This protocol is for a randomized, double-blind dose-response study of MDMA-assisted psychotherapy in people experiencing anxiety as a result of diagnosis with advanced- stage cancer. The study is intended to investigate the safety of MDMA-assisted psychotherapy in these subjects. The study will also measure anxiety, quality of life, and pain in order to determine whether a psychoactive dose of MDMA and/or a minimally active dose, will reduce anxiety, improve quality of life, reduce use of anxiety and pain medications, and increase life functioning.

The proposed study is primarily intended for two purposes. The first is to explore whether MDMA-assisted psychotherapy can safely be administered to cancer patients with a prognosis of less than 12 months who suffer from anxiety related to the advanced- stage cancer diagnosis who have either failed to respond adequately, if at all, to previous medications for anxiety or who have refused anxiolytic medications. The second purpose is to determine whether this therapy will produce improvements in symptoms of anxiety. Anxiety will be assessed prior to any intervention, immediately after the experimental intervention sessions, at a follow-up evaluation conducted two months after the second experimental session, and in review of a Daily Diary tracking use of anxiolytic and pain management medications. The Spielberger State Trait Anxiety Inventory (STAI; see below under "Measures") will serve as a primary outcome measure of anxiety. Participants must have a score of 40 or higher on the STAI in order to be enrolled in the study. Improvement will be indicated by lower scores on established outcome measures of anxiety symptoms (STAI, (the primary outcome measure for anxiety), HAM-A, and SCL-90-R) (see Table 3 for the key to abbreviated test names), and reduced use of anxiolytic medications.

A secondary aim of this proposed study is to evaluate whether the experimental intervention translates into meaningful improvements in quality of life. Clinician and participant-rated measures on quality of life will be administered and assessed throughout the study (see Table 1 for the timeline). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC-QLQ-C30 will serve as a primary outcome measure of quality of life. Additional measures assessing quality of life include hopelessness (BHS), suicidal ideation (SAHD), spiritual well-being (FACIT-Sp), self-expansiveness (SELF), depression (HAM-D and SCL-90-R), symptom prevalence and frequency and associated distress (MSAS), physical performance (KPRS), reductions in extent or intensity of experienced pain and resultant use of pain-relieving medications (VAPS, Daily Diary, and MSAS). (See Table 3 for more details on measures.)

As described above in the Introductory Statement to this protocol and in IND #63,384, MDMA is a ring-substituted phenylisopropylamine derivative with a unique profile of psychopharmacological effects that make it well-suited as an adjunct to intensive psychotherapy. MDMA has been hypothesized to represent a new class of psychoactive agents, called "entactogens" (Nichols 1986; Nichols and Oberlender 1990), producing feelings of closeness to others, empathy, well-being, and insightfulness, with little perceived loss of control (Grinspoon and Bakalar 1986; Hegadoren et al. 1999; Nichols 1986; Shulgin and Nichols 1978). There is considerable previous human experience with the use of MDMA in the context of psychotherapy. Before MDMA was classified in 1985 as a Schedule I controlled substance, a number of therapists employed it as an adjunct to psychotherapy in the United States and Europe (Adamson 1985; Gasser 1994; Greer and Tolbert 1998; Greer and Tolbert 1986; Grinspoon and Bakalar 1986; Metzner and Adamson 2001; Stolaroff 1997; Widmer 1997). Although no well-controlled trials were conducted, these therapists concluded that MDMA could safely be administered in an outpatient setting and was clinically useful in treating various psychiatric conditions, including anxiety associated with a diagnosis of advanced cancer. More recently, placebo-controlled clinical trials have confirmed reports from these therapists that MDMA produces an easily-controlled, time-limited alteration of emotion characterized primarily by euphoria, increased well-being, sociability, self-confidence, and extroversion (Cami et al. 2000; Harris et al. 2002; Liechti et al. 2001a; Tancer and Johanson 2001; Vollenweider et al. 1998).

Anxiety, depression, chronic pain, and unresolved family issues can become serious physical and mental health problems for individuals living with a terminal illness. End- of-life problems, including pain management, are increasingly understood by caregivers and the public as significant public health concerns (Potter et al. 2003; Randall-David et al. 2003; Shvartzman et al. 2003). Efforts to improve the quality of life for these individuals are clearly a public health priority. Recent efforts to devise more effective medication management for pain control (MacPherson 2002; Thomas and von Gunten 2003), improve family communication and support (Wells et al. 2003), and to diagnose and treat psychiatric conditions that may emerge after diagnosis are all examples of improving care for the terminally ill. The frustration experienced by people with terminal illness with respect to limited treatment options, inadequate pain control, fears of eventual loss of autonomy, fear of stigma associated with receiving psychological counseling, and resentment about dependence on psychopharmacological agents has left some of these individuals with overwhelming suffering in their remaining days of life. These are some of the problematic issues that also underscore the continued drive for legislation supporting physician-assisted suicide. The assisted suicide law in Oregon (the "Oregon Death with Dignity Act;" Oregon Revised Statute 127.800- 897; www.ohd.hr.state.or.us/chs/pas/pas.cfm), a 1994 voter initiative, allows adults who are terminally ill to make requests for assistance in their suicide from their physicians: 171 individuals have ended their life through this mechanism since the program commenced in 1997. This Oregon initiative indicates that approved treatments and supports (including hospice service) clearly fail to meet the needs of some terminally ill individuals. The scientific investigation of more effective treatments and a wider array of treatments is of substantial public health importance.

Pharmacotherapy and psychotherapy are two interventions employed towards reducing the symptoms of anxiety experienced by those with a medical condition that has a poor prognosis for survival. Developing drugs and psychotherapeutic treatments that can aid people with terminal illnesses in revising their assessment and management of stressors that promote the expression of anxiety, panic, and other symptoms of an anxiety disorder may be one means of broadening and improving upon the array of effective treatment options available as well as further alleviating some of the suffering of individuals who experience inadequate relief from standard treatment measures. In their recent report, McClain et al. (2003) support developing additional palliative care interventions to improve the well-being of people with advanced-stage cancer by "... keeping psychological distress of patients who are facing death to a minimum. What is less clear, however, is whether interventions exist that can help raise a terminally ill individual's sense of spiritual well-being." Anecdotal reports of past experience with MDMA-assisted psychotherapy suggest that it could serve as such a treatment. On the basis of past reports of successful treatment of anxiety associated with advanced-stage cancer with MDMA- assisted therapy, and on the basis of its reported entactogenic effects (Greer and Tolbert 1998; Holland 2001), we hypothesize that psychotherapy conducted in combination with MDMA will produce symptomatic improvement in patients with advanced-stage cancer. Moreover, resultant decreased use of anxiolytic agents may better preserve cognition and sensorium, and therefore could significantly improve the individual's quality of life. Chronic use of benzodiazepines for the treatment of anxiety, for example, induces side- effects of compromised sleep architecture, memory difficulties, a plethora of other cognitive impairments, and general lethargy.

