A battery of psychological and diagnostic assessments will be performed during the two weeks prior to the first experimental session in order to provide baseline measures of PTSD symptomatology, mood state and global functioning. All study measures described above, except WAI and the measure of subject beliefs on condition assignment, will be administered during baseline assessments.

Following the initial screening and data collection at baseline, all subjects will receive two ninety-minute introductory sessions with the therapists. The WAI will be administered during the second introductory psychotherapy session. During one of these introductory sessions the subject will be introduced to the attendant (an RN) who will be on duty the night after each experimental session. There will then be two individual experimental sessions conducted 3-5 weeks apart, each lasting approximately six to eight hours depending upon the participant's response. Three or four sixty to ninety-minute non-drug psychotherapy sessions will be conducted in the time intervening between the two experimental sessions. Participants will also see the investigators in a ninety-minute follow up session a day after each experimental session, and in two or three more psychotherapy sessions after the second experimental (MDMA or placebo) session but before the study has been completed. A final psychotherapy session will occur at the time of the final research follow-up two months from the second experimental session.

The attendant referred to above will be an RN, will always be of the same sex as the subject he or she will be staying with, and will be trained by Dr. Mithoefer to be on duty at the office following each experimental session. The attendants will be selected for their ability to act as reliable and compassionate attendants to the study subjects, and to recognize when to call Dr. Mithoefer in the event that a subject is experiencing physical or emotional distress during the night following an experimental session. A necessary quality for these individuals will be the ability to tolerate being in the presence of other people’s emotions without becoming emotionally reactive themselves. Attendants will be taught to be attentive to the subject's needs for food or liquids, and to offer companionship by sitting with them or taking a walk according to the subject's desires. They will be instructed to listen compassionately if the subject wants to talk, but not to attempt to interpret the subject's experiences or otherwise act as therapists. The emphasis will be on listening rather than talking and on being quietly present. The attendant will be taught to avoid initiating long conversations with the subject or being intrusive in any way on the subject's experience, other than to inquire about their physical or emotional needs and their comfort. This role will be further described below under Psychotherapeutic Procedures during Experimental Session.

Drugs and Dosing

Twelve individuals will receive 125 mg MDMA and eight individuals will receive lactose placebo in gelatin capsules on two occasions, 3-5 weeks apart. A dose of 125 mg MDMA has been selected for use in this study on the basis of prior reports of therapeutic effectiveness and tolerability. Doses equal to or greater than 125 mg have been well-tolerated in previous studies wherein MDMA was administered to humans (Cami et al, 2000; Grob et al, In preparation; Lester et al. 2000; Mas et al, 1999; Tancer et al, 2001; Vollenweider et al. 1998). MDMA will be supplied by David Nichols, Ph.D., Department of Medicinal Chemistry and Pharmacognosy, Purdue University. This MDMA is of confirmed identity and purity and has been used in all three Phase I clinical trials conducted in the United States.

Condition assignment will be randomized. Subjects will be stratified prior to randomization according to whether or not they have been Dr. Mithoefer's patients. The blind will be broken upon study completion. However, if there is an adverse event or other emergency, the blind may be broken for an individual participant.

All experimental (MDMA or placebo) sessions will begin at 10:00 AM and will take place in the clinical treatment office of Dr. Michael Mithoefer, located in South Carolina. Participants will have had nothing by mouth except alcohol-free liquids since 12:00 AM the evening before. Participants will not have consumed caffeine or nicotine for two hours before or six hours after drug administration. They will be asked to arrive at 9:00 AM for collection of a urine specimen for drug screening and, for females, a pregnancy test. These results must be negative for the participant to continue with the experimental session. Prior to drug administration, the researchers will verbally confirm that the participants have not recently ingested any medications (including herbal, over-the-counter, or prescription) that are not approved by the researchers or allowed in the protocol. After preliminary measurements (described in Monitoring for Acute Toxicity below) have been made and the researchers have discussed goals for this session and general procedures, participants will ingest gelatin capsules containing drug or placebo along with a glass of water. Subjects will remain overnight in the clinic until after the non-drug psychotherapy session the next morning. A subject’s decision to withdraw from the study at any time will be respected as is accepted practice in human research. In the event of withdrawal during an experimental session the subject will not be permitted to leave the clinic until Dr. Mithoefer has assured that he or she is in a safe and stable condition. Rules of withdrawal apply to the entire 2 experimental sessions while subjects are potentially on study medication. If they do withdraw from study participation, they will not leave the clinic until the study staff feels it is safe for them to do so, and when they leave, a friend or family member will drive them home. If transport is unavailable, the study staff will assist the subject in finding transport from the clinic.

