, these studies indicate that the overwhelming majority of ecstasy users are consuming less than four tablets during a 24-hour period. The rare individuals who binge on ecstasy self-report high maximum numbers of tablets ever taken in a week.

The evidence to support the argument that “heavy” ecstasy users are at risk is lacking, as most users are exposing themselves to low doses of MDMA and sharing their tablets among their friends or selling them.

FATAL ADVERSE REACTIONS

Despite the fact that there is no acknowledged LD50 for MDMA administered orally to humans, there have been many discussions of fatal adverse reactions to MDMA. However, the number of fatal adverse reactions to MDMA ingestion is extremely low compared to other controlled drugs.

TOLERANCE

Ecstasy users self-report that they have increased the number of tablets that they consume to compensate for a diminished effect. However, there are no laboratory studies of tolerance to MDMA in humans, and the effects of MDMA in animals are inconsistent.

Ecstasy users begin by taking small amounts of ecstasy, and then, as they become more experienced, they take more tablets over the same time period. The subjective effects of taking MDMA would also diminish across time as the novelty wears off and expectancy effects diminish.

Ecstasy tablets are highly variable, and this variability is likely to influence the experiences of regular ecstasy users. There are no data available that indicate the changes in the content of all ecstasy tablets available in local drug markets.

Ecstasy users are not regularly using MDMA at a high enough dose for a long enough period of time to develop tolerance. This suggests that users are not developing the level of tolerance observed in heroin users.

DEPENDENCE

MDMA is self-administered by animals, but the self-administration is not very robust and the amount of effort animals will exert in order to obtain MDMA is low. MDMA is unlikely to be a drug of dependence like alcohol, cocaine, and heroin.

The number of ecstasy users presenting to Specialist Drug Agencies within the EU is small, despite very large numbers of users, and it is not specified what disorders these ecstasy users are requiring treatment for and/or what other drugs are involved. However, there are sporadic reports of some individuals developing dependence problems with their use of MDMA.

There is no evidence that ecstasy users become dependent upon MDMA, and there are no significant numbers of ecstasy users presenting for treatment to SDA.

DENOVO PSYCHIATRIC PROBLEMS

Research into the long-term effects of MDMA/ecstasy use has found that some ecstasy users have elevated psychiatric symptomatology. However, it is not known whether any psychiatric problems observed in ecstasy users were present prior to the initiation of ecstasy use.

Many studies exclude participants with a history of psychiatric disorders, but it is rarely reported that any participants were excluded because of their psychiatric disorder. This suggests that ecstasy use is not causing psychiatric problems.

COGNITIVE DEFICITS

Research into the long-term effects of MDMA/ecstasy use has focused on cognitive deficits hypothesized to result from MDMA “neurotoxicity”. However, retrospective studies of ecstasy users are unable to discriminate the impact of individual drugs due to the simultaneous and/or sequential use of numerous controlled drugs.

There is substantial literature indicating that interpretations of cognitive performance can be influenced by expectancy effects and contextual factors, such as whether the participants believe others have made similar identifications, regardless of accuracy. Page and Handley (1993) found that dispelling myths about the negative effects of hypnosis was effective in reducing subjective reports of long-term negative sequelae following participation in hypnosis.

The social stigma of intellectual inferiority ascribed to some groups within society may contribute to their poor performance on tests, and this may reinforce the perception of intellectual inferiority. Ecstasy users may be experiencing stereotype threat, and this may be a greater problem than is currently believed.

There is a belief that ecstasy use causes cognitive deficits, but most users have not experienced them. The evidence is fraught with methodological problems, and the media attention given to this evidence may be contributing to the problems observed.

SUMMARY AND CONCLUSIONS

The current “ecstasy paradigm” is distorting our understanding of the short- and long-term effects of MDMA, because too many researchers are drawing conclusions without thinking about whether their findings support such conclusions.

MDMA poses a risk to users, but the evidence is distorted by the “ecstasy paradigm”. There is no sound evidence that many users have been damaged by their ecstasy use.

As an ecstasy researcher, I am likely to say that more research is needed, but I do not agree with the need for more flawed experiments.