Fall bulletin.for real

A Clinical Plan for MDMA (Ecstasy) in the Treatment of Post-Traumatic Stress Disorder (PTSD): Partnering with the FDA Rick Doblin, Ph.D. The following article was originally published in the April-June 2002 special MDMA issue of theJournal of Psychoactive Drugs (www.hafci.org). The article presents the rationale behind MAPS'efforts to sponsor research in Spain, the US and Israel investigating MDMA's potential in treatingpatients suffering from posttraumatic stress disorder (PTSD). This document is the clearest expres-sion to date of MAPS' role as a membership-based non-profit pharmaceutical company, as distinctfrom MAPS' other research and educational functions. We are reprinting this article in order toexplain in detail to MAPS' membership the vision and strategy animating MAPS' MDMA/PTSD researchprojects and associated fundraising efforts. A mission statement in a way, this article should help toexplain why MAPS has chosen the ambitious goal of developing MDMA into an FDA-approved prescrip-tion medicine in the treatment of PTSD. Since this article was written, the Spain MDMA/PTSD re-search project has been halted (hopefully temporarily) due to political pressure, and it has takenlonger than expected to obtain DEA and IRB permission to start the US MDMA/PTSD project. The Multidisciplinary Association for Psychedelic Studies (MAPS, www.maps.org), a member- ship-based non-profit research and educational organization, is sponsoring a series of studiesdesigned to develop MDMA into an FDA-approved prescription medicine, initially for the treatmentof post-traumatic stress disorder (PTSD). MAPS is currently sponsoring a pilot MDMA dose-escala-tion study in Madrid, Spain with PTSD patients, conducted under the direction of Dr. Pedro Sopelanaand 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, withInstitutional Review Board (IRB) approval in process (Mithoefer & Wagner 2001). MAPS is alsoworking 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 Planstarts with pilot studies and concludes with two FDA-required "adequate and well controlledinvestigations" of safety and efficacy. This discussion outlines a strategy for developing MDMAinto an FDA-approved prescription medicine. A series of regulatory, ethical and methodologicalissues for the investigation of psychedelic psychotherapy in the context of FDA-approved clinicaltrials, which form the basis for the Clinical Plan, are discussed in detail in the context of my PublicPolicy dissertation (Doblin 2001).
Given the political and scientific hurdles, a rational analysis of the likely return on invest- ment would probably not inspire any venture capitalists to invest their risk capital into thedevelopment of MDMA as a prescription medicine. MDMA is off patent, PTSD or any other psycho-logical disorder for which MDMA might be effective affect more than 200,000 people so thatpatent protection under FDA's Orphan Drug program cannot be obtained, and the political hurdlesdue to MDMA's non-medical use may not be surmountable within any time frame that an investor "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, as
part of a strategy for developing MDMA into an FDA-
approved prescription medicine."
would consider realistic. Though the for-profit and side effects, all serve the generally similar approach for the development of MDMA as a pre- function of increasing access to psychological, scription medicine is of questionable viability, emotional processes. As a result, psychedelics the non-profit approach is more likely to suc- can be used as general purpose adjuncts to psy- ceed. There are probably enough philanthropists chotherapy, in the treatment of many conditions who, from personal experiences or otherwise, for which people seek out psychotherapy or psy- appreciate the political, scientific and medical chiatric treatment. The limited resources avail- importance of supporting the struggle to de- able to fund psychedelic psychotherapy research velop MDMA into a legal prescription medicine.
make it essential to chose the best test case of This discussion begins by evaluating the a specific psychedelic drug used in treating a strategic advantages associated with the con- specific clinical indication.
duct of FDA-approved research with MDMA forPTSD, as compared to other psychedelics that Why MDMA?
could be used for psychotherapy and other po-tential patient populations. Proposed protocol On the one hand, the psychological safety designs and sample sizes for the studies evalu- profile of MDMA is superior to that of all the ating the potential use of MDMA in the treat- other psychedelics. MDMA is relatively short act- ment of PTSD are based in part on a review of ing with primary effects lasting only about 4 documents pertaining to Pfizer's successful de- hours with gradual return to baseline over the velopment of Zoloft into the first FDA-approved course of another 2 hours or so. MDMA rarely medicine for the treatment of PTSD. These docu- interferes with cognitive functioning or percep- ments were obtained from FDA by the author tion and usually produces a warm, emotionally through Freedom of Information Act (FOIA) re- grounded feeling with a sense of self-acceptance, quest. A FOIA request for FDA documents re- and a reduction of fear and defensiveness. Sub- lated to its approval of Paxil for PTSD is still jects under the influence of MDMA can usually "negotiate" with their emergent psychologicalmaterial and often retain the ability to move at Choosing Drug and Patient Population
will toward or away from certain thoughts oremotions. In contrast, LSD lasts 8 to 10 hours, The primary strategic issue in conducting interrupts rational cognitive processes, impacts psychedelic psychotherapy research is estimat- perception, requires surrender to inner emotional ing the probabilities of success in the FDA drug processes rather than permitting negotiation, development and approval process of the nu- and can result in feelings of loss of control, fear merous combinations of any of the psychedelic and panic, as well as more positive emotions.
