A Clinical Plan for MDMA (Ecstasy)
in the Treatment of Post-Traumatic Stress Disorder (PTSD):
Partnering with the FDA
by Rick Doblin, Ph.D.
[ Note:
This paper was originally published in the Journal of Psychoactive
Drugs, 34 (2), 2002: 185-194. Since its publication, the MAPS-sponsored Spanish
MDMA/PTSD pilot study was shut down after six subjects had been successfully
treated, with some suggestion of benefit and no lasting negative effects. The
Madrid Anti-Drug Authority, in response to positive reports about the study that
appeared in the Spanish media, pressured the hospital into withdrawing
permission for the study. The Ministry of Health has not withdrawn permission, so we
hope that after the US MDMA/PTSD protocol has been fully approved, it will
become possible for the Spain study to be resumed. For more information on the
Spain study, see:
http://www.maps.org/research/mdma/spain/index.html. ]
Abstract: The FDA and the Spanish Ministry of
Health have concluded that the risk/benefit ratio is favorable under certain
circumstances for clinical studies investigating MDMA-assisted psychotherapy. Both
agencies have approved pilot studies in chronic posttraumatic stress disorder
(PTSD) patients who have failed to obtain relief from at least one course of
conventional treatment. These studies, the only ones in the world into the
therapeutic use of MDMA, are being funded by a non-profit research and
educational organization, the Multidisciplinary Association for Psychedelic Studies
(MAPS, www.maps.org). A rationale is offered explaining why MAPS chose to focus
its limited resources on MDMA, and also on PTSD patients. A Clinical Plan is
elaborated for the conduct of the "adequate and well-controlled"
trials necessary to evaluate the safety and efficacy of MDMA-assisted
psychotherapy for PTSD, with the studies estimated to cost about $5 million
dollars and to take about 5 years. The Clinical Plan has been developed, in
part, through analysis of the studies conducted by Pfizer in its successful
effort to have Zoloft approved by the FDA for use with PTSD patients, and
through review of transcripts of the FDA's Psychopharmacologic Drugs Advisory Committee
meeting that recommended approval of Zoloft for PTSD.
The
Multidisciplinary Association for Psychedelic Studies (MAPS, www.maps.org),
a membership-based non-profit research and educational organization, is
sponsoring a series of studies designed to develop MDMA into an FDA-approved
prescription medicine, initially for the treatment of post-traumatic stress
disorder (PTSD). MAPS is currently sponsoring a pilot MDMA dose-escalation
study in Madrid, Spain with PTSD patients, conducted under the direction of Dr.
Pedro Sopelana and Jose Carlos Bouso, Ph.D. candidate (Sopelana & Bouso
1999). This is the world’s only on-going study of the efficacy of MDMA-assisted
psychotherapy. On November 2, 2001, a
MAPS-sponsored study under the direction of Dr. Michael Mithoefer was approved
by the FDA, with Institutional Review Board (IRB) approval in process
(Mithoefer & Wagner 2001). MAPS is also working to sponsor an MDMA/PTSD
study in Israel, under the direction of Dr. Moshe Kotler.
This paper elaborates a five-year, $5 million
Clinical Plan outlining a proposed sequence of studies to investigate
MDMA-assisted psychotherapy in the treatment of PTSD. This Clinical Plan starts
with pilot studies and concludes with two FDA-required “adequate and well
controlled investigations” of safety and efficacy. This discussion outlines a
strategy for developing MDMA into an FDA-approved prescription medicine. A series of regulatory, ethical and
methodological issues for the investigation of psychedelic psychotherapy in the
context of FDA-approved clinical trials, which form the basis for the Clinical
Plan, are discussed in detail in the context of my Public Policy dissertation
(Doblin 2001).
Given
the political and scientific hurdles, a rational analysis of the likely return
on investment would probably not inspire any venture capitalists to invest
their risk capital into the development of MDMA as a prescription medicine.
MDMA is off patent, PTSD or any other psychological disorder for which MDMA
might be effective affect more than 200,000 people so that patent protection
under FDA’s Orphan Drug program cannot be obtained, and the political hurdles
due to MDMA’s non-medical use may not be surmountable within any time frame
that an investor would consider realistic. Though the for-profit approach for the development
of MDMA as a prescription medicine is of questionable viability, the non-profit
approach is more likely to succeed. There are probably enough philanthropists
who, from personal experiences or otherwise, appreciate the political,
scientific and medical importance of supporting the struggle to develop MDMA
into a legal prescription medicine.
This
discussion begins by evaluating the strategic advantages associated with the
conduct of FDA-approved research with MDMA for PTSD, as compared to other
psychedelics that could be used for psychotherapy and other potential patient
populations. Proposed protocol designs and sample sizes for the studies
evaluating the potential use of MDMA in the treatment of PTSD are based in part
on a review of documents pertaining to Pfizer’s successful development of
Zoloft into the first FDA-approved medicine for the treatment of PTSD. These
documents were obtained from FDA by the author through Freedom of Information
Act (FOIA) request. A FOIA request for FDA documents related to its approval of
Paxil for PTSD is still pending.
The
primary strategic issue in conducting psychedelic psychotherapy research is
estimating the probabilities of success in the FDA drug development and
approval process of the numerous combinations of any of the psychedelic drugs
and patient populations. Psychedelic drugs, though each with a unique set of
actions and side effects, all serve the generally similar function of
increasing access to psychological, emotional processes. As a result, psychedelics can be used
as general purpose adjuncts to psychotherapy, in the treatment of many
conditions for which people seek out psychotherapy or psychiatric treatment.
The limited resources available to fund psychedelic psychotherapy research make
it essential to chose the best test case of a specific psychedelic drug used in
treating a specific clinical indication.
Why
MDMA?
On the one hand, the psychological
safety profile of MDMA is superior to that of all the other psychedelics. MDMA
is relatively short acting with primary effects lasting only about 4 hours with
gradual return to baseline over the course of another 2 hours or so. MDMA
rarely interferes with cognitive functioning or perception and usually produces
a warm, emotionally grounded feeling with a sense of self-acceptance, and a
reduction of fear and defensiveness. Subjects under the influence of MDMA can
usually “negotiate” with their emergent psychological material and often retain
the ability to move at will toward or away from certain thoughts or emotions.