The subject population was selected in part because patients with advanced-stage cancer can fail to obtain satisfactory relief from currently available treatments. Furthermore patient and therapist reports of MDMA-assisted psychotherapy conducted prior to the placement of MDMA into Schedule I are suggestive of therapeutic benefits not achievable through other interventions. The qualities that have been associated with MDMA-assisted psychotherapy in anecdotal reports (i.e. decreased defensiveness, decreased stress, and enhanced alliances between subject and therapist, or between the subject and other relatives present) may be particularly useful in the treatment of anxiogenic cognitions, behaviors, and resultant emotions associated with terminal illness. Anxiety disorders involve prominent fear responses including panic attack. In a structured psychotherapeutic environment, review of anxiogenic issues and fears (including the fear of death) affords the opportunity to reduce or eliminate symptoms of anxiety both during the therapy session as well as after. Early clinical experience with MDMA is consistent with the hypothesis that MDMA can increase the therapeutic effectiveness of psychotherapy for people with terminal illnesses. The combination of anxiolysis (reduction in fear and anxiety), euphoria, feelings of interpersonal closeness, and facilitated recall for past events may maximize or amplify the benefits of psychotherapeutic interventions.

Prior to placement into Schedule I, MDMA was used in combination with psychotherapy in the treatment of neuroses, relationship problems, and PTSD (Adamson 1985; Greer and Tolbert 1998; Metzner and Adamson 2001; d'Otalora 2001). It was also used in the treatment of some individuals with chronic pain (Holland 2001; Greer and Tolbert 1998) and in individuals with advanced cancer (Holland 2001; Stevens 1997; Stevens 1999; Stevens 2000). Case reports and narrative accounts of MDMA-assisted therapy indicate that the treatment was often successful (Adamson 1985; Gasser 1994; Greer and Tolbert 1998; Metzner and Adamson 2001; Stolaroff 1997; Widmer 1998). A discussion of MDMA-assisted psychotherapy and a discussion of several case studies appeared in a peer-reviewed journal (Greer and Tolbert 1998).

In a psychotherapeutic context, MDMA was reported to produce a lowering of defenses and greater ability to think about and reflect on distressing thoughts and feelings (Naranjo 2001; Greer and Tolbert 2001; Greer and Tolbert 1998; Metzner and Adamson 2001). When spending time with loved ones, individuals who took MDMA in therapeutic contexts often spent time discussing painful or emotionally sensitive topics, such as the impending death of a loved one in the advanced stages of cancer (Stevens 1997; Stevens 1999; Stevens 2000). Reduction in pain was often reported (Greer and Tolbert 1998; Holland 2001; Stevens 1997; Stevens 1999; Stevens 2000). In an uncontrolled study of MDMA-assisted therapy (described below), couples or groups undergoing MDMA- assisted therapy reported increased intimacy and closeness to others (Greer and Tolbert 1986).

Individuals with PTSD sometimes vividly recalled or re-experienced parts of traumatic events (d'Otalora 2001), sometimes experiencing great distress as they did so, but they were able to return to the state of reduced fear and trust induced by MDMA. While therapeutic contexts often differed across practitioners (compare Naranjo 2001 with Metzner and Adamson 2001), all practitioners used largely client-centered therapies aimed at fostering openness to the emotional and cognitive (insight and recall-related) effects of MDMA.

Greer and Tolbert's (1986) uncontrolled, non-blinded study of MDMA in a therapeutic context found that most of the 29 individuals with mild to moderate psychological difficulties reported obtaining at least some lasting benefits after MDMA-assisted therapy (Greer and Tolbert 1986). During MDMA-assisted therapy, nearly all participants described experiencing both positive and undesirable effects. Positive effects included increased closeness and positive changes in attitude, and undesirable effects included self-dissatisfaction and mild depression. Written follow-up questionnaires, completed two months to two years after the therapy session, found that many participants continued to experience positive life changes, including changes in attitudes and beliefs, strengthened interpersonal relationships, and decreased non-medical or habitual substance use. Given the lack of appropriate controls and unblinded study design, one cannot exclude the possibility that some factor other than MDMA produced these improvements, but the study does demonstrate that individuals with mild to moderate psychological disorders can safely undergo MDMA-assisted therapy without deterioration in mental health, and that they were more likely to have improved quality of life afterwards.

Controlled studies assessing the subjective effects of MDMA in a non-therapeutic context reported that MDMA produced an increase in positive mood and positively experienced alteration in consciousness, anxiety relating to fears of losing control, and alterations in perception (Cami et al. 2000; Grob et al. 1996; Harris et al. 2002; Liechti et al. 2001a; Tancer et al. 2003; Vollenweider et al. 1998). Effects appeared to be similar in individuals who had past experience with ecstasy (e.g. Cami et al. 2000; Grob et al. 1996; Harris et al. 2002; Tancer et al. 2003) and in drug-naive samples (e.g. Liechti et al. 2001a; Vollenweider et al. 1998). Though MDMA increased both positive and negative mood, participants in these studies tolerated these effects well. These effects are somewhat comparable to effects reported in therapeutic contexts. However, it is expected that individuals undergoing MDMA-assisted therapy may be liable to experience more intense dysphoria, especially in relation to the condition or disorder with which they are grappling. Conversely, individuals struggling with anxiety, grief, fear, or rage, whether as a result of advanced-stage cancer or from a traumatic event, may also reach a greater sense of compassion for the self and others in settings constructed to foster these feelings. It should be noted, however, that the therapy proposed for this study in the experimental MDMA-assisted treatment sessions will have the intention of confronting and working through difficult emotions. Hence, signs of psychological distress 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, fear, or panic, may arise during the experimental sessions and should be understood as an opportunity for addressing and dealing with these events (see the Treatment Manual; Ruse et al. 2004). Hence temporary intensification of anxiety, if it occurs, will be considered an important element of the therapeutic process that may contribute to resolution or improved acceptance of anxiety and other intense emotions associated with the participant's anxiety disorder.

In the current study, MDMA given in combination with psychotherapy within a comfortable setting is expected to reduce anxiety through confronting or accepting fears and concerns relating to deterioration in health and impending death. Anxiety is expected to decrease both acutely during the experimental session and on subsequent assessments performed one week after each experimental session and two months after the second session of MDMA-assisted therapy. It is expected that MDMA will be well-tolerated in this population. Quality of life is expected to increase after a fully active dose of MDMA as a result of reduced anxiety relating to the cancer diagnosis and increased self- acceptance. Participants are expected to use anxiolytic medication less often during the course of the study, and they will experience less pain at least immediately after a fully active dose of MDMA.

John H. Halpern, M.D., is Associate Director of Drug Abuse Research at McLean Hospital, Belmont MA. He is a licensed physician and will be re-certified in Advanced Cardiac Life Support (ACLS) prior to the first experimental session. Dr. Halpern has completed a multi-year research fellowship at McLean Hospital's Alcohol and Drug Abuse Research Center (ADARC), and he is Associate Director of Substance Abuse Research at the Biological Psychiatry Laboratory. Dr. Halpern is Board Certified in General Psychiatry (ABPN). For more information, please see the CV submitted along with this protocol in the Appendix. Dr. Halpern will administer the informed consent and perform psychiatric screening for all prospective participants. He will conduct all non- drug psychotherapy sessions along with Dr. Naidoo, and he and Dr. Naidoo will conduct both drug-assisted psychotherapy sessions. He will assess vital signs during experimental sessions, following the instructions of the internist. Dr. Halpern will administer outcome measures to participants, and he will store and computerize all data. As Principal Investigator, Dr. Halpern is responsible for all administrative and general issues related to conducting this study.

