This randomized, dose-response pilot study is double-blinded for dose and uses a low dose condition that functions as an active placebo control. The study will involve 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. All participants will be recruited from within the group practice of the co-investigator oncologist Dr. Todd Shuster at the Medical Oncology department at the Lahey Clinic. Each participant will receive at McLean Hospital six one-hour sessions of non-drug psychotherapy, as well as two day-long experimental sessions using MDMA, scheduled 2-3 weeks apart, with overnight observation at McLean Hospital. Additional sessions may also be requested during the course of the study. 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 - See Table 2 below) can be conducted at the participant's home. Following baseline measures and one introductory psychotherapy session, all participants will receive MDMA on each of the two day-long experimental sessions (on Days 14 and 28).
A initial medical examination including an assessment of physical functioning ability will be performed by the co-investigator oncologist at the Lahey Clinic's Medical Oncology Department and will occur prior to acceptance into the study. Additional medical tests will performed after an individual has consented to be a research participant but at least two weeks prior to the first experimental session. Another complete medical examination will be performed one week after the second MDMA session ("Day 36"). During experimental sessions ("Day 14" and "Day 28"), participants will be supervised at all times by a male and female co-therapist, both psychiatrists, and also by an internist who will be available throughout each experimental session to respond to any medical emergencies, and, after the session, a psychiatric resident will be hired to be exclusively available during the period of overnight observation.
Data will be analyzed by mixed analysis of variance (ANOVA), with experimental intervention condition (Experimental Intervention Dose MDMA versus Low Dose MDMA) serving as a between-group factor and time of measurement, or experimental session (first or second) serving as within-subjects factors. It is predicted that participants receiving the Experimental Intervention doses will exhibit lower scores on measure of anxiety, higher scores on quality of life, and performance, and reduced indicators of physical pain and medication use than the participants receiving the Low doses. Statistical significance will be set at 0.05. Separate time-course analyses will be performed for systolic blood pressure, diastolic blood pressure, heart rate, and body temperature assessed during each experimental session. Of these measures, it is expected that statistically significant changes will only be detected in heart rate and blood pressure. These changes are expected to last several hours when Experimental Intervention Dose MDMA-assisted psychotherapy is compared to Low Dose MDMA-psychotherapy.
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. Participants will be unpaid individuals, male or female, age 18 or older, who have been diagnosed by an oncologist (Dr. Shuster and/or colleagues) at the Lahey Clinic Medical Center with advanced-stage cancer who have or are reasonably predicted to have less than 12 months of life remaining. Advanced-stage cancer is defined specifically for each cancer, but generally refers to a condition where the cancer is considered incurable or inoperable. Subjects 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. We will only include patients who are not taking or have safely withdrawn from other psychotropic prescription medications (example, SSRI or MAOI antidepressants) that might present an unreasonable risk of drug-drug interaction or that might confound any findings of therapeutic benefit.
Individuals will be included as potential participants if they meet the following conditions:
1. Have a diagnosis of advanced-stage cancer, as defined for the relevant type of cancer, with an oncologist-estimated 12 months or less of remaining life.
2. Meet DSM IV criteria for Anxiety Disorder Due to a General Medical Condition (Diagnosis Code 293.84) as indicated by the SCID and a score of at least 40 on the STAI.
3. Have failed to respond adequately or at all to medication intended to reduce anxiety, or have refused to take anxiolytic medication.
4. Are at least 18 years of age.
5. Are willing to commit to medication dosing, experimental sessions with overnight hospital stay, follow-up sessions, and to complete evaluation instruments (although they may withdraw from the study at any time without cause).
6. Have completed or independently decided to end all direct cancer treatments, such as chemotherapy and radiation, two weeks prior to the first experimental (MDMA) session. If they wish to initiate or resume treatment for cancer at any point prior to the second experimental (MDMA) session, then they will be withdrawn from the study and will be asked to see the co- investigator oncologist for a final physical examination. Participants will not be withdrawn from the study if they initiate or resume treatment after the second experimental (MDMA) session.
7. Are willing to refrain from taking any psychiatric medications during the study period, except for anxiolytic medications taken as needed on days other than the experimental sessions. If they are being treated with antidepressants or are taking anxiolytic medications on a fixed daily regimen at the time they are first evaluated, these potential participants should independently review their use of these medications with their treatment providers. Such drugs must be discontinued long enough before the first MDMA treatment session to avoid the possibility of a drug-drug interaction (the interval will be at least 5 times the particular drug's half-life). Participants will be withdrawn from the study if they wish to start or resume psychiatric medications prior to the final evaluation session.