In contrast, LSD lasts 8 to 10 hours, interrupts rational cognitive processes,
impacts perception, requires surrender to inner emotional processes rather than
permitting negotiation, and can result in feelings of loss of control, fear and
panic, as well as more positive emotions. All the major psychedelics such as
psilocybin, mescaline, ibogaine, DMT, etc., resemble LSD more so than they
resemble MDMA. Even the effects of marijuana are more similar to the classic
psychedelics than to MDMA.
In
terms of therapeutic potential, MDMA is remarkable effective, gentle yet
profound. Because it operates on emotions more so than cognitive processing,
the MDMA state is only subtly different than normal. As a result, the thoughts
and emotions of the MDMA state can be easily remembered after the effects of
the drug have worn off, facilitating integration and long-term growth. Due to
its relative short-acting duration and its gentle action, MDMA has the greatest
opportunity of any psychedelic to be integrated into psychiatric practice. The
classic psychedelics can be equally or even more therapeutic but in different
ways and with greater personal struggles required of patients and therapists.
On
the other hand, the physiological safety profile of all the classic
psychedelics is superior to that of MDMA. The extreme position on risk is
expressed by Dr. Alan Leshner, ex-Director of the National Institute on Drug
Abuse (NIDA), who claims that “There is no safe way to use any of these drug
[such as MDMA],” (Mertl 2000) that “even experimenting with club drugs [such as
MDMA] is an unpredictable and dangerous thing to do,” and that chronic use of
MDMA may cause long-term problems with emotion, memory, sleep and pain (Leshner
2001).
When used recreationally in dance clubs, some users
of MDMA (mostly in combination with other drugs) have died from hyperthermia as
a result of overheating from vigorous dancing in high ambient temperature
environments with inadequate water or other fluid replacement. From 1994 through 1999, there have been
a total of 68 MDMA-related deaths (may or may not be causal) reported to the
Drug Abuse Warning Network (DAWN), though not all deaths were related to
hyperthermia. Medical Examiner data reports 1 death associated with MDMA in
1994, 6 in 1995, 8 in 1996, 3 in 1997, 9 in 1998, 41 in 1999 (Office of Applied
Studies, 2001a). Relatively few of the Medical Examiner cases were for MDMA
alone. Most were associated with MDMA used in combination with one or more other
drugs. The Medical Examiner numbers do not reflect national totals, which do
not exist, but are simply the totals reported by the Medical Examiner offices
that are included in the DAWN system. MDMA-related (though not necessarily
causally related) hospital Emergency Room visits reported to DAWN (these are
national estimates) totaled 247 in 1994, 422 in 1995, 319 in 1996, 637 in 1997,
1142 in 1998, 2850 in 1999, and 4511 in 2000. (Office of Applied Studies,
2001b).
Furthermore, with the exception of ibogaine, the
classic psychedelics have not been claimed to be “neurotoxic,” as has
MDMA. In primates, at doses
slightly higher than the amounts used in psychotherapy, MDMA has been linked to
minor persisting reductions in serotonin levels in a few brain regions
(Ricaurte et al. 1988), with
the no-effect level for serotonin reductions in primates being 2.5 mg/kg,
administered orally once every two weeks for four months (8X) (Ricaurte,
unpublished, cited in Vollenweider et al. 1999a). Whether therapeutic doses of
MDMA have any permanent impact on serotonin levels is a matter of substantial
controversy (Lieberman & Aghajanian 1999). If high doses of MDMA are
consumed frequently, a dosage pattern seen in some recreational users of MDMA,
MDMA may reduce serotonin levels for extended periods of time (McCann et al.
1998). Though there is evidence of recovery of serotonin levels over time,
serotonin does not reach initial levels in all brain regions while some brain
regions recover to levels higher than baseline (Fischer et al. 1995). Some
changes may be permanent (Hatzidimitriou, McCann & Ricaurte 1999).
Fortunately for the heavy recreational users of MDMA, these changes in
serotonin levels, if they do indeed occur in humans, seem largely asymptomatic.
Evidence for any functional consequences in animals or humans resulting from
even massive consumption of MDMA is weak. Concern centers around a series of
studies that show statistically significant but mostly clinically insignificant
reductions in a few memory functions in heavy poly-drug users who have consumed
large amounts of MDMA (Bolla, McCann and Ricaurte 1998; Reneman et al. 2001; Zakzanis &
Young 2001; Croft et al. 2001; Gouzoulis-Mayfrank et al. 2000; Gamma 2001).
Concerns that negative functional consequences associated
with MDMA use will increase over time as MDMA users age are hypothetical, and
are not evidence-based.
Research
has shown that neurotoxicity is exacerbated by high body temperatures and can
be eliminated by a slight cooling of body temperature (Malberg, Sabol &
Seiden 1996; Malberg & Seiden 1998). The effect of temperature makes data
about risk that is gathered from people who take MDMA at raves of limited
predictive value for estimating the risk of subjects exposed to MDMA in
clinical settings. MDMA’s increased risk profile is a
direct result of its use in recreational settings, with use in clinical
research settings relatively non-problematic (Vollenweider et al. 1999a). In
therapy, MDMA is not used on a daily basis but rather as an adjunct to psychotherapy
administered a relatively few times, with several weeks between therapy
sessions. The most sophisticated investigation of MDMA-neurotoxicity has been
conducted by Dr. Franz Vollenweider at the U. of Zurich. Dr. Vollenweider found
no evidence for serotonin reductions in MDMA-naive subjects who were given a
PET scan shortly before and then again four weeks after receiving a moderate
amount of MDMA in the therapeutic dose range (1.5-1.7 mg/kg) (Vollenweider
2001).
The combination of the remarkable therapeutic
potential of MDMA, along with its substantial safety for use in clinical
settings, makes it a very attractive choice for drug development. A comprehensive
risk/benefit analysis that lent support to the case for clinical psychotherapy
research with MDMA was funded by MAPS and submitted to FDA (Baggott, Jerome
& Stuart, 2001). Politically,
however, MDMA is not the easiest psychedelic to try to develop into a
prescription medicine. Its non-medical use is increasing, especially among
young people. In the 2001 Monitoring the Future survey, funded by NIDA, 11.7 % of high school
seniors reported that they had tried Ecstasy at some point, up from 11.0 % in
2000 and 8.0 % in 1999 (Johnston, O'Malley & Bachman 2001). Police authorities are seizing increasingly
large amounts. Customs officials have seized 9.3 million ecstasy pills in FY
2000, as compared to 3.5 million in FY 1999 and 750,000 in FY 1998 (Office of
Public Affairs, US Customs Service, 2000; National Drug Intelligence Center,
2000). NIDA has called the increased use of MDMA an epidemic (NIDA 2000).