Experimental Measures during Experimental Intervention Session

Measures made during the experimental sessions are primarily made for safety monitoring and are described below for "Monitoring for Toxicity." In addition, each experimental session will be audiotaped. Comparison of information gathered from these audiotapes may be qualitatively or quantitatively examined in an attempt to gain a better understanding of the effects of MDMA within a psychotherapeutic context.

Psychotherapeutic Procedures during Experimental Session

The MDMA or placebo sessions will be supervised and facilitated by the principal investigator, male investigator/psychiatrist (Michael C. Mithoefer MD.) accompanied by an experienced female registered nurse (Ann T. Mithoefer.). Both Michael and Ann Mithoefer will be present throughout the sessions. The sessions will be conducted following the principles developed by Stanislav Grof, MD for LSD psychotherapy (Grof, 1980, pp. 123-147) and for Holotropic Breathwork (Grof 2000: pp. 178-183) and adapted for MDMA-assisted psychotherapy by Metzner and by Greer and Tolbert (Metzner and Adamson 2001; Greer and Tolbert 1998). Both therapists have been trained and certified in Holotropic Breathwork facilitation by Grof, and have years of experience working therapeutically with this model in non-drug Holotropic Breathwork sessions. The principal investigator also has extensive experience treating PTSD in his psychiatric practice using both medications and psychotherapy. More detail on the psychotherapeutic approach to be used in this protocol can be found in a treatment manual draft for MDMA-assisted psychotherapy (Ruse et al. 2002). The protocols will be exactly the same for each experimental session.

At the beginning of the session, the researchers will discuss with the subject his or her intentions for the session, including intentions regarding working with psychological issues related to their PTSD. After the session begins, subjects will recline in a comfortable position with eyes closed or wearing eyeshades if preferred. They will listen to a program of music designed to support their experience by initially aiding relaxation and later evoking and supporting deep emotions and the emergence of unconscious material. (Bonny and Savary 1990; Grof 2000: pp.186-191; Grof 1980; Unkefer 1990). After the first hour, if the participant has not spoken spontaneously, the investigators will check in with him/her about the nature of the experience. For the rest of the experience, as appropriate, the investigators will engage with the participant to support and encourage emotional processing and resolution of whatever psychological material is emerging. The investigators will also encourage periods of time in which the participant remains silent with eyes closed and with attention focused inward in order to allow for the further unfolding of the inner experience.

Electrolyte containing fluids will be available ad lib throughout the session within the limits described in "Monitoring for Toxicity." Food will be available during the latter part of the session. Foods provided will include crackers or bread, fruit and vegetables, and soups. After the conclusion of the session, dinner will be made available by the attendant, with breakfast offered the next morning.