8. If in ongoing psychotherapy, those recruited into the study may continue to see their outside therapist, provided they sign a release for the investigators to communicate directly with their therapist. Participants should not change therapists, increase the frequency of therapy or commence any new type of therapy until after the evaluation session 2 months after the second MDMA treatment session.
9. Participants must agree that, for one week preceding each MDMA treatment session: a. They will refrain from taking any herbal supplement (except when judged by the research team to not affect study measures). b. They will not take any nonprescription medications (with the exception of non-steroidal anti-inflammatory drugs or acetaminophen unless with prior approval of the research team). c. They will not initiate any new prescription medications (except with prior approval of the research team).
10. Participants must agree to take nothing by mouth except for routine medications and water after 12 A.M. (midnight) the evening before each experimental intervention session. Participants must also refrain from the use of any psychoactive drug, with the exception of caffeine or nicotine, within 24 hours of each MDMA treatment session. They must agree not to use nicotine for at least 2 hours before and 6 hours after each dose of MDMA. The must agree not to ingest caffeinated beverages until at least 6 hours after each MDMA treatment session. They must agree to not ingest alcohol-containing beverages for at least 1 day before each MDMA treatment session. They will not take any PRN medications on the morning of the MDMA treatment session prior to arrival to the hospital, although routine daily medications for pain control or nausea may be taken provided this use has been reviewed by the research team and is judged not to pose an undue risk to the safety and well- being of the participant. Non-routine PRN medications for treating breakthrough pain that were taken in the 24 hours preceding the MDMA treatment session may result in rescheduling the treatment session to another date, with the decision at the discretion of the investigators after discussion with the participant.
Individuals will be excluded from study participation if they are:
1. Women who are pregnant or nursing, or of child bearing potential and are not practicing an effective means of birth control.
2. Meet DSM-IV criteria for any Dissociative Disorder, Anorexia Nervosa, Bulimia Nervosa, a primary psychotic disorder or affective disorder (other than Anxiety Disorder Due to a General Medical Condition and Simple Phobia).
3. Meeting DSM-IV criteria for abuse of or dependence on any substance (other than caffeine or nicotine) in the past 60 days.
4. Diagnosed with known primary or metastatic cancer of the CNS.
5. Diagnosed with significant, unstable hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, renal, gastrointestinal, immunocompromising, or neurological disease, including seizure disorder, that in the clinical judgment of the investigators poses too great a potential for side-effects.
6. Have baseline laboratory values indicative of severely compromised hepatic function. Exclusion will occur if total bilirubin is 2.0 mg/dL or greater (approximately twice the upper limit of normal) or if the transaminases ALT (SGPT) or AST (SGOT) are 5 times or greater the upper limit of normal. Five times the upper limit of normal for alanine aminotransferase (ALT) and for aspartate aminotransferase (AST) is 175 U/L.
7. Diagnosed with significant peripheral vascular disease, hepatic disease, renal insufficiency, or preexisting or past evidence of hyponatremia.
8. Diagnosed with hypertension, even if well-controlled with medication. A systolic blood pressure of 140 or greater and/or a diastolic blood pressure of 90 or greater will exclude the potential participant from this study.
9. Weighing less than 45 kg.
10. Reporting a history of use of "ecstasy" (illicit drug preparations purported to contain MDMA) at any time within the previous 3 months.
11. Reasonably judged to present a serious suicide risk or who are likely to require psychiatric hospitalization during the course of the study.
12. Requiring ongoing concomitant therapy with a psychotropic drug other than PRN as needed anxiolytic medications and pain control medications.