Yet the political controversy about MDMA
offers one crucial advantage that makes MDMA much more likely to become the
first psychedelic to be approved as a prescription medicine. As a result of the
millions of non-medical users of MDMA around the world, health authorities,
anti-drug authorities and research scientists have expended an amazing amount
of time, energy and money trying to understand the risks of MDMA, its
mechanisms of action, and the consequences of acute and long-term use.
The
number of scientific papers in the peer-reviewed scientific literature
reporting on research with MDMA in humans and animals, along with case reports
discussing adverse events, exceeds 1240 according to a Medline search conducted
by the author on May 1, 2002. Data in the peer-reviewed scientific
literature can be submitted to FDA as evidence in the assessment of MDMA’s risk
profile and safety, with the only cost being the time it takes to
systematically review the papers and organize the data for submission to FDA.
FDA is willing to accept published papers for review and has even approved
drugs “based primarily or
exclusively on published reports (FDA 1998).” The costs of conducting these published
MDMA studies is well over $20 million.
The availability of data from these studies dramatically reduces the
amount of additional funding that will be required to argue a case before FDA
for MDMA's safety and efficacy.
Several researchers
have administered MDMA to human subjects in clinical studies of MDMA's safety,
mechanism of action and physiological and psychological effects. More
frequently, researchers have compared people who have used MDMA in non-medical
contexts with controls. As of March 2002, more than 262 subjects had been
administered MDMA in the context of legal research. There was also data in the
scientific literature from more than 985 people who had used MDMA, sometimes in
astonishingly large amounts, in non-medical recreational contexts. These MDMA
users have been compared to more than 835 controls." An MDMA Phase I study with 18 patients has
been successful completed in the United States, though data on only the first 6
subjects have been published (Grob et al. 1996). Two other Phase I studies with MDMA focused on objectives other than
safety have also been conducted in the United States. An MDMA pharmacokinetic
study was conducted at UC San Francisco (Everhart et al. 1999) and a study
is underway investigating which brain neurotransmitter receptor sites are
involved in producing MDMA’s subjective effects (Tancer & Johanson 2001).
Studies in Switzerland have investigated MDMA’s action on brain
neurotransmitter receptor sites (Liechti et al. 2000), on
information processing (Vollenweider et al. 1999b) and on the psychological and
cardiovascular effects of a single dose of MDMA (Vollenweider 1998). Three MDMA
pharmacokinetic studies have been conducted in Europe in England (Fallon et al.
1999), Spain (de la Torre et al. 2000), and Switzerland (Helmlin et al. 1996).
A Phase I dose-response safety study has been completed place in Spain (Mas et
al. 1999; Cami et al. 2000), as well as a study investigating MDMA/alcohol
interactions (Hernandez-Lopez et al. 2002). A study investigating the hormonal effects of MDMA has taken
place in England (Henry et al. 1998) and a study investigating the
immunological effects has taken place in Spain (Pacifici et al. 1999). Yet with
all this research, there is not one single paper reporting data from a
controlled scientific study into the therapeutic use of MDMA. MAPS’
effort to initiate controlled, FDA-approved scientific research into the
therapeutic potential of MDMA in patient populations began in 1986, and has
taken 16 years to come to fruition. A Phase II dose-escalation pilot study
of MDMA-assisted psychotherapy in the treatment of post-traumatic stress
disorder (PTSD) has been approved in Spain. This is currently the only study into the therapeutic use of
MDMA approved anywhere in the world. The existence of the Spain study,
sponsored by MAPS, is an important practical factor behind the selection of
MDMA as the initial psychedelic drug to focus on developing into an
FDA-approved prescription medicine. The sixth patient in Spain, at the 75 mg.
dose level, was treated on April 15, 2002. The researchers conducting the study will gather the data in
a sufficiently rigorous manner so that it can be submitted to FDA for review.
With the approval of this study, the chance to develop the therapeutic
potential of MDMA is now more than a mirage. Why
Post-Traumatic Stress Disorder? In
choosing the patient population to study, one of the criteria was that the
unique properties of MDMA-enhanced psychotherapy needed to be matched to a
patient population in which MDMA therapy could offer a dramatic benefit.
Ideally, this benefit would require only from one to three drug sessions to
produce significant, measurable and long-lasting clinical progress. Alternative
medications for this patient population should be relatively ineffective, at
least in some subpopulation of patients. The patient population should also be
a group that the general public feels compassion towards, in order to help
overcome resistance to the idea of the therapeutic use of psychedelics. The
core of the MDMA experience has been described by one of the pioneering
psychiatrists who worked with MDMA-assisted psychotherapy in terminal cancer
patients as “reducing the fear response to a perceived emotional threat.” When
used therapeutically, MDMA is administered as an adjunct to psychotherapy on an
intermittent basis within a larger therapeutic relationship, usually fewer than
four times and frequently only once or twice. Numerous case histories and
anecdotal reports testify to MDMA’s ability to assist people struggling to come
to terms with difficult life events (Stevens 1999/2000; Otalora 1984). These reports suggest
that MDMA-assisted psychotherapy should initially be explored not in patients
whose psychiatric symptoms originated with biological imbalances with possible
genetic components, though MDMA might still be helpful in some ways with such
patients, but rather in patients who need some assistance in processing
difficult emotions that have a deep component of fear and/or anxiety. Two of the main categories of patients
that fit this description are people suffering from PTSD and people facing
terminal illness. People with
these two types of clinical conditions have been treated with MDMA with some
remarkable results in some patients. The
main advantage of working with a PTSD patient population instead of patients
with terminal illness is that PTSD patients as a group are probably in better
overall health than cancer patients and are taking fewer other medications,
making it less complicated to work with them. Once the MDMA/PTSD study is
underway in the US, MAPS will seek to obtain FDA approval for a study of
MDMA-assisted psychotherapy in hospice patients. In
the US market, there are only two conventional pharmacological treatments that
have been approved for patients with PTSD. On December 7, 1999, FDA approved
the drug known as Zoloft (sertraline) for PTSD, on the basis of four small
clinical trials (it was already on the market as an anti-depressant). Two of
the clinical trials showed no efficacy, two showed some efficacy. These studies
involved a total of 351 subjects.