After approximately eight hours, if all medical parameters are acceptable and the subject is alert, ambulatory and emotionally stable, the session will be ended. During the last 30 - 60 minutes of the session, the attendant (an RN) will join the investigators and the subject in order to become familiar with the subject's state of mind, and any wishes the subject might have in the way of food or activity during the evening. If the subject so desires, an additional designated support person (a spouse, partner, relative or friend) may join in this meeting. After the researchers leave (when they have judged the subject to be emotionally and medically stable), the subject will spend the rest of the evening and night in Dr. Mithoefer's offices where he or she will have a private room to sleep in. The room will be an office designated for that purpose and will be furnished with comfortable furniture and a sofa-bed. All records pertaining to the study and any other sensitive material will be securely stored in a separate area of the clinic. The attendant will be on duty during this time and will have a separate room in which to rest. The clinic has a kitchen with eating area, two bathrooms, several offices, and a yard with an outdoor table and chairs. Since the office is in a quiet, attractive area, the subject, accompanied by the attendant, may spend time in the yard, walk in the neighborhood to enjoy nature. Subjects will, however, be encouraged to use much of the time for rest and for a period of reflection and integration in a quiet atmosphere. The subject may request that a spouse, partner or friend also remain with them during the night, but this must be approved by Dr. Mithoefer after he has met this support person and has discussed the possible advantages and pitfalls with the study subject.

During the night following the experimental session, Dr. Mithoefer will be at home within ten minutes drive of the office, and the attendant will be instructed to call him if the subject is experiencing emotional difficulties or any other problems. Dr. Mithoefer will be willing to return to the office to meet additional needs or provide requested support to the subject, and will be available throughout the night of the experimental session. (At all other times during the study the principal investigator or a covering psychiatrist familiar with the study will be on call 24 hours a day, seven days a week, to handle any concerns or emergencies related to the protocol. The participant will be given a wallet card with a pager number to call immediately if any problems occur.)

When the researchers return to meet with the subject for the scheduled ninety-minute therapy session occurring on the following morning, the attendant will go off duty. After this psychotherapy session, a person previously selected by the subject will provide a ride home. If the subject is unable to locate an individual willing or able to take them home, or if the designated person is unable to assist the subject due to unforeseen events, the investigators will assist the subject in finding an alternative means of returning home.

Starting on the day of the non-drug psychotherapy session following each experimental session, one of the investigators will contact the subject via telephone on a daily basis for one week. The investigators will use clinical judgment to assess the psychological well-being of the subject during this period of time. If there are any indications of continuing anxiety or distress, the investigators may arrange to work on reducing the distress at a specially scheduled non-drug therapy session, through continuing contact, or at the next regularly scheduled non-drug therapy session. The subject may also initiate contact with the investigators at any time throughout the study.

Monitoring for Toxicity

There is now a considerable body of information indicating that the likelihood of significant toxicity from the doses of MDMA used in this kind of setting is very low. Phase 1 studies conducted in the United States and Europe have failed to demonstrate toxicity (Cami et al. 2000; Grob et al. 1996; Harris et al. 2002; Lester et al. 2000; Liechti et al. 2001; Mas et al. 1999; Tancer and Johanson 2001; Vollenweider et al. 1998). Doses of up to 2.5 mg/kg were employed in one of the studies conducted in the US (Grob et al., In Preparation), with eight subjects receiving doses equal to or exceeding the dose of 125 mg proposed in this study. In another US Phase I study (personal communication, Tancer, 2001), over twenty subjects were administered doses larger than 125 mg.

Likewise, psychiatrists in the US and Europe reported using MDMA in a large number of patients before the drug was made illegal. The therapists did not report any severe adverse effects occurring during or after MDMA-assisted psychotherapy sessions (Adamson 1985; Greer and Tolbert 1986; Gasser 1994; Metzner and Adamson 2001; Widmer 1997).

Although serious untoward reactions are unlikely, the researchers will closely and continuously monitor participants during experimental sessions. The researchers have extensively communicated with the FDA to ensure that sufficient personnel and equipment are available to manage even very unlikely acute adverse effects. Throughout all the sessions, participants will be attended by Michael Mithoefer, M.D., and Ann Mithoefer, BSN. Michael Mithoefer has been board certified in Emergency Medicine and Internal Medicine, and practiced emergency medicine for 10 years before going into psychiatry. Dr. Mithoefer will maintain Advanced Cardiac Life Support certification throughout the study. Ann Mithoefer was a nurse in a cardiac care unit before going into psychiatric nursing. In addition, the researchers will hire a currently practicing, board-certified, emergency physician and a currently practicing, emergency department nurse to be present in an adjoining room during at least the first five hours of each experimental session, well beyond the peak blood pressure effects of MDMA. These two additional staff members, along with the investigator and assisting investigator, will provide a team of two experienced emergency physicians and two registered nurses, which would be comparable to the emergency response team in a hospital.