Todd D. Shuster M.D. is a clinical oncologist at the Department of Medical Oncology at the Lahey Clinic Medical Center in Burlington, MA. Dr. Shuster is Board Certified in Internal Medicine, Oncology, and Hematology, and has maintained a fulltime medical oncology practice since completion of a Research Fellowship in Hematology/Oncology at the Beth Israel Hospital of Boston in 1995. Dr. Shuster will perform oncology assessments and will medically pre-screen his patients with advanced-stage cancer who are interested in study participation. He will administer pre-screening informed consent, review relevant information such as medical history, and will perform the initial medical examination and the examination occurring during the course of the study. Dr. Shuster will monitor all ongoing study data to ensure that subjects remain qualified for study participation.

Umadevi Naidoo is a psychiatrist working at the Erich Lindeman Mental Health Center. Dr. Naidoo is a board-eligible psychiatrist who has completed a Fellowship in Psychosocial Oncology at the Dana Farber Cancer Institute. She will conduct non-drug and experimental (drug-assisted) therapy sessions with the principal investigator. Arthur Siegel is Chief of Internal Medicine at McLean Hospital and is Board Certified in Internal Medicine. Dr. Siegel will examine and discuss the medical records and other relevant medical information of each prospective participant to ensure that they meet all criteria for study participation. He will act as on-site medical supervisor during the experimental sessions, remaining on-call and on-grounds during each experimental session, reachable through emergency radio if needed in the case of a medical emergency. Dr. Siegel will monitor all ongoing study data to ensure that subjects remain qualified for study participation.

John H. Halpern, M.D.
Associate Director of Substance Abuse Research
Biological Psychiatry Laboratory
Alcohol and Drug Abuse Research Cente>

Todd D. Shuster, M.D.
Senior Staff, Medical Oncology
Lahey Clinic Medical Center

Umadevi Naidoo, M.D.
Erich Lindemann Mental Health Center
Department of Psychiatr>

This protocol has been reviewed and approved by the Institutional Review Board of McLean Hospital, a psychiatric hospital affiliated with Harvard Medical School. The IRB at McLean Hospital may be reached through the following address:

The protocol has also been approved by the Institutional Review Board at the Lahey Clinic. The Lahey Clinic IRB may be reached at the following address:

Mary Oster
Director of Research Administration
Office of Research Administration
The Lahey Clinic Medical Center

The researchers will enroll twelve men and women diagnosed with advanced-stage cancer and with 12 months or less of expected remaining life who are experiencing diagnosis-associated anxiety. Participants will either be individuals who have failed to respond adequately, if at all, to anxiolytic medications or who refuse anxiolytic medications. Advanced-stage cancer is defined specifically for each cancer, but generally refers to a condition where the cancer is considered incurable or inoperable. Individuals may be men or woman aged 18 or older. Participants will have symptoms of anxiety and/or panic associated with the diagnosis of cancer (as opposed to a history of an anxiety disorder distinct from the diagnosis of cancer) that are clinically significant enough that the subject has been offered and/or prescribed standard medications or psychotherapy for alleviating these symptoms. Participants must have a score of 40 or higher on the Spielberger State Trait Anxiety Inventory (STAI; see below under "Measures.") The proposed study aims to enroll individuals who do not respond to anxiolytic medication or who refuse to take anxiolytics.

The first twelve participants who meet inclusion criteria without any exclusion criteria, and who are interested in study participation, will be included in the study. Participants will be referred from within the patient population from the group practice of co- investigator oncologist, Dr. Todd Shuster, at the Medical Oncology Department of the Lahey Clinic Medical Center. Any participants who drop out or are excluded between the first and the second experimental intervention sessions will be replaced. The investigators will attempt to recruit both men and women into this study. Similarly, it is anticipated that the racial/ethnic composition will be close to that of the regional population. The investigators will attempt to reach individuals of different ethnic or racial backgrounds in our recruitment efforts.

Individuals will be included as potential participants if they meet the following conditions:

Potential participants will be identified through the oncology practice at the Lahey Clinic Medical Center. Prospective participants will first give written informed consent before undergoing the medical examination and completing the Spielberger State-Trait Anxiety Inventory (STAI). Candidates will have been diagnosed with advanced-stage cancer that is not currently being actively treated with cytotoxic, biologic, hormonal (other than LHRH agonist injections for hormone refractory prostate cancer), or radiation therapy. As part of the screening process ("Day -1" - See Table 1 below), information regarding the type of malignancy, sites of disease spread, prior treatment, and expected prognosis will be collected.

Each prospective candidate's general medical condition will be assessed in the Medical Oncology Department by Dr. Shuster to determine suitability for study participation. This "pre-study screening" exam (see Table 1 for timeline) will be performed by co- investigator oncologist Dr. Shuster at the Lahey Clinic. Screening will last for up to 30 minutes and will involve gathering information regarding the type of malignancy, sites of disease spread, prior treatment, and expected prognosis. The medical examination will involve the following procedures: general medical history and physical exam, metabolic profile, assessment of serum electrolytes, Dr. Shuster will perform the medical examination. After an individual consents to participate in the study, Dr. Shuster or Dr. Halpern will perform additional medical tests to further establish participant eligibility. These include ECG, thyroid hormone levels and levels of TSH, HIV serology, and urine pregnancy test for females of childbearing potential. Results of HIV serology will be kept confidential, and appropriate referral for counseling will be made if necessary.

As part of the pre-study screening at the Lahey Clinic, prospective candidates will complete the STAI, a commonly used measure of anxiety. If an individual attains a STAI score of 40 or higher and if they meet all study criteria without meeting any exclusionary criteria, then the prospective participant will be provided with the informed consent for review at home, and contact information for reaching Dr. Halpern. If she or he is still interested in taking part in the study, the prospective participant will contact Dr. Halpern via telephone to discuss the study procedure, answer questions about the study and the informed consent, and arrange for an initial visit to take place at appropriate research facilities of or made available to the Biological Psychiatry Laboratory at McLean Hospital, where additional screening and written informed consent will occur. The pre- screening conversation will last 15 to 30 minutes and will be reviewed again at the beginning of the first scheduled meeting (see Table 1 for timeline) at McLean Hospital. All medical health data - including medical history, physical exam, electrocardiogram (ECG), and laboratory values - will be reviewed by the principal investigator, the co- investigator oncologist, and the co-investigator internist prior to accepting the candidate into the study. All three investigators must agree that all inclusion criteria have been met and that no exclusion criteria are present prior to this acceptance into the study. Any change in health status during the course of the study will necessitate a re-review by these three investigators to ensure that the inclusion/exclusion criteria are being met at least through the second experimental treatment session.