Subgroup analysis revealed that Zoloft was efficacious in female
patients but not in male patients. According to Dr. Katz, Director of the
Division of Neuropharmacological Drug Products, “The effect of the treatment
appears to come essentially completely from women (Katz 1999).” On December 14, 2001, FDA approved the use of Paxil
(paroxetine) in the treatment of PTSD. Unlike the Zoloft trials, studies with
Paxil showed efficacy in both men and woman. Interestingly, Zoloft and Paxil’s mechanism of action is to
increase the amount in the synapse of the brain neurotransmitter serotonin, the
same neurotransmitter that MDMA primarily impacts. The difference is that MDMA
increases serotonin acutely for a period of 4-8 hours after a single dose while
Zoloft increases serotonin chronically but must be taken on a daily basis. The patient group that will be tested with MDMA in
Spain is women survivors of sexual assault who suffer from chronic PTSD and who
have already failed on at least one course of conventional treatment. The patient group that will be
tested in the US will include men and women, survivors of sexual and/or
criminal assault, who have failed on one course of treatment with an SSRI such
as Zoloft or Paxil. The patient
group for the Israeli study will include patients who have PTSD as a result of
war or terrorism, as well as sexual or criminal assault, and who have failed on
one course of an SSRI. By choosing subjects who have already failed on one
course of conventional treatment, the risk/benefit ratio is improved in favor
of permitting the study to proceed. We hypothesize that MDMA will prove helpful in
resolving some of these subjects’ difficult and painful memories so that they
can move forward with some degree of resolution, not forgetting the past but
not as burdened by it either. MDMA-assisted psychotherapy also has the
potential advantage of being cost-effective, since it can be delivered within a
relatively short time. MDMA
in the treatment of PTSD is probably the best combination of psychedelic drug
and clinical indication that can most justify a focused drug development
effort. What such a drug
development plan might look like will be elaborated below, after a brief review
of the discussion of the Psychopharmacologic Drugs Advisory Committee that
recommended that Zoloft be approved for use in the treatment of PTSD. Pfizer’s
recent experience with its successful development of Zoloft for the treatment
of PTSD offers the most direct window into FDA policies and procedures for the
design of research protocols and the review of data for the pharmacological
treatment of PTSD. There are many analogous issues and also important
differences between the development of Zoloft, a medication that has been
approved by FDA for daily use for the relief of symptoms associated with PTSD,
and the development of MDMA, a drug that is meant to be administered from 1-3
times on an in-patient basis as an adjunct to psychotherapy for the relief of
the underlying causes of PTSD. The public record related to FDA approval of
Zoloft will be reviewed in order to understand FDA regulatory policy as it
applies directly to the development of medications to treat PTSD. The most
valuable documents in the public record include transcripts of the October 8,
1999 Psychopharmacologic Drugs Advisory Committee (Psychopharmacologic Drugs
Advisory Committee 1999), a slide show delivered at that meeting
by Dr. David Smith, Statistical Reviewer, FDA Office of Biostatistics (Smith
1999), and a complete file of the FDA approval package for Zoloft,
NDA19839,SO26, obtained from FDA through Freedom of Information Act (FOIA)
request. As of May 2002, FDA has not yet responded to a FOIA request for the
Paxil approval package. October 8, 1999 Psychopharmacologic Drugs Advisory
Committee Meeting: Study Design Issues Four
clinical trials were reviewed on October 8, 1999 by FDA’s Psychopharmacologic
Drugs Advisory Committee, advising the Division of Neuropharmacological Drug
Products. Outcome data was
presented at the meeting by Pfizer and FDA representatives. The
Advisory Committee meeting began with an overview presented to the Committee by
Dr. Tom Laughren, Team Leader for Psychopharmacology at FDA. He indicated that PTSD
is a chronic disorder and FDA, “ordinarily uses parallel group studies although
one might ask whether a crossover design might be appropriate even for a
chronic condition, if the condition is very stable over time and there is a
return to baseline if the treatment is stopped (Psychopharmacologic Drugs
Advisory Committee 1999: 10).” Dr.
Laughren further noted that, “this is a chronic disorder and one may ask the
question whether or not there is a need for long-term data and at what point in
development should that information become available should that become an
issue for approvability. Now, as an aside, I should say that we never, up until
now, made that a requirement for approving a new indication in psychiatric
disorders (Psychopharmacologic Drugs Advisory Committee 1999: 11).” Dr.
Farfel, a Pfizer scientist, indicated that “subjects were dosed once daily
beginning with 25 mg/dy in the first week
[dosing was not initially based on mg/kg] and then continuing flexibly
titrated between 50 and 200 mg/dy thereafter (Psychopharmacologic Drugs
Advisory Committee 1999: 33).” FDA’s Dr. Temple commented about the titration
design, indicating that he would have preferred fixed doses. He said, “I would
be curious as to why that design was chosen. If it was chosen to avoid adverse
effect, that would make some sense, but ordinarily I think you would learn more
from a randomization to fixed doses, even if you inched your way up to those doses...Now
you could analyze this to see if there was a dose/response hidden in Psychopharmacologic
Drugs Advisory Committee 1999: 127).” Dr. Hammer, Advisory Committee member,
made the suggestion that one of the major studies should have been fixed dose
and the other flexible, so as to have gained some information about
dose/response relationships in one of the studies. Dr.