drugs and patient populations. Psychedelic All the major psychedelics such as psilocybin, drugs, though each with a unique set of actions mescaline, ibogaine, DMT, etc., resemble LSD more so than they resemble MDMA. Even the tively few of the Medical Examiner cases were effects of marijuana are more similar to the clas- for MDMA alone. Most were associated with sic psychedelics than to MDMA.
MDMA used in combination with one or more In terms of therapeutic potential, MDMA is other drugs. The Medical Examiner numbers do remarkable effective, gentle yet profound. Be- not reflect national totals, which do not exist, cause it operates on emotions more so than cog- but are simply the totals reported by the Medi- nitive processing, the MDMA state is only sub- cal Examiner offices that are included in the tly different than normal. As a result, the DAWN system. MDMA-related (though not nec- thoughts and emotions of the MDMA state can essarily causally related) hospital Emergency be easily remembered after the effects of the Room visits reported to DAWN (these are na- drug have worn off, facilitating integration and tional estimates) totaled 247 in 1994, 422 in long-term growth. Due to its relative short-act- 1995, 319 in 1996, 637 in 1997, 1142 in 1998, ing duration and its gentle action, MDMA has 2850 in 1999, and 4511 in 2000. (Office of Ap- the greatest opportunity of any psychedelic to plied Studies, 2001b).
be integrated into psychiatric practice. The clas- Furthermore, with the exception of sic psychedelics can be equally or even more ibogaine, the classic psychedelics have not been therapeutic but in different ways and with claimed to be "neurotoxic," as has MDMA. In greater personal struggles required of patients primates, at doses slightly higher than the and therapists.
amounts used in psychotherapy, MDMA has been On the other hand, the physiological safety linked to minor persisting reductions in seroto- profile of all the classic psychedelics is superior nin levels in a few brain regions (Ricaurte et al.
to that of MDMA. The extreme position on risk 1988), with the no-effect level for serotonin is expressed by Dr. Alan Leshner, ex-Director of reductions in primates being 2.5 mg/kg, admin- the National Institute on Drug Abuse (NIDA), istered orally once every two weeks for four who claims that "There is no safe way to use months (8X) (Ricaurte, unpublished, cited in any of these drugs [such as MDMA]," (Mertl 2000) Vollenweider et al. 1999a). Whether therapeu- that "even experimenting with club drugs [such tic doses of MDMA have any permanent impact as MDMA] is an unpredictable and dangerous on serotonin levels is a matter of substantial thing to do," and that chronic use of MDMA may controversy (Lieberman & Aghajanian 1999). If cause long-term problems with emotion, memory, high doses of MDMA are consumed frequently, a sleep and pain (Leshner 2001).
dosage pattern seen in some recreational users When used recreationally in dance clubs, of MDMA, MDMA may reduce serotonin levels for some users of MDMA (mostly in combination with extended periods of time (McCann et al. 1998).
other drugs) have died from hyperthermia as a Though there is evidence of recovery of seroto- result of overheating from vigorous dancing in nin levels over time, serotonin does not reach high ambient temperature environments with initial levels in all brain regions while some brain inadequate water or other fluid replacement.
regions recover to levels higher than baseline From 1994 through 1999, there have been a total (Fischer et al. 1995). Some changes may be per- of 68 MDMA-related deaths (may or may not be manent (Hatzidimitriou, McCann & Ricaurte causal) reported to the Drug Abuse Warning 1999). Fortunately for the heavy recreational Network (DAWN), though not all deaths were users of MDMA, these changes in serotonin lev- related to hyperthermia. Medical Examiner data els, if they do indeed occur in humans, seem reports 1 death associated with MDMA in 1994, largely asymptomatic. Evidence for any functional 6 in 1995, 8 in 1996, 3 in 1997, 9 in 1998, 41 consequences in animals or humans resulting in 1999 (Office of Applied Studies, 2001a). Rela- from even massive consumption of MDMA is weak. Concern centers around a series of stud- 2001). Politically, however, MDMA is not the ies that show statistically significant but mostly easiest psychedelic to try to develop into a pre- clinically insignificant reductions in a few scription medicine. Its non-medical use is in- memory functions in heavy poly-drug users who creasing, especially among young people. In the have consumed large amounts of MDMA (Bolla, 2001 Monitoring the Future survey, funded by McCann and Ricaurte 1998; Reneman et al. 2001; NIDA, 11.7 % of high school seniors reported Zakzanis & Young 2001; Croft et al. 2001; that they had tried Ecstasy at some point, up Gouzoulis-Mayfrank et al. 2000; Gamma 2001).