Each prospective participant will next meet with Dr. Halpern at an appropriate research facility of or made available to the Biological Psychiatry Laboratory at McLean Hospital. This baseline evaluation ("Day 0" on Table 1) is expected to last approximately two to three hours. After face-to-face discussion of the study procedures and alternatives to study participation and any other questions that may arise while reviewing the contents of the informed consent, the potential participant will be given a written quiz on the contents of the informed consent. Wrong answers on this quiz will not disqualify the individual from study participation but will be used as a tool to clarify understanding the contents of the information contained in the informed consent. After obtaining informed-consent and providing a copy to the participant, Dr. Halpern will commence with the baseline evaluation by first administering the SCID, a structured psychiatric interview (First et al. 1997) to provide a DSM-IV diagnosis of Anxiety Disorder Due to a General Medical Condition and to rule out the presence of exclusionary Axis I diagnoses (i.e., substance dependence, psychotic disorder, dissociative disorder, major affective disorder, or eating disorder). Prospective participants will also complete the STAI again to confirm a score !

40. Other outcome measures administered at this baseline meeting include observer-rated measures of symptoms of anxiety, depression, hopelessness, and quality of life; subject- rated measures of symptoms and quality of life; and psychiatrist-administered tests of mental status and diagnosis (see Table 1 for schedule and Table 3, in "Measures" for details on measures). Participants will also be instructed on keeping the Daily Diary and measures of daily pain. Specifically, the Daily Diary logs daily use of all medications and need for symptom-specific medications for acute symptoms of anxiety and/or pain. The Daily Diary will also ask the participant to rate their prior 24 hours of pain each day using the VAPS. Completing the Daily Diary is expected to take six to eight minutes. A urine sample will also be obtained for drug testing. Any remaining medical tests (such as EKG or laboratory tests) that have not been completed at the Lahey Clinic will be collected at this baseline evaluation visit at McLean Hospital. If it is more convenient for the participant to have these laboratory tests performed at the Lahey Clinic, this may be done in coordination with Dr. Shuster, provided all tests have been completed with sufficient time for all elements of the medical assessment to be reviewed by the investigators prior to the first scheduled treatment session day.

Potential participants who do not meet eligibility criteria at this point or who do not wish to participate will be referred for alternate standard treatment.

The proposed study is a randomized, double-blind dose-response study of MDMA- assisted psychotherapy in people with advanced-stage cancer and diagnosis-related anxiety. Upon enrollment, participants will be randomly assigned to one of two conditions, Low Dose or Experimental Intervention dose (see Table 2). The McLean Hospital Pharmacy will generate and maintain the randomization code and procedure. Four of the twelve participants will be assigned to the Low Dose condition, and eight of twelve participants will be assigned to the Experimental Intervention dose. Condition assignment will be maintained throughout the course of the study, since this study does not employ a crossover design.

Group assignment will be randomized using a table of random numbers generated by and placed on file at the McLean Hospital Pharmacy. The group assignment of each participant will be provided in a sealed envelope to investigators and a copy will be maintained at the McLean Hospital Pharmacy. If there is an adverse event or other emergency requiring knowledge of participant's condition assignment, as when pharmacological intervention is necessary, the blind may be broken for an individual participant.

Participants in the Low Dose condition will receive an initial dose of 25 mg MDMA followed 2.5 hours later by a supplemental dose of 12.5 mg on both experimental sessions, for a total of 37.5 mg MDMA on each session. On the first experimental session, participants in the Experimental Intervention condition will receive an initial dose of 83.3 mg MDMA followed 2.5 hours later by 41.7 mg MDMA, for a total of 125 mg overall. On the second experimental session, participants in the Experimental Intervention condition will receive an initial dose of 125 mg MDMA followed 2.5 hours later by a supplemental dose of 62.5 mg, for a total of 187.5 mg. For more details, see "Drugs and Dosage."

The study includes six conventional (non-drug assisted) psychotherapy sessions with Dr. Halpern and Dr. Naidoo, with all sessions lasting one hour, two experimental (MDMA- assisted) sessions, with the second experimental session scheduled two to three weeks after the first experimental session (See Table 2 in "Drugs and Dosage" below), and six administrations of outcome measures lasting from 60 to 90 minutes. A participant will have completed the study approximately three and a half months after screening, and two months after the second experimental session.

The timeline for participation in the study is outlined below in Table 1. Visits are to be scheduled within the week that the below numbered days fall within.

Table 1. Schedule of Visits Timeline

STUDY MEASURE	DAY
	-1	0	7	14 S^a	15	21	28 S^a	29	35	36	84
Pre-study Screening	x
Informed Consent		x
Baseline Evaluation		x
SCID		x
SCL-90-R		x									x
SELF		x									x
MMSE		x		x		x	x		x		x
HAM-D		x		x		x	x		x		x
HAM-A		x		x		x	x		x		x
STAI	x	x		x		x	x		x		x
EORTC QLQ-C30		x		x		x	x		x		x
FACIT-Sp		x		x		x	x		x		x
SAHD		x		x		x	x		x		x
BHS		x		x		x	x		x		x
MSAS		x		x		x	x		x	x	x
Psychotherapy			x		x	x		x	x		x
MDMA Treatment Session				x			x
Metabolic profile	x									x
Liver FCT	x									x
Drug Screen		x		x			x
Medical exam	x									x
KPRS	x									x
Daily Diary & VAPS		x	x	x	x	x	x	x	x	x	x
Number of days from first MDMA session				0	1	7	15	22	28	29	70
Conducted at Lahey Clinic	x									x
Conducted at McLean Hospital^b		x	x	x	x	x	x	x	x		x

a) "S" indicates study day with experimental treatment session.
b) Day 35 and Day 84 may alternately be performed at the participant's home if the participant requests doing so because declining health precludes travel to McLean Hospital.

All participants will undergo an introductory psychotherapy session prior to the first experimental session, where they will review their cancer-related anxiety and discuss what will occur during the experimental session. Psychotherapy with Dr. Halpern and Dr. Naidoo will also occur on the day after each experimental session, and one week after each experimental session, with the participant and investigators exploring and discussing the events of the experimental session. Participants will also receive a psychotherapy session approximately one week after each experimental session. The final psychotherapy session will occur eight weeks after the second experimental session. (See Table 1). If any additional psychotherapy sessions are conducted, participants will complete outcome measures before that session as well. If the participant's health precludes traveling to McLean Hospital after the second experimental session, then meetings for administration of measures and psychotherapy (on Day 35 and Day 84) can be conducted at the participant's home.

During the introductory psychotherapy session, the investigators and the participant will review the participant's anxiety and will discuss any other issues or goals the participant has for the initial experimental session. Participants will learn more about the procedures occurring during and after each experimental session, and the investigators will discuss the effects of MDMA and what might occur during an experimental session. The participant will also learn more about the rules and restrictions concerning the experimental sessions. The investigators and participant work together to formulate a goal or goals for the experimental sessions.