Blood pressure and pulse will be measured at the outset of each experimental session, once every 15 minutes for 4 hours, and then every 30 minutes for 2 more hours if the established thresholds for normal blood pressure and pulse have not been exceeded. If at any time the blood pressure exceeds 160 systolic or 110 diastolic or pulse exceeds 110, measurements will be taken every 5 minutes until the values fall below these levels. Body temperature will be measured at the outset and then hourly for 6 hours. The physician may also call for more frequent measurements in the event of clinically significant changes. The SUD (a brief self-report measure of volunteer distress) will be repeated at 60-90 minute intervals.

Both non-drug sessions and experimental sessions will be conducted in the psychiatric offices of Michael Mithoefer MD. The offices are located 2.6 miles from the nearest emergency room. The office will be equipped with a "crash cart" containing the emergency drugs and equipment necessary to respond to any complications. Benadryl, injectable epinephrine and other standard emergency drugs and equipment will be available on-site as a means of treating any potential allergic reactions or other medical emergencies. Available emergency medications include antihypertensive agents (such as nitroprusside and labetolol), pressor agents, anxiolytics, and intravenous fluids. In addition to drugs, the crash cart will contain a defibrillator (with telemetry capability), an oxygen tank, a 12-lead electrocardiogram (EKG) device, a suction device, a pulse oxometer, an IVAC pump and intubation equipment (including laryngoscope, and endotracheal tubes). We will have equipment for placing an arterial line and monitoring arterial pressure. The researchers have established (in communication with the FDA) contingency plans for responding to those adverse events that appear most likely, based on a comprehensive review of case reports of toxicity in illicit MDMA users reported in the Investigator’s Brochure (See Appendix). With these personnel and equipment, the researchers would be able to stabilize a subject in the office and then transport them by ambulance if hospital admission were required. The researchers have contacted the Charleston County Emergency Medical Services and learned that, in 2001, the average response time for an ambulance to arrive at a location in the sector where the research will be conducted was 8 minutes, 55 seconds. Transportation time to the East Cooper Medical Center Emergency Room should take no more than 10 minutes.

An assay of liver enzymes will be performed at research follow-up four days after the second MDMA/placebo session so as to detect any change or decline in liver function. Participants will be closely monitored for any change in emotional or cognitive function in the weeks following each session employing the experimental intervention.

Written notice will be given to the IRB and the FDA within five days of the occurrence of a life-threatening adverse event, and within 15 days of the occurrence of any serious but not life-threatening events.

The Data Safety Monitoring Board (DSMB) will be composed of three individuals, at least one of whom is psychiatrist and another a psychotherapist. The DSMB will have scheduled meetings after the first five subjects have completed their first experimental sessions, again after these same subjects have completed their final follow-ups, after subjects 6-10 have completed their final follow-ups, and after subjects 11-15 have completed their final follow-ups. DSMB meetings will also be held to review every report of a serious adverse event, or more frequently if the DSMB so chooses. After each meeting, the DSMB will present a report to the sponsor, the IRB and the FDA recommending whether the study should be continued as is, modified, or halted. Any new findings deemed relevant to study participation will be communicated to each potential participant during informed consent.

We feel that these precautions and the contingency plans described in the appendix represent a very cautious approach to the remote possibility of a serious complication.

The follow-up will begin 4 days after the first experimental (MDMA or placebo) session. There will be a total of three research follow-up interviews. The first two will be done 4 days after the first and second experimental sessions, respectively. The CAPS, IES and SCL-90-R will be administered as outcome measures to be compared with baseline scores. All outcome measures will be administered by Mark Wagner PhD, a consultant experienced in administering psychological and neurocognitive assessments. He will have no involvement in the experimental sessions and will be blinded to what occurs during the sessions. A research follow-up will also be done at two months after the second experimental session. The measures of cognitive function administered during baseline (RBANS, PASAT and Rey-Osterrieth Complex Figure) will be administered again at the last research follow-up, and the measures of PTSD symptoms will be administered again.