from 11.0 % in 2000 and 8.0 % in 1999 Concerns that negative functional consequences (Johnston, O'Malley & Bachman 2001). Police associated with MDMA use will increase over time authorities are seizing increasingly large as MDMA users age are hypothetical, and are amounts. Customs officials have seized 9.3 mil- not evidence-based.
lion ecstasy pills in FY 2000, as compared to Research has shown that neurotoxicity is 3.5 million in FY 1999 and 750,000 in FY 1998 exacerbated by high body temperatures and can (Office of Public Affairs, US Customs Service, be eliminated by a slight cooling of body tem- 2000; National Drug Intelligence Center, 2000).
perature (Malberg, Sabol & Seiden 1996; Malberg NIDA has called the increased use of MDMA an & Seiden 1998). The effect of temperature makes epidemic (NIDA 2000).
data about risk that is gathered from people Yet the political controversy about MDMA who take MDMA at raves of limited predictive offers one crucial advantage that makes MDMA value for estimating the risk of subjects exposed much more likely to become the first psyche- to MDMA in clinical settings. MDMA's increased delic to be approved as a prescription medicine.
risk profile is a direct result of its use in recre- As a result of the millions of non-medical users ational settings, with use in clinical research of MDMA around the world, health authorities, settings relatively non-problematic (Vollenweider anti-drug authorities and research scientists have et al. 1999a). In therapy, MDMA is not used on expended an amazing amount of time, energy a daily basis but rather as an adjunct to psycho- and money trying to understand the risks of therapy administered a relatively few times, with MDMA, its mechanisms of action, and the con- several weeks between therapy sessions. The sequences of acute and long-term use.
most sophisticated investigation of MDMA-neu- The number of scientific papers in the peer- rotoxicity has been conducted by Dr. Franz reviewed scientific literature reporting on re- Vollenweider at the U. of Zurich. Dr. Vollenweider search with MDMA in humans and animals, along found no evidence for serotonin reductions in with case reports discussing adverse events, MDMA-naive subjects who were given a PET scan exceeds 1240 according to a Medline search con- shortly before and then again four weeks after ducted by the author on May 1, 2002. Data in receiving a moderate amount of MDMA in the the peer-reviewed scientific literature can be therapeutic dose range (1.5-1.7 mg/kg) submitted to FDA as evidence in the assessment of MDMA's risk profile and safety, with the only The combination of the remarkable thera- cost being the time it takes to systematically peutic potential of MDMA, along with its sub- review the papers and organize the data for sub- stantial safety for use in clinical settings, makes mission to FDA. FDA is willing to accept pub- it a very attractive choice for drug development.
lished papers for review and has even approved A comprehensive risk/benefit analysis that lent drugs "based primarily or exclusively on pub- support to the case for clinical psychotherapy lished reports (FDA 1998)." The costs of con- research with MDMA was funded by MAPS and ducting these published MDMA studies is well submitted to FDA (Baggott, Jerome & Stuart, over $20 million. The availability of data from these studies dramatically reduces the amount (Mas et al. 1999; Cami et al. 2000), as well as a of additional funding that will be required to study investigating MDMA/alcohol interactions argue a case before FDA for MDMA's safety and (Hernandez-Lopez et al. 2002). A study inves- tigating the hormonal effects of MDMA has taken Several researchers have administered place in England (Henry et al. 1998) and a study MDMA to human subjects in clinical studies of investigating the immunological effects has MDMA's safety, mechanism of action and physi- taken place in Spain (Pacifici et al. 1999). Yet ological and psychological effects. More fre- with all this research, there is not one single quently, researchers have compared people who paper reporting data from a controlled scien- have used MDMA in non-medical contexts with tific study into the therapeutic use of MDMA.
controls. As of March 2002, more than 262 sub- MAPS' effort to initiate controlled, FDA- jects had been administered MDMA in the con- approved scientific research into the therapeu- text of legal research. There was also data in tic potential of MDMA in patient populations the scientific literature from more than 985 began in 1986, and has taken 16 years to come people who had used MDMA, sometimes in as- to fruition. A Phase II dose-escalation pilot tonishingly large amounts, in non-medical rec- study of MDMA-assisted psychotherapy in the reational contexts. These MDMAusers have been compared to "Psychedelic drugs, though each with a
more than 835 controls." unique set of actions and side effects,
An MDMA Phase I study with 18 patients has been suc- all serve the generally similar function
cessful completed in the United of increasing access to psychological,
States, though data on only thefirst 6 subjects have been pub- emotional processes. As a result,
lished (Grob et al. 1996). Two psychedelics can be used as general
other Phase I studies with MDMAfocused on objectives other than purpose adjuncts to psychotherapy."