Psychotherapy follow-up sessions will be conducted in the morning on the day after the experimental sessions at McLean Hospital (see "Day 15" and "Day 29" on Table 1). The investigators and participant will review the events of the experimental session. They will seek to integrate the thoughts, feelings or insights that arose during the experimental session. Psychotherapy occurring after the first experimental session may also involve preparation for the second experimental session, if all involved have concluded that it is safe and appropriate for a second experimental session to occur. The participant will be instructed to not drive a motor vehicle or operate heavy machinery during this day. The participant will arrange a ride home from the facilities, and if he or she is unable to do so, the investigators will assist in locating transport from the research facilities. At time of discharge (or as soon as possible), a duplicate videotape of the prior day's experimental session will be provided to the participant (see "Experimental Sessions" below for more details on videotaping of sessions). This duplicate videotape will be edited to remove any portions of the videotape that the participant instructed to not be copied and to remove any silent/non-relevant portions of videotape (such as of the participant reclining with eye shades on and listening to recorded music).

Participants will undergo psychotherapy with the investigators approximately one week after each experimental session ("Day 21" and "Day 35" on Table 1). Each of these psychotherapy sessions will occur after the completion of outcome measures. The participant and the investigators will continue to review, discuss and explore the events of the preceding experimental session. Psychotherapy will continue to focus on reducing anxiety, but may also address other issues that arose during or after the experimental sessions. Psychotherapy conducted a week after the second experimental session may encompass the events of both the first and the second experimental sessions. As noted above, the participant may request additional psychotherapy sessions during the course of the study.

The final meeting between the participant and the investigators will occur approximately eight weeks after the second experimental session. After a final administration of all outcome measures, the investigators will speak with the participant about his or her anxiety level and quality of life in the interval between psychotherapy sessions. The investigator and participant may re-examine the goals set out for each experimental session, or they may return to the discussions and work that occurred during the previous psychotherapy session.

Outcome measures will be administered on six occasions; once prior to the initial psychotherapy session, on the day of each experimental session prior to drug administration, prior to each psychotherapy session scheduled a week after an experimental session, and on the final day of the study, two months after the second experimental session. No outcome measures, except for the Daily Diary and pain measures, will be administered prior to psychotherapy sessions conducted the day after each experimental session. Observer-rated and participant rated outcome measures will be administered during each approximately 60 to 80 minute research follow-up session, with research follow-ups occurring in appropriate research facilities of or made available to the Biological Psychiatry Laboratory at McLean Hospital. Daily Diaries will also be reviewed during these meetings. These instruments will include the participant-rated BHS, EORTC QLQ-C30, FACIT-Sp, MSAS, SAHD, SELF, STAI, and SCL-90-R, and the investigator-rated HAM-A and HAM-D (See Table 3). Participants will complete outcome measures on days when any additional sessions are scheduled (see "Psychotherapy.") More details about each measure can be found in "Measures" below. Daily Diaries will also be reviewed at these meetings. The Spielberger State-Trait Anxiety Inventory (STAI) will serve as the primary outcome measure of anxiety, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) will serve as the primary outcome measure of quality of life.

Participants will also be reassessed for psychological and physical status by the physician-investigators immediately following and one week after each session. This will occur during psychotherapy sessions. Physical assessment and examination will also be completed by the co-investigator oncologist one-week post completion of the second experimental intervention session (on "Day 36" on Table 1). The second medical examination will include a complete physical examination and a second metabolic profile and serological assessment of liver function. Any change in health status not related to the progression of the participant's advanced-stage cancer discovered during this second physical examination will be treated as an adverse event and will be reported as such.

Participants will undergo two experimental sessions with Dr. Halpern and Dr. Naidoo. Each experimental session will last for six to eight hours and will include an overnight stay at the research facilities. After the investigators have determined that the participant can undergo the experimental session, each participant will receive an initial dose of MDMA, as described in "Drugs and Dosage" below. The participant will lie or sit comfortably while listening to a musical program designed to facilitate introspection and deep emotions. Blood pressure and pulse will be measured at the outset of each treatment 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. Body temperature will be measured at the outset and then every thirty minutes for 6 hours with an automatic temperature sensor and telemetry device worn on the skin. The physician may also call for more frequent measurements in the event of clinically significant changes (for more details on measures of physiological effects, see "Monitoring for Toxicity" below). Approximately 2.5 hours after the initial dose, and at the discretion of the investigators, a second supplemental dose of MDMA will be administered, as described in "Drugs and Dosage" below. The supplemental dose will always be one half of the initial dose. Participants may have a significant other, such as a spouse, close friend or relative, accompany them during part or all of the experimental session and including the overnight stay at the research facilities. More details on each experimental session are provided below. The experimental session ends six to eight hours after the administration of the initial dose of MDMA. If the acute psychological and physiological effects of MDMA are no longer present and the participant appears well and in good mental and physical health, then the investigators will leave the facilities, to return the next day when a psychotherapy session will be conducted.

All MDMA treatment sessions will begin at 11:00 AM and will take place at an appropriate research facility of or made available to the Biological Psychiatry laboratory at McLean Hospital, located in Belmont, Massachusetts. 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 of childbearing potential, a pregnancy test. At this time, they will also complete measures of anxiety, quality of life, performance, and pain (as outlined in Table 2 below). Urinary pregnancy test results must be negative for the participant to continue with the experimental session, and urinary drug screens should be negative for all substances (marijuana, phencyclidine, opiates, cocaine, and amphetamines). A positive result from this drug screen may result in the participant being withdrawn from the study (for evidence of use of a non-prescribed drug) or having the experimental treatment session rescheduled to another day (a positive result for opiates will require careful review with the investigators to confirm that this result is due to the participant's standard and routine use of opiates for pain control and is not due in whole or in part to additional opiates taken as a P.R.N. for breakthrough pain in the prior 24 hours). Prior to MDMA 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 Toxicity" below) have been made and the researchers have discussed goals for this session and general procedures, participants will ingest gelatin capsules containing MDMA along with a glass of water, as described in "Drugs and Dosage" below.

Each experimental session will be videotaped. Comparison of information gathered from these videotapes may be qualitatively or quantitatively examined in an attempt to gain a better understanding of the effects of MDMA within a psychotherapeutic context. Participants will also be provided with an edited copy of the treatment session videotape, with lengthy periods of silence removed from the recording, for their personal use to aid in reviewing, recalling, and deepening the therapy between experimental treatment sessions as well as after the second experimental treatment session. Only one copy will be provided, and this copy will clearly be labeled "Confidential, not for duplication or broadcast," will have the contact information for the principal investigator, and will expressly forbid any viewing by any third-parties, other than the participant, people of the participant's choosing, and the participant's outside therapist.

The MDMA treatment sessions will be supervised and facilitated by the principal investigator, psychiatrist (John H. Halpern, M.D.) accompanied by an experienced female co-investigator/co-therapist (Umadevi Naidoo, M.D.). Both co-therapists will be present throughout the treatment sessions. The sessions will be conducted following the principles developed by Grof for LSD psychotherapy (Grof, 1980, pp. 123-147) and adapted for MDMA-assisted psychotherapy by Metzner and Adamson (2001) and by Greer and Tolbert (1998). The principal investigator has extensive experience treating anxiety and other psychiatric conditions in his psychiatric practice using both medications and psychotherapy. The co-investigator also has an extensive history of treatment within her practice and, in particular, has expertise in palliative care. General details on the psychotherapeutic approach to be used in this protocol can be found in a draft treatment manual for MDMA-assisted psychotherapy for PTSD (Ruse et al. 2002) and for anxiety associated with advanced-stage cancer (Ruse et al. 2004). The treatment method will be the same for each experimental session.