Participants will see the investigators one day after each of the two experimental (MDMA or placebo) sessions. During these 90-minute follow-up sessions, participants will be encouraged to describe their experiences during the experimental sessions and to freely express any thoughts, feelings, questions or concerns they have. The WAI, the measure of quality of working alliance administered during the second introductory session, will be administered again at each therapy follow-up session. Participants will also be asked to indicate whether they believe they received MDMA or placebo at each follow-up session. The primary purpose of these sessions will be to support the participant in further processing, understanding and integrating of the experience. It will also be an opportunity for the investigators to gather information, in an unstructured format, about the effects of MDMA or placebo and to provide data with which to evaluate after the conclusion of the study whether the blind was maintained for subjects.

Costs to Participants.

There will be no costs to the study participants. The sponsor will cover all costs of study participation. Charges for treatment of the participant’s condition that are unrelated to the research study or any of its procedures will continue to be billed to the health insurance provider of the participant or to the participant him or herself. It is anticipated that there will not be any charges for treatment that is unrelated to the study except in the case of participants who previously received therapy from the principal investigator and who will continue to receive ongoing treatment that is not related to participating in the study.

Treatment of a study-related emergency would first be billed to a participant’s health insurance provider. The sponsor will cover any direct costs relating to the treatment of a study-related emergency that are not covered by a participant’s health insurance. Most study-related emergencies can be treated by the investigators as described under "Monitoring for Toxicity and within the Appendix. If the investigator cannot treat a study-related emergency, then there are contingency plans for the transport of participants to the nearest hospital, East Cooper Medical Center.

Blood specimens will be obtained from the subjects during the evaluation and follow-ups as listed above. Temporary discomfort may arise as a result of sampling blood. Participants may experience temporary discomfort at the blood drawing site. There is also a remote possibility of inflammation or infection at the blood drawing site. Blood samples will be used for the most part to determine whether the participant is healthy and can safely take part in the study. Hence the temporary discomfort is outweighed by the need to ensure that participants are healthy, meet all inclusion criteria at screening, and are not experiencing adverse effects after the MDMA or placebo sessions.

Medical data will be collected via history and physical examination, and via measurement of vital signs. Submitting to a full medical examination may be time consuming, and may be distressing or uncomfortable for some. Because medical examinations are part of the screening procedure, they cannot be omitted from the study design.

Psychological and neuropsychological data will be obtained through interviews and neuropsychological testing. Because these interviews require individuals to discuss their condition, they may prove upsetting for some. Because psychiatric interviews and discussion of PTSD symptoms are used during screening, they cannot be avoided. The investigators have experience working with people with PTSD, and they will seek to reduce anxiety and distress during these interviews.

During non-drug and experimental sessions, participants will be asked to think about and discuss their thoughts and emotions relating to the traumatic event or events. They may experience intense emotional responses to recalling and speaking about this material. Even in a therapeutic context, thinking about and discussing the trauma, symptoms related to the trauma or the effects of PTSD on life function can produce distress during and immediately after non-experimental and experimental sessions. Psychotherapy is conducted as part of the research study, including the experimental intervention (MDMA-assisted psychotherapy), and people undergoing psychotherapy are expected to confront unpleasant thoughts, feelings and memories in the process of therapy. Because psychotherapy is an integral part of the research study design, the potential distress arising from psychotherapy is unavoidable.