safety have also been conductedin the United States. An MDMA pharmacokinetic treatment of post-traumatic stress disorder study was conducted at UC San Francisco (PTSD) has been approved in Spain. This is cur- (Everhart et al. 1999) and a study is underway rently the only study into the therapeutic use of investigating which brain neurotransmitter re- MDMA approved anywhere in the world. The ex- ceptor sites are involved in producing MDMA's istence of the Spain study, sponsored by MAPS, subjective effects (Tancer & Johanson 2001).
is an important practical factor behind the se- Studies in Switzerland have investigated MDMA's lection of MDMA as the initial psychedelic drug action on brain neurotransmitter receptor sites to focus on developing into an FDA-approved (Liechti et al. 2000), on information processing prescription medicine. The sixth patient in Spain, (Vollenweider et al. 1999b) and on the psycho- at the 75 mg. dose level, was treated on April logical and cardiovascular effects of a single dose 15, 2002. The researchers conducting the study of MDMA (Vollenweider 1998). Three MDMA phar- will gather the data in a sufficiently rigorous macokinetic studies have been conducted in manner so that it can be submitted to FDA for Europe in England (Fallon et al. 1999), Spain review. With the approval of this study, the (de la Torre et al. 2000), and Switzerland chance to develop the therapeutic potential of (Helmlin et al. 1996). A Phase I dose-response MDMA is now more than a mirage.
safety study has been completed place in Spain Why Post-Traumatic Stress Disorder?
The main advantage of working with a PTSD patient population instead of patients with ter- In choosing the patient population to study, minal illness is that PTSD patients as a group one of the criteria was that the unique proper- are probably in better overall health than can- ties of MDMA-enhanced psychotherapy needed cer patients and are taking fewer other medica- to be matched to a patient population in which tions, making it less complicated to work with MDMA therapy could offer a dramatic benefit.
them. Once the MDMA/PTSD study is underway Ideally, this benefit would require only from one in the US, MAPS will seek to obtain FDA ap- to three drug sessions to produce significant, proval for a study of MDMA-assisted psycho- measurable and long-lasting clinical progress.
therapy in hospice patients.
Alternative medications for this patient popula- In the US market, there are only two con- tion should be relatively ineffective, at least in ventional pharmacological treatments that have some subpopulation of patients. The patient been approved for patients with PTSD. On De- population should also be a group that the gen- cember 7, 1999, FDA approved the drug known eral public feels compassion towards, in order as Zoloft (sertraline) for PTSD, on the basis of to help overcome resistance to the idea of the four small clinical trials (it was already on the therapeutic use of psychedelics.
market as an anti-depressant). Two of the clini- The core of the MDMA experience has been cal trials showed no efficacy, two showed some described by one of the pioneering psychiatrists efficacy. These studies involved a total of 351 who worked with MDMA-assisted psychotherapy subjects. Subgroup analysis revealed that Zoloft in terminal cancer patients as "reducing the fear was efficacious in female patients but not in response to a perceived emotional threat." When male patients. According to Dr. Katz, Director of used therapeutically, MDMA is administered as the Division of Neuropharmacological Drug Prod- an adjunct to psychotherapy on an intermittent ucts, "The effect of the treatment appears to basis within a larger therapeutic relationship, come essentially completely from women (Katz usually fewer than four times and frequently only 1999)." On December 14, 2001, FDA approved once or twice. Numerous case histories and an- the use of Paxil (paroxetine) in the treatment of ecdotal reports testify to MDMA's ability to as- PTSD. Unlike the Zoloft trials, studies with Paxil sist people struggling to come to terms with showed efficacy in both men and woman. In- difficult life events (Stevens 1999/2000; Otalora terestingly, Zoloft and Paxil's mechanism of ac- 1984). These reports suggest that MDMA-assisted tion is to increase the amount in the synapse of psychotherapy should initially be explored not the brain neurotransmitter serotonin, the same in patients whose psychiatric symptoms origi- neurotransmitter that MDMA primarily impacts.
nated with biological imbalances with possible The difference is that MDMA increases seroto- genetic components, though MDMA might still nin acutely for a period of 4-8 hours after a be helpful in some ways with such patients, but single dose while Zoloft increases serotonin rather in patients who need some assistance in chronically but must be taken on a daily basis.