At the beginning of the session (11:00 A.M.), the co-therapist researchers will discuss with the participant his or her intentions for the session, including intentions regarding working with psychological issues related to their episodes of anxiety for which they may have previously taken PRN anxiolytic medications or antidepressants. After the session begins, participants 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 experimental session 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). The music will consist of instrumental music, as for example the recording "Santosh" by P.C. Davidoff and Friends. Dr. Halpern will maintain a limited but varied selection of instrumental recordings, including classical music, jazz, and other forms of instrumental music, and the participant may request a specific musical style for his or her session. 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 experimental session, 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 introspectively on his or her sense of self and life-history in order to increase the psychological insights mediated by the MDMA treatment.

Electrolyte-containing fluids will be freely available throughout the session within the limits described in "Monitoring for Toxicity" below. Food will be available during the latter part of the session. Foods provided will include crackers or bread, fruit and vegetables, and soups.

At the participant's request and after making arrangements with the investigators, a spouse, partner, relative, or friend may join the participant and investigators during the experimental session in order to offer support.

After approximately six to eight hours, if all medical parameters are acceptable and the participant is alert, ambulatory, and emotionally stable, the session will conclude and videotaping will stop. The co-investigator internist, Dr. Siegel will at this time also review the collected vital sign data with Drs. Halpern and Naidoo and may, if warranted, check on the participant to confirm health status. Participants will remain at McLean Hospital for an overnight stay, allowing for continued observation. A psychiatric resident will be hired for overnight availability and coverage during this time. The support person may also remain overnight if approved by the investigators. Staff at McLean Hospital will be available to treat any adverse event occurring during the overnight stay. 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 and their support person will be given the pager number of the principal investigator or the covering physician to call immediately if any problems occur.

The two doses of MDMA chosen for the Low Dose condition have been selected on the basis of their ability to produce minimal but detectable subjective effects (Grob et al. unpublished; Harris et al. 2002) and thus serve as an active placebo. The cumulative dose of 37.5 mg is not expected to produce any of the predicted subjective effects or improvements in anxiety, quality of life, or pain. The initial and supplemental dose of MDMA for Session 1 in the Experimental Intervention was selected so as to make the cumulative dose equal to that of the initial dose for Session 2 (125 mg), with the initial dose serving as a comparison for dose-response analysis. On the basis of previous research (Grob et al. unpublished; Mas et al. 1999; Lamers et al. 2004; Tancer and Johanson 2001), this dose is expected to produce most of the expected effects of MDMA without producing the full array of effects. The maximum initial dose of 125 mg MDMA in Session 2 has been selected for use in this study on the basis of prior reports of therapeutic effectiveness and tolerability (Greer and Tolbert 1998). Doses equal to or greater than 125 mg have been well-tolerated in previous studies of MDMA administered to humans (Cami et al, 2000; Grob et al, Unpublished; Harris et al. 2002; Lester et al. 2000; Mas et al, 1999; Tancer and Johanson, 2003; Tancer and Johanson 2001; Vollenweider et al. 1998). The cumulative dose of 187.5 mg has been exceeded by single doses in some previous research studies without any adverse events (Grob et al., unpublished, data cited on p. 52 of Dr. Mithoefer's protocol, IND# 63,384). With participants carefully monitored for any indicators of adverse events, this dose should prove tolerable and will produce the full array of subjective and physiological effects.

Table 2. Dose Regimen

	Session 1		Session 2^a
	Dose 1^b	Dose 2^c	Dose 1	Dose 2^c
Low Dose Group N = 4	MDMA 25 mg	MDMA 12.5 mg	MDMA 25 mg	MDMA 12.5 mg
Experimental Intervention Dose Group N = 8	MDMA 83.3 mg	MDMA 41.7 mg	MDMA 125 mgs	MDMA 62.5 mg

a) Session 2 is scheduled 2-3 weeks after safe completion of Session 1.
b) All doses administered are encapsulated with uniform shape, size, and weight.
Doses are taken orally with water.
c) Dose 2 is administered 2.5 hours after Dose 1, if ongoing assessment of safety and subject participation supports continuing the experimental session.

Each participant will receive an initial dose of MDMA followed 2.5 hours later by a supplemental dose of half the initial dose. The supplemental dose will be administered only if observation indicates that the participant is tolerating the first dose, and if both the researchers and the participant agree to proceed. The advantages of splitting the total amount of MDMA to be administered during a session include extending the duration of the session without increasing the peak effects of the predicted treatment and reducing the initial amount of MDMA administered to a patient population that may be more sensitive to dose-dependent effects than a healthy, normal population.

Each dose will consist of the specified amount of racemic MDMA mixed with inactive compound. Staff at the McLean Hospital Pharmacy will weigh out the appropriate amount of MDMA in gelatin capsules along with an inactive compound, such as lactose to ensure that the investigators cannot distinguish Low Dose and Experimental Intervention dose capsules by weight or appearance. Each participant will receive the same number of capsules during an equivalent session (first or second experimental session) so as to maintain the blind for condition assignment. Both Low Dose and Experimental Intervention Dose participants receive an identical number of capsules. MDMA will be administered p.o. along with 250 to 300 mL water.

Participants will receive MDMA on two experimental sessions spaced 2-3 weeks apart and described above in "Methods" on "Day 14" and "Day 28" (see Table 1). During these two experimental sessions, eight participants will be randomly assigned into the Experimental Intervention MDMA Group and will receive, in Session 1, 83.3 mg MDMA followed 2.5 hours later by an additional dose of 41.7 mg MDMA, and in Session 2, 125 mg MDMA followed 2.5 hours later by an additional dose of 62.5 mg MDMA. Four other participants will also be randomly assigned into the Low MDMA Group and will receive, in Session 1, 25 mg MDMA followed 2.5 hours later by an additional dose of 12.5 mg MDMA, and in Session 2 they will receive 25 mg MDMA followed 2.5 hours later by an additional dose of 12.5 mg MDMA.

Outcome measures were selected primarily because they are well-validated, clinically- relevant, and repeatable. These include observer-rated measures of symptoms of anxiety, depression, hopelessness, and quality of life; subject-rated measures of symptoms, quality of life, daily pain, and daily diary (logging medication use); oncologist-rated measures of physical health, review of laboratory values, and physical functioning; and psychiatrist- administered tests of mental status and diagnosis. Observer-rated and subject-rated measures of symptoms of anxiety and depression will be made at baseline, on the morning of each experimental session ("Day 14" and "Day 28"), one week after each experimental session ("Day 21" and "Day 35"), and at two months after the second experimental session ("Day 84"). This will be the case for all measures except for SCID, administered only at baseline, and SCL-90-R and SELF, administered only at baseline and two months following last experimental session. Observer-rated and participant-rated measures of hopelessness, desire for a hastened death, spiritual well-being, measures of quality of life, and of symptom prevalence, frequency, and distress will also be administered at these same times. Participants will be asked to keep a daily diary that logs daily use of all medications and need for symptom-specific medications for acute symptoms of anxiety and/or pain. Participants will also be asked to rate their prior 24 hours of pain each day using the VAPS. The measures that will be used in the course of this study are in Table 3 and listed below.