In doses similar to those proposed for this study, MDMA produces sympathomimetic effects similar to the effects of a moderate dose of methamphetamine or other stimulants (Cami et al. 2000; Grob et al. In Preparation; Grob et al. 1996; Harris et al. 2002; Lester et al. 2000; Liechti et al. 2001a; Tancer et al. 2002; Vollenweider et al. 1998). The amount of MDMA used in this study is not likely to produce changes in blood pressure or heart rate greater than 40% of resting values. These changes should last no more than six hours. These changes have been well-tolerated by volunteers in previous studies and should not pose large risks to our participants, who have been carefully screened for cardiovascular and related problems. In less than 5% of volunteers, increases in blood pressure were higher. Clinical intervention was not required in any of these cases. Nonetheless, careful monitoring of participants and predefined contingency plans will allow the researchers to rapidly identify and manage any related toxicity.

MDMA also may produce mild alterations in perception and altered perception of time (Cami et al. 2000; Vollenweider et al. 1998). Women may be more sensitive to these effects of MDMA (Liechti et al 2001a). Some participants receiving MDMA report experiencing periods of increased anxiety (Harris et al. 2002; Tancer and Johanson 2001; Vollenweider et al. 1998). Psychological distress could arise at any time after the onset of the effects of MDMA, from the first indications of drug effects until the last effects have dissipated (approximately 3 to 5 hours after drug administration). Anxiety or distress may last for as little as 15 minutes or for as long as 5 hours. In previous Phase I studies, these symptoms have been modest, self-limiting, and responded well to reassurance from investigators. In the proposed study, participants will have the intention of confronting and working through traumatic experiences. Hence signs of psychological distress, panic or other unpleasant psychological reactions are to be expected. During the preparatory sessions, participants will be made aware of the fact that difficult emotions, including grief, rage and fear or panic, may arise during the MDMA sessions and should be understood as presenting an opportunity for addressing and dealing with these traumatic events. If significant anxiety persists more than a few hours after the expected end of the experimental session, contingency plans (described in appendix) include the continued presence of the investigators, support and assistance provided by an individual close to the participant, and the possibility of administering anti-anxiety agents.

Side effects of MDMA are modest and generally have not been associated with serious discomfort by volunteers in previous studies (Cami et al. 2000; Liechti et al 2001a; Tancer 2001; Vollenweider et al. 1998). Decreased appetite, jaw clenching, and dry mouth are commonly reported during peak MDMA effects, while fatigue may be felt up to several days afterward. Less commonly, mild anxiety and depressed mood are reported one and three days after MDMA administration (Harris et al. 2002; Liechti et al. 2001a; Liechti et al. 2000b; Liechti and Vollenweider 2000a; b; Vollenweider et al. 1998). Some of these effects are very likely to occur, but proper preparation and follow-up support will reduce the difficulties participants might have with acute or sub-acute side effects, so that they will not be unduly troubled by them.

MDMA may produce modest changes in immune functioning, lasting two to three days.

A research team in Spain has studied the immunological effects appearing after the administration of one or two doses of 100 mg MDMA (Pacifici et al. 2000; Pacifici et al. 2001). They reported a decline in CD4 cells, smaller CD4/CD8 ratio, attenuated lymphocyte proliferation in response to mitogen, and an increase in natural killer (NK) cells, with effects diminishing but still detectable 24 hours after drug administration. MDMA decreased production of pro-inflammatory cytokines, including IL-2 and interferon-Gamma and increased production of anti-inflammatory cytokines, including IL-4 and IL-10. Generally, MDMA appeared to decrease the concentration of Th1 cytokines and increase the amount of Th2 cytokines measured in blood. The mechanism of this MDMA-induced immunomodulation is unclear but may involve MDMA-induced glucocorticoid release or sympathomimetic activity. Changes of similar magnitude and duration have been previously noted after ingestion of other psychoactive agents, such as alcohol or cocaine (Pacifici et al. 2000; Pacifici et al. 2001). Because of their limited duration, these changes are not likely to have clinical significance beyond a possibly increased risk of the common cold or similar illness for several days. Previous Phase I studies have not reported any indication of increased risk of illness occurring after MDMA administration. Individuals who are positive for HIV or have other immunocompromising diseases will be excluded from the protocol.