processing difficult emotions that have a deep The patient group that will be tested with component of fear and/or anxiety. Two of the MDMA in Spain is women survivors of sexual main categories of patients that fit this descrip- assault who suffer from chronic PTSD and who tion are people suffering from PTSD and people have already failed on at least one course of facing terminal illness. People with these two conventional treatment. The patient group that types of clinical conditions have been treated will be tested in the US will include men and with MDMA with some remarkable results in some women, survivors of sexual and/or criminal as- sault, who have failed on one course of treat- ment with an SSRI such as Zoloft or Paxil. The proval of Zoloft will be reviewed in order to un- patient group for the Israeli study will include derstand FDA regulatory policy as it applies di- patients who have PTSD as a result of war or rectly to the development of medications to treat terrorism, as well as sexual or criminal assault, PTSD. The most valuable documents in the pub- and who have failed on one course of an SSRI.
lic record include transcripts of the October 8, By choosing subjects who have already failed 1999 Psychopharmacologic Drugs Advisory Com- on one course of conventional treatment, the mittee (Psychopharmacologic Drugs Advisory risk/benefit ratio is improved in favor of per- Committee 1999), a slide show delivered at that mitting the study to proceed.
meeting by Dr. David Smith, Statistical Reviewer, We hypothesize that MDMA will prove help- FDA Office of Biostatistics (Smith 1999), and a ful in resolving some of these subjects' difficult complete file of the FDA approval package for and painful memories so that they can move Zoloft, NDA19839,SO26, obtained from FDA forward with some degree of resolution, not for- through Freedom of Information Act (FOIA) re- getting the past but not as burdened by it ei- quest. As of May 2002, FDA has not yet responded ther. MDMA-assisted psychotherapy also has the to a FOIA request for the Paxil approval pack- potential advantage of being cost-effective, since it can be delivered within a relatively shorttime.
October 8, 1999 Psychopharmacologic Drugs
MDMA in the treatment of PTSD is probably Advisory Committee Meeting: Study Design
the best combination of psychedelic drug and clinical indication that can most justify a fo-cused drug development effort. What such a Four clinical trials were reviewed on Octo- drug development plan might look like will be ber 8, 1999 by FDA's Psychopharmacologic Drugs elaborated below, after a brief review of the dis- Advisory Committee, advising the Division of cussion of the Psychopharmacologic Drugs Ad- Neuropharmacological Drug Products. Outcome visory Committee that recommended that Zoloft data was presented at the meeting by Pfizer and be approved for use in the treatment of PTSD.
The Advisory Committee meeting began FDA Review of Zoloft for PTSD
with an overview presented to the Committeeby Dr. Tom Laughren, Team Leader for Psychop- Pfizer's recent experience with its success- harmacology at FDA. He indicated that PTSD is ful development of Zoloft for the treatment of a chronic disorder and FDA, "ordinarily uses par- PTSD offers the most direct window into FDA allel group studies although one might ask policies and procedures for the design of research whether a crossover design might be appropri- protocols and the review of data for the phar- ate even for a chronic condition, if the condi- macological treatment of PTSD. There are many tion is very stable over time and there is a re- analogous issues and also important differences turn to baseline if the treatment is stopped (Psy- between the development of Zoloft, a medica- chopharmacologic Drugs Advisory Committee tion that has been approved by FDA for daily use for the relief of symptoms associated with Dr. Laughren further noted that, "this is a PTSD, and the development of MDMA, a drug chronic disorder and one may ask the question that is meant to be administered from 1-3 times whether or not there is a need for long-term on an in-patient basis as an adjunct to psycho- data and at what point in development should therapy for the relief of the underlying causes that information become available should that of PTSD. The public record related to FDA ap- become an issue for approvability. Now, as an "There are many analogous issues and also important
differences between the development of Zoloft.and the
development of MDMA."
aside, I should say that we never, up until now, adopted. In testing MDMA-assisted psycho- made that a requirement for approving a new therapy for PTSD, parallel groups are more ap- indication in psychiatric disorders (Psychophar- propriate than a crossover design since the hy- macologic Drugs Advisory Committee 1999: 11)." pothesis is that there will not be a return to Dr. Farfel, a Pfizer scientist, indicated that baseline after the MDMA treatment is over. This "subjects were dosed once daily beginning with is different for Zoloft, which offers mostly symp- 25 mg/dy in the first week [dosing was not tomatic relief with a significant number of sub- initially based on mg/kg] and then continuing jects relapsing once the use of Zoloft is ended.
flexibly titrated between 50 and 200 mg/dy From a financial perspective, this seems ideal thereafter (Psychopharmacologic Drugs Advisory for a pharmaceutical company since patients Committee 1999: 33)." FDA's Dr. Temple com- have a continued need to purchase the product mented about the titration design, indicating or the symptoms will return. In contrast, MDMA- that he would have preferred fixed doses. He assisted psychotherapy has been helpful in some said, "I would be curious as to why that design reported case histories after one to three ses- was chosen. If it was chosen to avoid adverse sions, with no additional MDMA sessions required effect, that would make some sense, but ordi- to maintain clinical improvement.
narily I think you would learn more from a ran- The fact that the Zoloft design allowed ti- domization to fixed doses, even if you inched tration suggests that it might also be possible your way up to those doses.Now you could to titrate the number of doses of MDMA-assisted analyze this to see if there was a dose/response psychotherapy a patient receives in one of the hidden in Psychopharmacologic Drugs Advisory Phase III trials, to match the treatment to the Committee 1999: 127)." Dr. Hammer, Advisory depth and speed at which the patient is able to Committee member, made the suggestion that resolve issues related to the original trauma.
one of the major studies should have been fixeddose and the other flexible, so as to have gained Sample Size for Efficacy
some information about dose/response relation-ships in one of the studies.