Table 3. Test Measures

Assessment	Abbreviation	Measure of	Time Needed	Clinician Rated	Participant Self-Rated	Screening or Outcome Measure
Beck Hopelessness Scale	BHS	Pessimism / hopelessness	5-10 minutes		X	Outcome
Daily Diary	--	Anxiolytic and Pain- control Rx	5 minutes		X	Outcome
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire^a	EORTC QLQ- C30	Global quality of life - five functional scales, and nine symptom scales	10-15 minutes		X	Outcome
Functional assessment of chronic illness therapy- spiritual well-being scale	FACIT-Sp	Spiritual well-being	5 minutes		X	Outcome
Hamilton Anxiety Rating Scale	HAM-A	Anxiety	5-10 minutes	X		Both
Hamilton Depression Rating Scale	HAM-D	Depression	5-10 minutes	X		Outcome
Karnofsky Performance Rating Scale	KPRS	Physical functioning ability	5 minutes	X		Outcome
Memorial Symptom Assessment Scale	MSAS	Symptom prevalence, frequency, and distress	10-15 minutes		X	Outcome
Mini-Mental Status Exam	MMSE	Cognition examination	10 minutes	X		Both
Schedule of Attitudes Toward Hastened Death	SAHD	Desires for a hastened death	5-10 minutes		X	Outcome
Self-Expansiveness Level Form	SELF	Transpersonal identity	10 minutes		X	Outcome
Spielberger State-Trait Anxiety Inventory^a	STAI	Anxiety	5-10 minutes		X	Both
Structured Clinical Interview for DSM-IV	SCID	Past and present psychiatric health	50 to 120 minutes	X		Screening
Symptom Checklist-90-Revised	SCL-90-R	General current mental health and quality of life	12-15 minutes		X	Both
Visual-Analog Pain Scale	VAPS	Rating of subjective pain experienced	2 minutes		X	Outcome

Total estimated time to complete all screening measures: 82-165 minutes
Total estimated time to complete all outcome measures: 94-132 minutes.

As noted in "Subjects" above, the oncologist investigator will administer the STAI during the pre-screening examination, and the participant must have a STAI score of 40 or higher to be considered for study participation. All outcome measures except for the Daily Diary and the VAPS will be administered during the baseline (introductory) session at the start of the study. Participants will be instructed on how to complete the Daily Diary and VAPS. As described in "Methods" above, participants will complete outcome measures on six separate occasions across the course of the study. In all cases, outcome measures will be completed prior to psychotherapy.

Measures made during the experimental sessions are primarily made for safety monitoring and are described below in "Monitoring for Toxicity." These measures consist of assessing blood pressure, pulse and body temperature periodically throughout the experimental session. The investigators will also measure ambient temperature during each experimental session.

There is now a considerable body of information indicating that the likelihood of significant toxicity is very low from the doses of MDMA proposed in this study. To date, MDMA has been administered to over 230 people in controlled and uncontrolled trials in clinical settings. Phase I studies conducted in the United States and Europe have failed to demonstrate toxicity (Boone et al. unpublished; Cami et al. 2000; Chang et al. 2000; de la Torre 2000a; de la Torre 2000b; Gamma et al. 2000; Frei et al. 2001; Grob et al. unpublished; Grob et al. 1996; Hernandez-Lopez et al. 2003; Lester et al. 2000; Lamers et al. 2004; Liechti and Vollenweider 2000a; Liechti and Vollenweider 2000b; Liechti et al. 2001a: Liechti et al. 2001b; Mas et al. 1999; Navarro et al. 2001; Pacifici et al. 2004; Pacifici et al. 2002; Pacifici et al. 2001; Pacifici et al. 2000; Pichini et al. 2003; Pichini et al. 2002; Pizarro et al. 2003; Pizarro et al. 2002; Segura et al. 2001; Tancer and Johanson 2003; Tancer and Johanson 2001; Vollenweider et al. 1998; Vollenweider et al. 1999). Single doses of up to 2.5 mg/kg were employed in one of the studies conducted in the US (Grob et al. unpublished), with eight subjects receiving single doses equal to or exceeding 125 mg MDMA, and two subjects receiving single doses over 187.5 mg during one session (data cited on p. 52 of IND #63,384). In another Phase I study in the US (Tancer and Johanson 2001), over twenty subjects were administered doses larger than 125 mg. The same team of researchers administered 2 mg/kg to subjects in a subsequent study (Tancer and Johanson 2003), including 9 single doses above 125 mg (Tancer 2003, personal communication to L Jerome, January 17, 2003).

Likewise, psychiatrists in the US and Europe reported using MDMA in a large number of patients before the drug was placed into Schedule I. When describing their experiences as therapists in books (Adamson 1985; Widmer 1998), book chapters (Metzner and Adamson 2001), articles in peer-reviewed (Greer and Tolbert 1998; 1986) and non- reviewed journals (Gasser 1994), these therapists did not report any severe adverse effects occurring during or after MDMA-assisted psychotherapy sessions.

Although serious untoward reactions are unlikely, the researchers will closely monitor participants during experimental sessions. Throughout all the sessions, participants will be attended to by Drs. Halpern and Naidoo, whose credentials are detailed above and in their attached CVs. Dr. Siegel (McLean Hospital's Chief of Internal Medicine) will remain available for contact over emergency radio and will be on-call and on grounds and available via the medical emergency response system set up for McLean throughout the hours of each experimental session. In addition, internal medicine will provide additional clinical supervision with site visits throughout the first two experiment sessions in addition to being available through radio coverage. Dr. Siegel will be directly available for consultation and for any emergency calls and will be able to come directly to the treatment site within a few minutes. Dr. Siegel will review medical status with Drs. Halpern and Naidoo at the conclusion of each experimental session.

The experimental sessions will be conducted at an appropriate research facility of or made available to the Biological Psychiatry Laboratory at McLean Hospital, which is less than 4 miles from the Mt. Auburn Hospital emergency room. The facilities will be equipped with a "crash cart" containing the emergency drugs and equipment necessary to respond to any complications. Diphenhydramine, injectable epinephrine, and other standard emergency drugs and equipment will be available in the treatment room if needed for countering an allergic reaction or another medical emergency. Available emergency medications include antihypertensive agents (such as nitroprusside and labetolol), pressor agents, anxiolytics, and intravenous fluids. In addition to these medications, the crash cart contains a defibrillator (with telemetry capability), an oxygen tank, a 12-lead electrocardiogram (ECG) device, a suction device, a pulse oxometer, an IVAC pump, and intubation equipment (including laryngoscope, and endotracheal tubes). Contingency plans for responding to adverse events are based on a comprehensive review of case reports of toxicity in illicit users reported in the Investigator's Brochure, and in a number of reviews (Cole and Sumnall 2003; Baggott 2002; Henry and Rella 2001), and represent a very cautious approach to the remote possibility of a serious complication. With these personnel and equipment, the researchers should be able to stabilize a patient on the research unit and then transport them by ambulance if medical hospital admission were required.