Laughlen said, “One thing that we like to see for an indication that is more
mature in some sense than this is, from a regulatory standpoint, we like to see
an active control arm in a trial to help us in interpreting it, so that if an
active standard drug, which is believed to work, also fails, we are more
inclined to discount that study. This is obviously not a strategy you can use
early on in the development of a new indication (Psychopharmacologic Drugs
Advisory Committee 1999: 145).” This
suggestion of an active control arm for subsequent treatments for PTSD should
be adopted. In testing
MDMA-assisted psychotherapy for PTSD, parallel groups are more appropriate than
a crossover design since the hypothesis is that there will not be a return to
baseline after the MDMA treatment is over. This is different for Zoloft, which
offers mostly symptomatic relief with a significant number of subjects
relapsing once the use of Zoloft is ended. From a financial perspective, this
seems ideal for a pharmaceutical company since patients have a continued need
to purchase the product or the symptoms will return. In contrast, MDMA-assisted
psychotherapy has been helpful in some reported case histories after one to three
sessions, with no additional MDMA sessions required to maintain clinical
improvement. The
fact that the Zoloft design allowed titration suggests that it might also be
possible to titrate the number of doses of MDMA-assisted psychotherapy a
patient receives in one of the Phase III trials, to match the treatment to the
depth and speed at which the patient is able to resolve issues related to the
original trauma. Dr. Gary Ryan, Group Director of
Clinical Research, Pfizer, stated, “Our PTSD Clinical Trial program consisted
of four placebo controlled trials enrolling a total of 757 patients (Psychopharmacologic
Drugs Advisory Committee 1999: 16).” Though Dr. Ryan reported a total of 757
patients, the data presented in the slides by Dr. Smith indicated only 597
subjects, with the difference due to attrition. Pfizer’s Dr. Farfel reported
that, “the mean number of subjects in each treatment group was approximately
95, for a total of 376 subjects treated with sertraline and 381 treated with placebo (Psychopharmacologic
Drugs Advisory Committee 1999: 32).” In the two clinical trials that
demonstrated efficacy, a total of 385 patients were enrolled, 191 who received
Zoloft and 194 who received placebo (Smith Slide #9). Dr. Charles Marmar, Professor
and Vice Chairman, Department of Psychiatry, UC San Francisco, spoke for Pfizer
and noted that “you can see that for the most part the effects, while
meaningful, have been modest (Psychopharmacologic Drugs Advisory Committee 1999:
29),” indicating that sample sizes may need to be fairly large,
especially in a comparison study between MDMA and Zoloft or Paxil. Dr.
Katz, Director of the Division of Neuropharmacological Drug Products,
stated, “There are conditions
where we have considered studies positive or approved drugs on the basis of
fairly small studies, but in which the treatment has been statistically
significantly different from the control. Of course, the smaller the study, the
more likelihood that there is some bias creeping in or that there is an
imbalance is an important characteristic that you don’t really know how to test
for, you don’t even know what they are necessarily. So we like to see larger
studies but there is no specific requirement for numbers (Psychopharmacologic
Drugs Advisory Committee 1999: 149).” Dr.
Laughren mentioned that, “this program overall was relatively small, and so in making a judgement about the
safety of Zoloft, we relied heavily on the safety experience on other
populations. So, a question is, is that a reasonable extrapolation? (Psychopharmacologic
Drugs Advisory Committee 1999: 14) ” Dr. Farfel commented on safety reporting,
“Safety was investigated in 757 subjects, and nothing that was found in this
development program suggests a risk that has not already been identified in
previous trials and indications, and is already not described in the labeling (Psychopharmacologic
Drugs Advisory Committee 1999: 55).” The
minimal number of MDMA-assisted psychotherapy sessions that will be
administered to subjects, along with all the safety data already gathered about
MDMA from clinical trials around the world, may enable the safety of MDMA in
PTSD patients to be investigated with as few subjects as were used in the
studies of Zoloft in the treatment of PTSD. This is a reasonable assumption
that would change depending on the strength and clarity of the data actually
gathered in the clinical studies. Based
on FDA’s review of research into the use of Zoloft in the treatment of PTSD,
the power of Pfizer’s studies as designed was considered inadequate for
subgroup analysis but adequate for group comparisons. The studies as completed
had roughly 75 subjects per group. According to Dr. Farfel, the groups had a
mean initial enrollment of about 95 subjects, with about 75 per group
completing the trial and included in final data analysis. Until
the effect size and variance of response to MDMA-assisted psychotherapy is
determined, sample sizes cannot be estimated with accuracy. The more pronounced
the treatment effect and the smaller the variation in outcomes, the smaller the
sample size needs to be to generate significant results (Friedman, Furberg
& Demets 1985). In order to reduce variance so as to
reduce sample size, a homogenous patient population with a relatively uniform
response should be selected. In the Zoloft studies, there was a substantial
difference in response between men and women. The Phase III MDMA studies should
be able to avoid this problem through the review of data gathered in the Phase II
trials that will evaluate the effectiveness of MDMA in men and in women. The
Phase III trials can then be designed either with all men, all women, or a
combination. With an advantage in uniformity over the Zoloft designs, it will
probably be possible to obtain adequate power with 80 subjects in each of the
three treatment groups and 40 in the psychotherapy-alone sub-threshold dose
condition. It might even be
possible to use only 70 subjects per group, since Dr. Kazdin has
estimated, “for comparing two
treatments [for superiority, not equivalence, making this a high estimate for a
test of equivalence]...a sample size of 71 per group would be needed to retain
power at the desired level for the median ES ([effect size] (Kazdin & Bass
1989). The studies of Zoloft that Pfizer
submitted for review were designed as 12-week trials. Dr. Marmar noted that
“suicide rates are an important issue both in the acute and chronic form (Psychopharmacologic
Drugs Advisory Committee 1999: 27),” suggesting caution in the use of placebo
groups in PTSD patients with a risk factor for suicide. Relatively short treatment courses
should be employed to minimize the amount of time patients are receiving
placebo, or instead psychotherapy-alone with a sub-threshold dose of MDMA,
which will maximize suggestion without providing a direct pharmacological
effect of MDMA. Dr. Domingez, Advisory Committee Member,
suggested that 12 weeks was sufficient for the study since most people respond
by then. She noted that there was a trade-off between the desire to extend
treatment in order to give enough time to find an effect and the desire not to
keep people on placebo for an unnecessarily long period of time (Psychopharmacologic
Drugs Advisory Committee 1999: 129). This
discussion supports limiting the length of MDMA treatment in the clinical
trials to 12 weeks, though longer-term follow-up data should also be gathered. Dr.
Marmar stated that the lifetime prevalence for PTSD in the American adult
population is 7.8%. Dr. Bonnie Green, Professor of Psychiatry at Georgetown
University Medical School, President Elect of the International Society for
Traumatic Stress Studies (ISTSS) commented that any one time, 5% of women and
2-3% of men have PTSD (Psychopharmacologic Drugs Advisory Committee 1999: 22).