MDMA may cause modest changes in cerebral blood flow lasting several weeks after drug exposure. These changes have been hypothesized to be the result of short-term down-regulation of serotonergic receptors controlling cerebral vasodilatation (Reneman et a. 2002; Reneman et al. 2000). MDMA induced decreased regional and global cerebral blood flow (CBF) 10 to 21 days after administration (Chang et al. 2000), as reported in a study of 10 ecstasy users given two separate ascending doses of MDMA at a two-week interval, with comparisons made at baseline and after the administration of both doses. Doses per administration in this study ranged from approximately 17 mg (0.25 mg/kg) to approximately 175 mg (2.5 mg/kg). The authors did not find differences in regional or global CBF when 21 MDMA-experienced volunteers (with a reported 211 ± 340 exposures) were compared to 21 nonusers (data are presented in the same paper), suggesting that effects on CBF do not last indefinitely. There are no known consequences of these changes and neurocognitive performance was not altered in these volunteers.

Serious MDMA toxicity is rare even in uncontrolled settings, considering the millions of users taking ecstasy of unknown identity, potency, and purity (Baggott, 2002; see Investigator’s Brochure). Many users routinely consume estimated MDMA doses that are several times higher than those proposed in the current protocol without any apparent toxicity. Under unsupervised and nonmedical conditions, the most common serious adverse event involves hyperthermia, which often appears to be influenced by prolonged physical exertion (dancing) and other unsafe conditions of use, such as high ambient temperature. In addition to hyperthermic syndromes, other rare adverse events include dysphoric responses, hyponatremia, and hepatotoxicity. In the proposed clinical study, volunteers will be carefully monitored for signs and symptoms of these unlikely events. Contingency plans for responding to these events are described in an appendix.

Risks posed by MDMA to pregnant women are not known. One of two studies of ecstasy users suggests that use of ecstasy and other drugs during pregnancy may be associated with some abnormalities at birth, but the meaning of these findings are in dispute. Women who are able to bear children will be required to use effective contraception during the study and pregnant women will be excluded from participation, with pregnancy tests performed before each drug administration.

MDMA is classified as a Schedule I compound, largely on the basis of its growing popularity at night clubs and parties in the early to mid-1980s. Whether or not MDMA’s abuse potential will negatively affect people with PTSD exposed to MDMA when given along with psychotherapy is an open question for which there is no direct data. However, instead of experiencing euphoria, people with PTSD undergoing MDMA-assisted psychotherapy during the experimental sessions are likely to experience painful and frightening emotions and memories related to the original traumatic incident. As a result, it seems unlikely that people with PTSD undergoing this emotionally challenging experimental intervention will find the experience pleasurable or safe enough to pursue MDMA use in unsupervised and uncontrolled settings.

There is no evidence that MDMA-naïve healthy volunteers exposed to MDMA in previous Phase 1 clinical studies have been motivated to seek out and use MDMA in non-medical settings. For example, Liechti et al. (2001) reviewed the effects of MDMA in 54 male and 20 female volunteers who had participated in clinical studies. Liechti and colleagues stated that "none of the participants expressed any interest in taking MDMA as a recreational drug" after participation in an MDMA study.

There is known to be significant comorbidity for substance abuse among individuals with PTSD, though specific data on the relationship between MDMA use and PTSD have not been reported. Currently, there is no definite evidence concerning the causal relations between the two disorders, and it is unclear whether PTSD precipitates substance abuse or whether people with pre-existing substance abuse are at greater risk for PTSD. The most commonly accepted hypothesis for the relationship between PTSD and substance abuse is that of self-medication (Meisler, 1996). Since individuals undergoing the proposed experimental intervention will be encouraged to confront traumatic events during the experimental intervention rather than defending against them or avoiding them, it seems likely that these individuals will subsequently be less inclined to choose to self-medicate through the self-administration of MDMA.

In the currently proposed study, diversion is not an issue because MDMA will only be administered under supervision of a psychiatrist and no take-home doses will be permitted. MDMA will be handled following all regulations pertaining to the handling and dispensing of controlled substances within research studies.