Written notice of the occurrence of a life-threatening adverse event will be given to the Lahey Clinic Medical Center and McLean Hospital IRBs within 24 hours and will be given to the FDA within 72 hours. Written notice of the occurrence of any serious but not life-threatening events will be given within 15 days. After the conclusion of the experimental session, a psychiatric resident will be hired for overnight availability and coverage. Participants or their support people, if present, will be able to contact the psychiatry resident (as well as the principal investigator) during their overnight period of observation if necessary. The investigators will monitor the following variables in order to detect possible adverse events during or after MDMA-assisted therapy.

The investigators will monitor for the occurrence of hypertension and related complications through frequent measures of blood pressure. Blood pressure and pulse will be measured at the outset of each treatment 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 values stabilize and the participant remains asymptomatic, or show signs of trending downward. Dr. Halpern will monitor the participant for signs and symptoms of a hypertensive crisis during the experimental session, with requested assistance from Dr. Siegel if and when applicable. The participant will be transferred to the Mt. Auburn Hospital if there is any indication that the participant experiencing a severe cardiovascular event. Reasons for moving a participant to the Mt. Auburn Hospital would include, but not be limited to, severe headache in the setting of hypertension, angina or neurological deficits regardless of blood pressure. A crash cart will be immediately available at the McLean Hospital research facilities and will contain nitroprusside in addition to the usual resuscitation drugs and equipment. This will allow treatment to be instituted without transferring the patient if that should become necessary. The physician/therapist may, at any time, make a clinical judgment to transfer the patient to Mt. Auburn Hospital for closer monitoring and additional treatment.

The investigators will observe the participant and note any complaints of chest pain. If a participant experiences ischemic type chest pain, whether or not it is associated with hypertensive crisis, he or she will undergo a STAT ECG, receive oxygen and an IV and will be monitored as described above. He or she will be given nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain pending transport to the hospital. If further evaluation at the hospital reveals that the participant has had an acute myocardial infarction (AMI), he or she will be well within the time frame required for definitive therapy. The American College of Cardiology/American Heart Association guidelines for the treatment of AMI recommend percutaneous transluminal coronary angioplasty (PTCA) as the treatment of choice when it can be performed within 90 minutes of arrival at the hospital in patients who present within 12 hours of an episode of chest pain lasting more than 30 minutes and who have ECG evidence of AMI (J Am Coll Cardiol 34:890, 1999).

The investigators will attend to any signs or symptoms of neurological deficit or confusion that is more extensive than might be expected from MDMA or from psychological distress. If any participant has neurological deficits, whether or not they are associated with hypertensive crisis, he or she will receive oxygen and an IV and will be monitored as described above. He or she will be transported to the Mt. Auburn Hospital for a head CT scan and further management. If evaluation at the hospital reveals a nonhemorrhagic stroke, there will be time to administer recombinant tissue plasminogen within the 3 hour time frame recommended in the American Academy of Neurology/American Heart Association guidelines (Neurology 47:835, 1996).

Both psychotherapist investigators will observe the participant for any indications of extreme anxiety or panic throughout the experimental session. They will offer support to the participant when requested and will make all efforts to assist the participant in confronting deep emotions while noting any signs of intense fear or rage, or signs of psychosis. If, after eight hours, the participant is still extremely distressed or extremely anxious, the investigators will remain with the participant until anxiety has returned to manageable levels or until the investigators conclude that the participant is in danger of harming him or herself or others. In the event that a participant appears to be in danger of harming the self or others, the investigators may hospitalize the participant until he or she returns to stable condition.

In the event of a participant's experiencing severe, persisting emotional distress, such as panic attacks, severe generalized anxiety, or persisting insomnia following an MDMA session, the investigators may prescribe a benzodiazepine or zolpidem as a "rescue medication." If a participant should become psychotic or suicidal, arrangements will be made for him or her to be admitted to the nearest inpatient psychiatric facility of their choice or directly to McLean Hospital. Residual symptoms will be addressed during the frequent follow-up psychotherapy visits with the investigators.

Body temperature will be measured at the outset and then every thirty minutes for 6 hours with an automatic temperature sensor and telemetry device worn on the skin. The physician may also call for more frequent measurements in the event of clinically significant changes. Ambient temperature will be measured and recorded hourly for six hours, starting immediately after drug administration. Elevation in body temperature that exceeds 1 degree Centigrade is unlikely to occur, and elevation great enough to be considered hyperthermia is not expected to occur.

As described above, water or electrolyte containing fluids will be available during each experimental session, and participants may request fluids at any time, within the restrictions described below. Dehydration within the context of a controlled laboratory setting and in the absence of rigorous exercise is not expected to occur.

Participants will be given electrolyte-containing solutions such as Gatorade instead of water in order to decrease the likelihood of dilutional hyponatremia. They will not be allowed to drink more than 3 L of fluids, and fluid intake will be appropriately spread out across the session. If there are any signs or symptoms of hyponatremia, a stat serum sodium will be drawn and fluids will be withheld until the results are obtained. If the serum sodium is less than 125mEq/L, serum and urine osmolality and sodium will be measured, and the patient will be transported to the Mt. Auburn Hospital, where further intervention can be provided.

Liver enzymes will be measured as part of the initial screening visit. Volunteers with preexisting abnormalities will be excluded from the study. Liver enzymes will be measured 4 days after the second MDMA session. Any participant who shows abnormalities on any of the liver enzyme determinations will receive further evaluation and follow-up by a gastroenterologist.

Psychological and neurological status will be clinically monitored by the therapists during the MDMA sessions and during therapy sessions at frequent intervals thereafter. If, on clinical examination during that period, a participant is found to have cognitive deficits that persist for more than two weeks, this participant will not be given a second MDMA session. Any participant who develops mania or psychosis will not be given a second MDMA session and will receive appropriate psychiatric treatment.

As discussed in the Investigator's Brochure, one of two studies of polydrug-using ecstasy users found a possibly increased incidence of developmental abnormalities when pregnant women used illicit drugs including ecstasy (McElhatton et al. 1999). Pregnant women will be excluded from participation in the proposed study and urine pregnancy tests will be performed before each drug administration. Women of child- bearing potential enrolled in the study must practice a reliable method of birth control, and they must have a negative pregnancy screen before undergoing each experimental session. A positive pregnancy screen will be cause for removal from the study.

MDMA is classified as a Schedule I compound with a high potential for abuse, primarily because of its use in settings such as "rave" dance parties. A survey of a representative sample of young people living in the Munich, Germany area found that about 6% of the sample reporting ecstasy use showed signs of ecstasy abuse or dependence (Lieb et al. 2002; Von Sydow et al. 2002). A sample of largely drug-naive participants who received MDMA in a controlled setting indicated that they would not seek out ecstasy again (Liechti et al. 2000; Liechti et al. 2001).

Individuals diagnosed with substance abuse or dependence disorders within sixty days of screening will not be admitted to the study. Prospective participants and participants will be encouraged to discuss their concerns about the abuse potential of MDMA with the investigators, and with their therapist or physician when applicable. Diversion will not be an issue in the proposed study because MDMA will only be administered under supervision of the investigating psychiatrists. No take-home doses will be permitted. As discussed elsewhere, MDMA will be stored and handled in compliance with Federal and local regulations for Schedule I compounds.