Since the adult population of the United States is greater than 170
million, PTSD clearly does not
qualify as an Orphan disease since there are more than 200,000 potential
patients in any given year.
MAPS’ Clinical Plan for MDMA for PTSD The
following outline is of a sequence of studies designed to evaluate the risks
and benefits of the use of MDMA-assisted psychotherapy in the treatment of post
traumatic stress disorder (PTSD). This plan includes only studies focused on
the safety and efficacy of the use of one to four sessions of MDMA-assisted
psychotherapy in patients with PTSD.
The Clinical Plan begins with a Phase II study since Phase I MDMA safety
studies have already been conducted in the United States, Spain and
Switzerland. As
the studies of MDMA in patients with PTSD are conducted, additional safety
issues may become apparent. Further research addressing specific issues related
to the safety of MDMA may be required by FDA before there will be sufficient
information to justify a New Drug Application (NDA). These additional studies,
if needed, may involve issues that will be addressed by government-funded
research teams around the world already working to assess questions of safety
and mechanisms of action.
Alternatively, these issues may need to become the subject of research
by MAPS-funded scientific teams. However, based on what is already known about
MDMA, it is likely that any safety issues related to the use of MDMA in PTSD
patients can be adequately addressed by the proposed studies in PTSD patients. This
study, being conducted by Dr. Pedro Sopelano and Jose Carlos Bouso, Ph.D.
candidate, U. Autonoma de Madrid, is currently the only MDMA psychotherapy
study underway anywhere in the world in which MDMA is being administered to
patients. The goals of this study are, 1) to evaluate whether a single dose of
MDMA can be administered safely to 29 female survivors of sexual assault with
chronic PTSD, 2) to gather preliminary evidence about therapeutic efficacy and,
3) to determine which dose or doses should be used in subsequent larger-scale
studies. This study treated the sixth
subject on April 15, 2002 and is scheduled to complete the testing of all 29
subjects by May 2003. The Phase II dose/response study in
Spain will cost $65,000, or $2,240 per subject. The Spain study involves just
one treatment session per subject. The study is being coordinated by Jose
Carlos Bouso, a Ph.D. candidate working on the study for his dissertation.
Under these circumstances, a cost of $2,240 per subject can be obtained. This is the lower limit for the
cost-per-patient of any MDMA protocol. A research team under the director of
Dr. Michael Mithoefer has worked with MAPS to design and obtain FDA-approval to
conduct an MDMA/PTSD pilot study in the United States. The protocol was
approved by the FDA on November 2, 2001. As of May 2002 , the protocol is still in the
midst of the IRB approval process. The study should begin Summer 2002. The
protocol will involve 20 subjects with PTSD, both male and female. All 20 subjects will receive about 12
hours of non-drug psychotherapy. Twelve subjects will also receive two sessions
of MDMA-assisted psychotherapy scheduled three to five weeks apart, with a dose
of 125 mgs at each session, while 8 subjects will receive 2 placebo sessions.
The goals of this study are 1) to evaluate whether MDMA can be safely administered
to PTSD patients and 2) to determine whether there is any preliminary evidence
of therapeutic efficacy and, if so, to develop an estimate of the effect
size. The entire treatment course will be
conducted in 12 weeks or less, in accordance with the recommendations made in
the FDA Pharmacologic Drugs Advisory Committee meeting that reviewed the data
from the trials of Zoloft in the treatment of PTSD, If
the study does begin in Summer 2002, the research team should be able to
complete both sessions in all 20 patients by Summer 2003. The analysis of
initial data can be completed by Fall 2003, with six month follow-up data
analysis completed by Winter 2003. The final report can be completed by Spring
2004. The
cost of the study is estimated to be $12,000 per subject or $240,000. The costs
of this study include non-drug psychotherapy hours as well as thorough
neuropsychological evaluations, and quite a substantial cost for administrative
work on the FDA and IRB approval process. Subsequent studies will probably
require fewer non-drug psychotherapy hours and may not require any
neuropsychological evaluations, depending on the results from this initial
pilot study. Since administrative costs have been averaged over a small number
of subjects, subsequent studies with much larger subject populations, at least
10 times the size of this pilot study, can be conducted with significantly less
cost per patient. Phase
III Trials - 4 -Arm Multi-Site
Study, United States The goal of this study is to be one of
the two primary FDA-required “adequate and well-controlled investigations”
demonstrating safety and efficacy of the use of MDMA in patients with PTSD. Depending on the data from the pilot
studies, the study will focus either on women, on men, or on both. The study
will be designed with a psychotherapy-alone group receiving a subthreshold
(placebo) dose of MDMA, a medium dose group, a full dose group and a Zoloft or
Paxil comparison group. The
number of sessions will be titrated by agreement of patient and therapeutic
team, with a maximum of 4 sessions within a 12 week period. This study will hopefully start in
Spring 2004 and will take three years to conduct. The study will enroll
approximately 280 subjects, 80 in each drug treatment group and 40 in the
psychotherapy-alone group. Due to economies of scale, the study should be able
to be conducted for about $8,000 per subject, for a total cost of $2,240,000. The
second large-scale trial will be conducted outside of the United States, in
Spain or possibly in Israel. FDA will accept data gathered outside of the
United States, if it is gathered according to standards set by FDA. With one
study conducted in the United States and one in Spain or Israel, it should be
possible to obtain marketing approval in both the United States and the
European Community. The
goal of this study is to be one of the two primary “adequate and well-controlled
investigations” demonstrating safety and efficacy. Depending on the data from
the pilot studies, the study will focus either on women, on men, or on
both. The study will be designed
with a psychotherapy-alone group receiving a subthreshold (placebo) dose of
MDMA, a medium dose group, a full dose group and a Zoloft or Paxil comparison
group. The study will enroll
approximately 280 subjects, 80 in each drug treatment group and 40 in the
psychotherapy-alone group. This study will involve a fixed number of sessions
administered within a 12 week period. This study will involve three sessions
for each subject, once every four weeks, with no titration permitted. The use
of two different designs for the two different Phase III studies, with the US
study using a variable number of treatment sessions depending upon patient and
therapist decision and the foreign study employing a fixed number of three
sessions, is based on the recommendation made by Dr. Hammer during the October
8, 1999 meeting of FDA’s Pharmacologic Drugs Advisory Committee. This
study will hopefully start in Spring 2004 and will take three years to conduct.
