Introductory Comments by Rick Doblin, Ph.D.
to
Does Ecstasy Cause Memory Deficits?
A Review of Studies of Memory Function in Ecstasy Users
Conducted for MAPS
by Alex Gamma, Ph.D.
	
MAPS' Mission
	MAPS sponsors government-approved scientific research on the risks and benefits 
of MDMA, other psychedelics and marijuana. MAPS' primary goal is to develop
these 
drugs into FDA-approved medicines to treat patients suffering from a variety of medical 
conditions. MAPS also has an educational mission and seeks to provide non-medical users 
of these drugs with accurate, balanced scientific information about potential risks and 
benefits associated with the use of these drugs in non-medical contexts.
	 In addition to sponsoring original research, MAPS continuously reviews and 
analyzes the published scientific literature on psychedelics and marijuana. Much of the 
human research is conducted on non-medical users and provides information about the 
risks of non-medical use. Through extrapolation, research conducted with non-medical 
users can also generate useful data about the risks faced by subjects in clinical research 
studies investigating the therapeutic potential of these drugs. In most cases, however, risks 
identified in studies of non-medical users of illicitly manufactured drugs taken in 
recreational settings are likely to overestimate the risks faced by patients administered pure, 
measured doses in controlled, clinical contexts. 
	
MDMA and Memory Research
	The most controversial area of research with MDMA involves the issue of MDMA 
neurotoxicity and the possibility of functional or behavioral consequences that may result 
from such neurotoxicity, if it does indeed occur at the dose levels actually consumed. 
Persisting, long-term reductions in serotonin levels after exposure to MDMA have been 
confirmed in animal studies. In human studies, groups of heavy MDMA users have been 
found, on average, to have somewhat lower serotonin levels than control groups. It 
remains uncertain whether these differences are due to MDMA or pre-existing differences 
between the subjects in the groups. Fortunately,  most studies in animals and in humans 
have failed to identify clinically significant functional or behavioral consequences resulting 
from the use of substantial doses of MDMA. Several animal and human studies have, 
however, suggested that certain subtypes of memory may be negatively impacted in people 
who have used MDMA on a frequent basis. 
	The special report that follows, written for MAPS by Alex Gamma, Ph.D., focuses 
on human studies that have investigated the possibility that substantial non-medical use of 
MDMA could have a long-term deleterious impact on memory.  The report concludes that 
the research studies conducted to date do suggest, but do not conclusively prove, that the 
use of MDMA, in certain amounts and frequencies, may negatively impact some aspects of 
memory function. 
	The studies seeking to analyze the impact of the frequent recreational use of MDMA 
on memory have produced only tentative conclusions,  primarily because of the 
methodology of the studies that have been conducted. The studies reviewed by Gamma 
involved the comparison of memory function in groups of poly-drug users who have also 
self-administered MDMA with memory function of matched controls who have not used 
MDMA. Studies of this design involve an inherent methodological weakness based on the 
difficulties in matching control subjects to the MDMA-using subjects on all relevant 
characteristics that may affect the primary outcome variable, in this case memory. Due to 
the difficulties in obtaining perfectly matched controls, it is impossible to rule out pre-
existing differences in memory that have nothing to do with MDMA. It is also possible that  
pre-existing differences may have had an impact on the decisions of the MDMA-using 
subjects to try MDMA in the first place and to continue its use in substantial amounts.