Dr. Gary Ryan, Group Director of Clinical Dr. Laughlen said, "One thing that we like Research, Pfizer, stated, "Our PTSD Clinical Trial to see for an indication that is more mature in program consisted of four placebo controlled some sense than this is, from a regulatory stand- trials enrolling a total of 757 patients (Psychop- point, we like to see an active control arm in a harmacologic Drugs Advisory Committee 1999: trial to help us in interpreting it, so that if an 16)." Though Dr. Ryan reported a total of 757 active standard drug, which is believed to work, patients, the data presented in the slides by Dr.
also fails, we are more inclined to discount that Smith indicated only 597 subjects, with the dif- study. This is obviously not a strategy you can ference due to attrition. Pfizer's Dr. Farfel re- use early on in the development of a new indi- ported that, "the mean number of subjects in cation (Psychopharmacologic Drugs Advisory each treatment group was approximately 95, for Committee 1999: 145)." a total of 376 subjects treated with sertraline This suggestion of an active control arm and 381 treated with placebo (Psychopharma- for subsequent treatments for PTSD should be cologic Drugs Advisory Committee 1999: 32)." In the two clinical trials that demonstrated chotherapy sessions that will be administered efficacy, a total of 385 patients were enrolled, to subjects, along with all the safety data al- 191 who received Zoloft and 194 who received ready gathered about MDMA from clinical trials placebo (Smith Slide #9). Dr. Charles Marmar, around the world, may enable the safety of MDMA Professor and Vice Chairman, Department of Psy- in PTSD patients to be investigated with as few chiatry, UC San Francisco, spoke for Pfizer and subjects as were used in the studies of Zoloft in noted that "you can see that for the most part the treatment of PTSD. This is a reasonable as- the effects, while meaningful, have been mod- sumption that would change depending on the est (Psychopharmacologic Drugs Advisory Com- strength and clarity of the data actually gath- mittee 1999: 29)," indicating that sample sizes ered in the clinical studies.
may need to be fairly large, especially in a com-parison study between MDMA and Zoloft or Paxil.
Estimates for Sample Sizes for the MDMA
Dr. Katz, Director of the Division of Neu- Phase III Trials
ropharmacological Drug Products, stated, "Thereare conditions where we have considered stud- Based on FDA's review of research into the ies positive or approved drugs on the basis of use of Zoloft in the treatment of PTSD, the power fairly small studies, but in which the treatment of Pfizer's studies as designed was considered has been statistically significantly different from inadequate for subgroup analysis but adequate the control. Of course, the smaller the study, for group comparisons. The studies as completed the more likelihood that there is some bias creep- had roughly 75 subjects per group. According ing in or that there is an imbalance is an impor- to Dr. Farfel, the groups had a mean initial en- tant characteristic that you don't really know rollment of about 95 subjects, with about 75 how to test for, you don't even know what they per group completing the trial and included in are necessarily. So we like to see larger studies final data analysis.
but there is no specific requirement for num- Until the effect size and variance of re- bers (Psychopharmacologic Drugs Advisory Com- sponse to MDMA-assisted psychotherapy is de- mittee 1999: 149)." termined, sample sizes cannot be estimated withaccuracy. The more pronounced the treatment Sample Size for Safety
effect and the smaller the variation in outcomes,the smaller the sample size needs to be to gen- Dr. Laughren mentioned that "this program erate significant results (Friedman, Furberg & overall was relatively small, and so in making a Demets 1985). In order to reduce variance so judgement about the safety of Zoloft, we relied as to reduce sample size, a homogenous patient heavily on the safety experience on other popu- population with a relatively uniform response lations. So, a question is, is that a reasonable should be selected. In the Zoloft studies, there extrapolation? (Psychopharmacologic Drugs Ad- was a substantial difference in response between visory Committee 1999: 14) " Dr. Farfel com- men and women. The Phase III MDMA studies mented on safety reporting, "Safety was inves- should be able to avoid this problem through tigated in 757 subjects, and nothing that was the review of data gathered in the Phase II tri- found in this development program suggests a als that will evaluate the effectiveness of MDMA risk that has not already been identified in pre- in men and in women. The Phase III trials can vious trials and indications, and is already not then be designed either with all men, all women, described in the labeling (Psychopharmacologic or a combination. With an advantage in unifor- Drugs Advisory Committee 1999: 55)." mity over the Zoloft designs, it will probably be The minimal number of MDMA-assisted psy- possible to obtain adequate power with 80 sub- "Yet the political controversy about
MDMA offers one crucial advantage
40 in the psycho- that makes MDMA much more likely
to become the first psychedelic to
dose condition.