The study will enroll 280 subjects, should cost in the range of $8,000 per
subject, for $2,240,000. The
total cost of the sequence of studies enumerated above amounts to
$4,720,000. Additional animal or
human toxicity studies may be needed, though it is likely that these studies
will have already been government-funded with the data in the public
domain. The
Clinical Plan elaborated above suggests that a rough estimate of about $5
million will need to be expended over a five-year period to develop MDMA into a
prescription medicine for just one clinical indication, PTSD. After MDMA is
approved initially for PTSD, only one adequate and well controlled
multi-site investigation might be
sufficient for the approval of subsequent uses of MDMA in closely related
disorders, such as in the psychotherapeutic treatment of anxiety and depression
in cancer patients. REFERENCES Baggott, M.; Jerome, I.
& Stuart R. 2001.
3,4-methylenedioxymethamphetamine (MDMA)- a
review of the English-language
scientific and medical literature.
Submitted to FDA as part of IND # 63,384. MAPS website.
Bolla,
K.; McCann, U. & Ricaurte, G. 1998. Impairment in abstinent MDMA
("Ecstasy") users. Neurology 51(6):1532-7. Croft,
R.; Mackay, A.; Mills, A. & Gruzelier, J. 2001. The
relative contributions of ecstasy and cannabis to cognitive impairment. Psychopharmacology
(Berlin) 153(3): 373-9. Cami,
J.; Farre, M.; Mas, M.; Roset, P.; Poudevida, S.; Mas, A.; San,
L. & de la Torre, R. 2000.
Human pharmacology of 3,4-methylenedioxymethamphetamine ("ecstasy"):
psychomotor performance and subjective effects. Journal of Clinical
Psychopharmacology 20(4):455-66. de
la Torre, R.; Farre, M.; Ortuno,
J.; Mas, M.; Brenneisen, R.; Roset, P.; Segura, J. & Cami, J. 2000. Non-linear pharmacokinetics of
MDMA ('ecstasy') in humans. British Journal of Clinical Pharmacology 49(2):104-9. Doblin,
R. 2001. The Regulation of the medical use of psychedelics and marijuana. Unpublished Public Policy doctoral dissertation,
Kennedy School of Government, Harvard University. Everhart,
E.; Jacob III, P.; Shwonek, P.;
Baggott, M.; Jones, R. & Mendelson, J. 1999. Estimation of the Metabolic Disposition of MDMA and
MDA Enantiomers in Humans. Abstracts - College on Problems of Drug
Dependence (CPDD) Annual Meeting : 41.
Food and Drug Administration. 1998.
Providing Clinical Evidence of Effectiveness for Human Drug and
Biological Products.
FDA Guidance for Industry.
Lieberman,
J. & Aghajanian, G. 1999. Caveat emptor: researcher beware. Neuropsychopharmacology
21(4):471-3. Fallon,
J.; Kicman, A.; Henry, J.; Milligan, P.;
Cowan, D. & Hutt, A. 1999. Stereospecific analysis and enantiomeric
disposition of 3, 4-methylenedioxymethamphetamine (Ecstasy) in humans. Clinical Chemistry 45 (7):1058-69 (Published erratum appears in Clinical
Chemistry 45(9):1585. Fischer,
C.; Hatzidimitriou, G.; Wlos, J.; Katz, J. & Ricaurte, G. 1995. Reorganization of ascending 5-HT
axon projections in animals previously exposed to the recreational drug
(+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). Journal of Neuroscience 15(8):5476-85. Friedman,
L.; Furberg, C. & Demets, D.
1985. The Fundamentals of Clinical Trials. 2nd Edition. St Louis: Mosby-Year Book. Gamma,
A. 2001.
Does Ecstasy cause memory deficits.
A review of studies of memory function in Ecstasy users. MAPS website
Grob,
C.; Poland, R.; Chang, L. & Ernst, T. 1996. Psychobiologic effects of
3,4-methylenedioxymethamphetamine in humans: methodological considerations and
preliminary observations. Behavior and Brain Research. 73 (1-2):103-7. Gouzoulis-Mayfrank,
E.; Daumann, J.; Tuchtenhagen, F.; Pelz, S.; Becker, S.; Kunert, H.; Fimm,
B. & Sass, H. 2000. Impaired cognitive performance in drug free users of
recreational ecstasy (MDMA). Journal of Neurology, Neurosurgery and
Psychiatry 68 (6):719-25. Hatzidimitriou,
G.; McCann, U. & Ricaurte, G. 1999. Altered serotonin innervation patterns
in the forebrain of monkeys treated with (+/-)3,4-methylenedioxymethamphetamine
seven years previously: factors influencing abnormal recovery. Journal of Neuroscience 19(12):5096-5107. Helmlin,
H.; Bracher, K.; Bourquin, D.; Vonlanthen, D. & Brenneisen, R. 1996. Analysis of
3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in plasma and
urine by HPLC-DAD and GC-MS. Journal
of Analytical Toxicology 20
(6):432-40. Henry,
J.; Fallon, J.; Kicman, A.; Hutt, A.; Cowan, D. & Forsling, M. 1998 Low-dose MDMA
("ecstasy") induces vasopressin secretion. Lancet 351 (9118):1784. Hernandez-Lopez,
C.; Farre, M.; Roset, P.; Menoyo, E.; Pizarro, N.; Ortuno,
J.; Torrens, M.; Cami, J. & de La Torre R. 2002. 3,4-methylenedioxymethamphetamine
(ecstasy) and alcohol interactions in humans: psychomotor performance,
subjective effects, and pharmacokinetics. Journal of Pharmacology and
Experimental Therapeutics
300 (1):236-44. Johnston,
L.; O'Malley, P. & Bachman, J.