Ethical Aspects of a Prospective Study
	The study design that can most conclusively investigate the impact of MDMA on 
memory would be a prospective study in which MDMA-naive subjects were administered 
memory tests before and after exposure to a substantial number of doses (for example, 
>20) of pure MDMA in a clinical setting. In a design of this type, subjects would serve as 
their own controls, eliminating the possibility of confounded results due to pre-existing 
differences between the MDMA group and an imperfectly matched control group. Yet 
government regulatory agencies and the Institutional Review Boards that review studies to 
ensure that they are safe to human subjects are not likely to approve a study designed 
specifically to see if a substantial number of doses of MDMA will have a harmful effect on 
the memory function of healthy subjects.  On the other hand, studies of the therapeutic use 
of MDMA in patients are most likely to involve the administration of only one to three 
doses of MDMA. Based on Phase 1 MDMA safety studies already conducted in healthy 
volunteers, this amount of MDMA is almost certainly not enough to produce clinically 
significant amounts of neurotoxicity or any long-term impact on memory, even if more 
frequent use of MDMA would indeed produce such effects. Given these ethical and 
methodological issues and limitations, a definitive answer to the question of whether or not 
substantial use of MDMA has a deleterious effect on memory is not likely to be produced 
any time soon. 
	There is, however, one study design that I think could pass ethical review and 
could generate useful information about the effect of multiple doses of MDMA on memory. 
This design would involve the administration of memory tests to several hundred young 
people who had not yet taken MDMA but were seriously considering doing so in non-
medical, recreational contexts at some point in the future. There are currently many 
hundreds of thousands of people every year who do take MDMA for the first time, so 
finding several hundred people who say they might do so would not be difficult. The 
subjects in the study would be administered memory tests in order to obtain a baseline 
measure of their memory performance. Subjects would be retested again after three to five 
years. The researchers would not administor MDMA to these subjects in a clinical setting 
but would rather instruct the subjects to keep a drug diary recording the drugs that they did 
consume during the period of years between the first and subsequent memory tests. Some 
subjects would have chosen to try MDMA and some would have chosen not to do so. The 
memory scores of the subjects who chose to take MDMA would be examined to determine 
if there had been any changes before and after the consumption of MDMA. These subjects 
would provide the most important direct data on the impact of MDMA on memory function. 
The subjects who chose not to take MDMA would serve as a control group and would 
provide information on whether their memory scores changed over time for reasons other 
than the use of MDMA.
	This study design is not perfect.  Since those subjects who chose to take MDMA 
would be limited to illicit supplies, it is not definite that they were taking pure MDMA, or 
indeed any MDMA at all. Furthermore, it is possible that other factors associated with 
taking MDMA, perhaps the rave lifestyle that can involve poly-drug use and prolonged lack 
of sleep, would have an impact memory performance, thus confounding the results. 
Though not the last word on the subject, this study would still generate important and 
useful data, more reliably than all the restrospective studies comparing MDMA users to 
supposedly matched controls.
	The major ethical criticism of this design is that participating in the study might 
promote drug use. While an argument could be made that enrolling in the study might 
encourage the subjects to use MDMA more than they otherwise might have done if they had 
not been part of the study,  this hypothetical outcome is certainly open for debate. 
	Dr. Alan Leshner, Director of the National Institute on Drug Abuse (NIDA) and 
Gen. Barry McCaffrey, who recently resigned as Director of the Office of National Drug 
Control Policy (aka the Drug Czar), have stated on several occasions that the primary 
reason that the use of MDMA has increased so dramatically in the past several years is that 
young people think MDMA is harmless. Yet in any study involving human volunteers, 
subjects must sign an Informed Consent Form that outlines the risks of the experiment in 
which they are about to participate. Though the researchers would not be administering 
MDMA, the Informed Consent Form would still need to list all the possible risks to the 
subjects from taking MDMA. The subjects in the study who are thinking of taking MDMA 
would thus be exposed to a detailed elaboration of the potential risks of MDMA, in a 
document that was carefully prepared. This written document would certainly dispel any 
illusions that the subjects might have that taking MDMA was completely risk-free. It is 
therefore quite possible that participation in the study would dissuade many of the subjects 
from ever trying MDMA in the first place, thus reducing rather than increasing the use of 
MDMA by the subjects in the study. The argument that the study will increase drug use 
among its participants is based on questionable assumptions and is not, in my opinion, a 
solid ethical argument against conducting the study.
	 There is also a powerful ethical argument for conducting the study.  There is at 
least some possibility that the millions of current MDMA users are placing some aspects of 
their memory function at some degree of risk.  Yet at present, many users of MDMA either 
distrust or discount the warnings about the risks of MDMA that they hear from government 
sources. This is in part due to the preliminary and potentially confounded nature of the data 
on risks and in part due to the exaggerated and shrill bombast of the anti-ecstasy message 
that equates all use with abuse and blurs the distinctions between consumption of one or 
several doses with consumption of hundreds of doses.  In such circumstances, an 
argument can be made that it is ethically justified to ask a few hundred people to volunteer 
for a research project that will generate the most credible and persuasive data  about the 
risks of actions that they are considering undertaking anyway (consuming MDMA) and that 
millions of MDMA-users are already exposing themselves to without the benefit of the 
high-quality data that can be generated by a prospective study.
	 
Conclusion
	The review of the MDMA and memory studies by Gamma indicates that there exists 
a possibility that frequent use of MDMA may have a persisting deleterious effect on certain 
components of memory function.  Prospective studies that do not rely on the 
methodologically weak use of imperfectly matched control groups will be necessary to 
clarify whether this risk is indeed genuine. A prospective study with several hundred 
subjects can cost about $250,000, which MAPS still needs to raise.  If there are any 
interested donors, please contact me.
At present, our government considers all use to be abuse worthy of criminal 
sanctions.  If people choose to take MDMA regardless of the legal consequences, it would 
be wise for them to minimize the possibility of risk by considering the consumption of 
lower doses of MDMA used less frequently.  It would also be wise to confine the use of 
MDMA to environments and with companions that are likely to maximize the beneficial 
aspects of the MDMA experience. 
	MAPS will continue to devote its energies to sponsoring  and reviewing research on 
both the medical and non-medical uses of MDMA.  MAPS seeks to enable people to make 
informed decisions regarding whether to consume MDMA, thus taking responsibility for 
their own lives.  This careful review by Alex Gamma of the studies evaluating the impact of 
MDMA on memory performance is an important contribution to that effort.

Rick Doblin, Ph.D.
MAPS President
November 21, 2000