Orphan Drug
be approved as a prescription
Not Possible
only 70 subjectsper group, since Dr. Kazdin has estimated, "for Dr. Marmar stated that the lifetime preva- comparing two treatments [for superiority, not lence for PTSD in the American adult population equivalence, making this a high estimate for a is 7.8%. Dr. Bonnie Green, Professor of Psychia- test of equivalence].a sample size of 71 per try at Georgetown University Medical School, group would be needed to retain power at the President Elect of the International Society for desired level for the median ES [effect size]." Traumatic Stress Studies (ISTSS) commented that (Kazdin & Bass 1989).
any one time, 5% of women and 2-3% of menhave PTSD (Psychopharmacologic Drugs Advisory Duration of Studies
Committee 1999: 22). Since the adult popula-tion of the United States is greater than 170 The studies of Zoloft that Pfizer submitted million, PTSD clearly does not qualify as an Or- for review were designed as 12-week trials. Dr.
phan disease since there are more than 200,000 Marmar noted that "suicide rates are an impor- potential patients in any given year.
tant issue both in the acute and chronic form(Psychopharmacologic Drugs Advisory Commit- MAPS' Clinical Plan for MDMA for PTSD
tee 1999: 27)," suggesting caution in the useof placebo groups in PTSD patients with a risk The following outline is of a sequence of factor for suicide. Relatively short treatment studies designed to evaluate the risks and ben- courses should be employed to minimize the efits of the use of MDMA-assisted psychotherapy amount of time patients are receiving placebo, in the treatment of post traumatic stress disor- or instead psychotherapy-alone with a sub- der (PTSD). This plan includes only studies fo- threshold dose of MDMA, which will maximize cused on the safety and efficacy of the use of suggestion without providing a direct pharma- one to four sessions of MDMA-assisted psycho- cological effect of MDMA.
therapy in patients with PTSD. The Clinical Plan Dr. Domingez, Advisory Committee Member, begins with a Phase II study since Phase I MDMA suggested that 12 weeks was sufficient for the safety studies have already been conducted in study since most people respond by then. She the United States, Spain and Switzerland.
noted that there was a trade-off between the As the studies of MDMA in patients with desire to extend treatment in order to give PTSD are conducted, additional safety issues may enough time to find an effect and the desire become apparent. Further research addressing not to keep people on placebo for an unneces- specific issues related to the safety of MDMA sarily long period of time (Psychopharmacologic may be required by FDA before there will be suf- Drugs Advisory Committee 1999: 129).
ficient information to justify a New Drug Appli- This discussion supports limiting the length cation (NDA). These additional studies, if needed, of MDMA treatment in the clinical trials to 12 may involve issues that will be addressed by gov- ernment-funded research teams around the world MDMA/PTSD pilot study in the United States.
already working to assess questions of safety The protocol was approved by the FDA on No- and mechanisms of action. Alternatively, these vember 2, 2001. As of May 2002, the protocol is issues may need to become the subject of re- still in the midst of the IRB approval process.
search by MAPS-funded scientific teams. How- The study should begin Summer 2002. The pro- ever, based on what is already known about tocol will involve 20 subjects with PTSD, both MDMA, it is likely that any safety issues related male and female. All 20 subjects will receive to the use of MDMA in PTSD patients can be about 12 hours of non-drug psychotherapy.
adequately addressed by the proposed studies Twelve subjects will also receive two sessions of in PTSD patients.
MDMA-assisted psychotherapy scheduled threeto five weeks apart, with a dose of 125 mgs at Phase II Spain Dose-Finding Pilot Study in
each session, while 8 subjects will receive 2 pla- Women Survivors of Sexual Assault
cebo sessions. The goals of this study are 1) toevaluate whether MDMA can be safely adminis- This study, being conducted by Dr. Pedro tered to PTSD patients and 2) to determine Sopelano and Jose Carlos Bouso, Ph.D. candi- whether there is any preliminary evidence of date, U. Autonoma de Madrid, is currently the therapeutic efficacy and, if so, to develop an only MDMA psychotherapy study underway any- estimate of the effect size.
where in the world in which MDMA is being ad- The entire treatment course will be con- ministered to patients. The goals of this study ducted in 12 weeks or less, in accordance with are, 1) to evaluate whether a single dose of the recommendations made in the FDA Pharma- MDMA can be administered safely to 29 female cologic Drugs Advisory Committee meeting that survivors of sexual assault with chronic PTSD, reviewed the data from the trials of Zoloft in 2) to gather preliminary evidence about thera- the treatment of PTSD, peutic efficacy and, 3) to determine which dose If the study does begin in Summer 2002, or doses should be used in subsequent larger- the research team should be able to complete scale studies. This study treated the sixth sub- both sessions in all 20 patients by Summer 2003.
ject on April 15, 2002 and is scheduled to com- The analysis of initial data can be completed by plete the testing of all 29 subjects by May 2003.