2001. Rise in ecstasy use among American teens begins to slow.
University of Michigan News and Information Services: Ann Arbor, MI. Katz,
R. 1999. Memorandum, December 6,
1999 from Director of Division of Neuropharmacological Drug Products to File,
NDA 19-839/S-026. Obtained from FDA through FOIA request, along with entire
approval package for Zoloft. Kazdin,
A. & Bass, D. 1989. Power to detect differences between alternative
treatments in comparative psychotherapy outcome research. Journal of Consulting and Clinical
Psychology 57 (1):
138-147. Leshner,
A. 2001. Club Drugs Aren't
"Fun Drugs." NIDA website. http://www.drugabuse.gov/Published_Articles/fundrugs.html Liechti,
M.; Baumann, C.; Gamma, A. &
Vollenweider, F. 2000 Acute
psychological effects of 3,4-Methylenedioxymethamphetamine (MDMA,
"Ecstasy") are attenuated by the serotonin uptake inhibitor
Citalopram. Neuropsychopharmacology.
22(5): 513-521. Malberg,
J.; Sabol, K. & Seiden, L.
1996. Co-administration of MDMA
with drugs that protect against MDMA neurotoxicity produces different effects
on body temperature in the rat. Journal of Pharmacology and Experimental
Therapeutics 278 (1):258-67. Malberg,
J. & Seiden, L. 1998. Small changes in ambient temperature cause large
changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin
neurotoxicity and core body temperature in the rat. Journal of Neuroscience 18 (13): 5086-94. Mas,
M.; Farre, M.; de la Torre, R.; Roset, P.; Ortuno, J.;
Segura, J. & Cami, J. 1999. Cardiovascular and neuroendocrine effects and pharmacokinetics
of 3, 4-methylenedioxymethamphetamine in humans. Journal of Pharmacology and Experimental Therapeutics 290 (1):136-45. McCann,
U.; Szabo, Z.; Scheffel, U.; Dannals, R.; Ricaurte, G. 1998. Positron emission
tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain
serotonin neurons in human beings.
Lancet 352(9138):1433-7. Mertl,
M. 2000. Ecstasy and the Brain:
Club Drug Rants and Raves. Brain.com. April 11. Mithoefer, M. & Wagner,
M. 2001.
A human phase II study — safety and efficacy of 3,4-methylenedioxymethamphetamine
(MDMA)-assisted psychotherapy in the treatment of chronic posttraumatic stress
disorder (PTSD). FDA IND # 63,384. MAPS website
National Drug Intelligence Center. October 2000.
Draft National Drug Threat Assessment 2001: The Domestic Perspective
National
Institute on Drug Abuse (NIDA). 2000. Emerging Drug Epidemics: Club Drugs.
NIDA website
Office
of Applied Studies. 2001a. Mortality
Data from the Drug Abuse Warning Network-2000. Substance Abuse Mental Heath Services
Administration. National Institutes
of Health, Drug Abuse Warning Network. http://www.samhsa.gov/statistics/statistics.html.. Office of Applied Studies. 2001b. Updated weighted
emergency department estimates
for the coterminous U.S.by year: 1994 to 2000.
Substance Abuse Mental Heath Services Administration. National Institutes of Health, Drug Abuse Warning Network. (3/2001,
update).
Office
of Public Affairs, United States Customs Service. January 5, 2000. Ecstasy Seizures and Smuggling
Methods Fact Sheet. Otalora
M. 1984. MDMA and LSD therapy in the treatment of posttraumatic stress disorder
in a
case of sexual abuse. MAPS
Website
Pacifici,
R.; Zuccaro, P.; Farre, M.;
Pichini, S.; Di Carlo,
S.; Roset, P.; Ortuno, J.; Segura, J.
& de la Torre, R.1999.
Immunomodulating properties of MDMA alone and in combination with
alcohol: a pilot study. Life Sciences 65(26): PL309-16. Pharmacologic Drugs
Advisory Committee. October 8, 1999
meeting transcript
on the FDA website
. Reneman,
L.; Lavalaye, J.; Schmand, B.; de Wolff, F.; , van den Brink, W.; den Heeten G, & Booij, J. 2001. Cortical serotonin
transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine
(MDMA or "ecstasy"): preliminary findings. Archives of General
Psychiatry 58 (10): 901-6. Ricaurte,
G.; DeLanney, L.; Irwin, I.; Langston, J. 1988. Toxic effects of MDMA on
central serotonergic neurons in the primate: importance of route and frequency
of drug administration. Brain Research 446 (1):165. Smith,
D. 1999.
Sertraline for PTSD:
NDA 19-839 on the FDA Website
Sopelana,
P. & Bouso, J. 1999. Administration of 3,4-methylenedioxymethamphetamine
(MDMA) to women with chronic Posttraumatic Stress Disorder (PTSD) as a
consequence of sexual assault: a dose-finding pilot study. Spanish Drug Agency Code # 99-0309. MAPS Website
Stevens,
S. 1999/2000.
Speaking the silence:
MDMA in a couple dealing with cancer. Bulletin of the
Multidisciplinary Assocation for Psychedelic Studies 9
(4): 31-34.
Tancer,
M. & Johanson CE. The subjective effects of MDMA and mCPP in moderate MDMA
users. Drug and Alcohol Dependence
2001 Dec 1;65(1):97-101. Vollenweider,
F.; Gamma, A.; Liechti, M. &
Huber, T. 1998. Psychological and
cardiovascular effects and short-term sequelae of MDMA ("ecstasy") in
MDMA-naive healthy volunteers. Neuropsychopharmacology 19(4): 241-51. Vollenweider,
F.; Gamma, A.; Liechti, M. & Huber, T. 1999a. Is a single dose of MDMA harmless? Neuropsychopharmacology 21(4):
598-600. Vollenweider,
F.; Remensberger, S.; Hell, D. & Geyer, M. 1999b. Opposite effects of
3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus
healthy humans. Psychopharmacology
(Berlin) 143 (4): 365-72. Vollenweider,
F. 2001. Personal communication. 9/14/01. Zakzanis,
K. & Young, D. 2001. Memory impairment in abstinent MDMA
("Ecstasy") users: a longitudinal investigation. Neurology 56(7):966-9. FDA Review of Zoloft for PTSD
Sample Size for Efficacy
Sample Size for Safety
Estimates for Sample Sizes for the MDMA Phase III Trials
Duration of Studies
Orphan Drug Designation: Not Possible
Phase II Spain Dose-Finding Pilot Study in Women Survivors of Sexual
Assault
Phase II United States Full-Dose Pilot Study in Male and Female PTSD
patients
Phase III Trials- 4-Arm Study
Spain or Israel
Total Cost