Fall 2003, with six month follow-up data analy- The Phase II dose/response study in Spain sis completed by Winter 2003. The final report will cost $65,000, or $2,240 per subject. The can be completed by Spring 2004.
Spain study involves just one treatment session The cost of the study is estimated to be per subject. The study is being coordinated by $12,000 per subject or $240,000. The costs of Jose Carlos Bouso, a Ph.D. candidate working this study include non-drug psychotherapy hours on the study for his dissertation. Under these as well as thorough neuropsychological evalua- circumstances, a cost of $2,240 per subject can tions, and quite a substantial cost for adminis- be obtained. This is the lower limit for the cost- trative work on the FDA and IRB approval pro- per-patient of any MDMA protocol.
cess. Subsequent studies will probably requirefewer non-drug psychotherapy hours and may Phase II United States Full-Dose Pilot Study
not require any neuropsychological evaluations, in Male and Female PTSD patients
depending on the results from this initial pilotstudy. Since administrative costs have been av- A research team under the director of Dr.
eraged over a small number of subjects, subse- Michael Mithoefer has worked with MAPS to de- quent studies with much larger subject popula- sign and obtain FDA-approval to conduct an tions, at least 10 times the size of this pilot study, can be conducted with significantly less the study will focus either on women, on men, cost per patient.
or on both. The study will be designed with apsychotherapy-alone group receiving a sub- Phase III Trials - 4 -Arm Multi-Site Study,
threshold (placebo) dose of MDMA, a medium dose group, a full dose group and a Zoloft orPaxil comparison group. The study will enroll The goal of this study is to be one of the approximately 280 subjects, 80 in each drug two primary FDA-required "adequate and well- treatment group and 40 in the psychotherapy- controlled investigations" demonstrating safety alone group. This study will involve a fixed num- and efficacy of the use of MDMA in patients with ber of sessions administered within a 12 week PTSD. Depending on the data from the pilot period. This study will involve three sessions for studies, the study will focus either on women, each subject, once every four weeks, with no on men, or on both. The study will be designed titration permitted. The use of two different de- with a psychotherapy-alone group receiving a signs for the two different Phase III studies, subthreshold (placebo) dose of MDMA, a me- with the US study using a variable number of dium dose group, a full dose group and a Zoloft treatment sessions depending upon patient and or Paxil comparison group.
therapist decision and the foreign study employ- The number of sessions will be titrated by ing a fixed number of three sessions, is based agreement of patient and therapeutic team, with on the recommendation made by Dr. Hammer a maximum of 4 sessions within a 12 week pe- during the October 8, 1999 meeting of FDA's riod. This study will hopefully start in Spring Pharmacologic Drugs Advisory Committee.
2004 and will take three years to conduct. The This study will hopefully start in Spring study will enroll approximately 280 subjects, 80 2004 and will take three years to conduct. The in each drug treatment group and 40 in the psy- study will enroll 280 subjects, should cost in chotherapy-alone group. Due to economies of the range of $8,000 per subject, for $2,240,000.
scale, the study should be able to be conductedfor about $8,000 per subject, for a total cost of Total Cost
The total cost of the sequence of studies Phase III Trials- 4-Arm Study Spain or
enumerated above amounts to $4,720,000. Ad- ditional animal or human toxicity studies maybe needed, though it is likely that these studies The second large-scale trial will be con- will have already been government-funded with ducted outside of the United States, in Spain or the data in the public domain.
possibly in Israel. FDA will accept data gathered The Clinical Plan elaborated above suggests outside of the United States, if it is gathered that a rough estimate of about $5 million will according to standards set by FDA. With one need to be expended over a five-year period to study conducted in the United States and one develop MDMA into a prescription medicine for in Spain or Israel, it should be possible to ob- just one clinical indication, PTSD. After MDMA tain marketing approval in both the United is approved initially for PTSD, only one adequate States and the European Community.
and well controlled multi-site investigation The goal of this study is to be one of the might be sufficient for the approval of subse- two primary "adequate and well-controlled in- quent uses of MDMA in closely related disor- vestigations" demonstrating safety and efficacy.
ders, such as in the psychotherapeutic treatment Depending on the data from the pilot studies, of anxiety and depression in cancer patients.
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