13. Is unable to fully understand the potential risks and benefits of the study and give informed consent.
14. Is enrolled as a participant in any other medical research protocol.
3.2.3 Recruitment and Informed Consent
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 or completing the Spielberger State-Trait Anixety Inventory (STAI). After this initial examination and administration of the STAI, Dr Shuster, the oncologist investigator, will provide participants with consent materials and information for contacting Dr. Halpern if they wish to take part in the study. Prospective participants who meet the inclusion and exclusion criteria and express an interest in participating will contact by the principal investigator by telephone. In addition to answering any questions about the study during this phone conversation, Dr. Halpern will again discuss and review the study procedures (including risks, potential benefits, and alternatives) with the participants before participants give written informed consent at the first scheduled meeting ("Baseline Evaluation" - "Day 0") at McLean Hospital. Participants will be encouraged to ask questions and consider their alternatives. The prospective participant's comprehension of material in the informed consent will be assessed through a 17-item quiz administered after the prospective participant has read the consent form. The investigators will address any misunderstandings identified through incorrect quiz responses, and will use the quiz as a guide for further discussion of the study if necessary. Additional medical tests performed by the oncologist-investigator or by Dr. Halpern to assess study eligibility will occur after the participant has given consent to take part in the study, within two weeks before scheduling the first experimental session.
3.2.4 Oncology Assessment and Initial screening
Candidates for study participation will be referred to the other investigators through the oncology practice of co-investigator Dr. Todd Shuster at the Lahey Clinic's Medical Oncology Department. 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 2 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 ("Day -1") 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 5-minute Spielberger State-Trait Anxiety Inventory (STAI). If a score of 40 or higher is recorded, and other eligibility criteria are met, an informed consent form will then be provided to the patient for review at home. Patients will then be contact Dr. Halpern 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 ("Baseline Evaluation"; "Day 0") 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") 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 (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 2 for schedule and Table 3 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.
We 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. We will attempt to reach individuals of different ethnic or racial backgrounds in our recruitment efforts.
Interview and test procedures will generally be conducted in an appropriate research facility of or made available to the Biological Psychiatry Laboratory at McLean Hospital. The facilities will have overnight accommodations as well as full access to the ancillary facilities of the hospital. Following pre-study evaluation, individuals who meet the study criteria (as confirmed by review of this data by the principal investigator, co-investigator oncologist, and co- investigator internist) and who agree to participate will be scheduled for an introductory psychotherapy session ("Day 7") to be administered within 7-14 days prior to their first MDMA session ("Day 14"). Participants will be randomized to either the Low Dose Group (N = 4) or the Experimental Intervention Dose Group (N = 8) (see Table 1 below), and group assignment will be maintained throughout the study (this protocol does not have a crossover-design component). The McLean Hospital Pharmacy will generate and maintain the randomization code and procedure.
Table 1. Dose Regimen
| Session 1 | Session 2a | Dose 1b | Dose 2c | Dose 1 | Dose 2c |
| 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 |
The safety monitoring measures that will be used during the experimental sessions will include automated blood pressure and pulse monitoring equipment and a thermometer for reading body temperature. Blood pressure and pulse will be measured at the outset of each experimental 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 the values stabilize and the participant remains asymptomatic, or they show signs of trending downward. Body temperature will be measured and reviewed at the outset and then every thirty minutes for 6 hours with a tympanic temperature sensor and an automatic temperature sensor will be recording core body temperature throughout the experiment for later detailed review. The physician may also call for more frequent tympanic temperature measurements in the event of clinically significant changes. Ambient temperature will be measured and reviewed hourly for six hours, starting immediately after drug administration. After the occurrence of an adverse event, such as extremely elevated blood pressure or an extreme panic reaction, the investigators may arrive at a clinical judgment not to administer either the supplemental dose of MDMA within an experimental session, or a second experimental session. Monitoring participants throughout the study should effectively detect and respond to any cardiovascular or thermoregulatory problems during the study, especially with the co-investigator internist or appropriate designate immediately available for the first five hours of each experimental session by remaining in a room adjacent to the treatment room.
On experimental session days ("Day 14" and "Day 28"), 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. Doses of MDMA in the Low group will range from 25 mg (initial dose in both sessions) to 37.5 mg total per session. These doses are predicted to be slightly psychoactive (Grob et al. 1996; Harris et al. 2002) and are predicted to serve as an active placebo-control test condition. The Experimental Intervention doses of MDMA range from 83.3 mg (initial dose for Session 1) to 187.5 mg (total dose in Session 2).
The above-mentioned Phase 1 studies of MDMA with healthy normals, as well as anecdotal reports in cancer patients pre-dating the scheduling of MDMA, suggest that 83.3 mg of MDMA is a dose that will not achieve the full psychotherapeutic effects reported after 125 mg. Therefore, the experimental treatment paradigm is to explore the optimal strategy for administration of MDMA in this dosage range, with Experimental Session 1 administering 125 mg split into two doses, and with Experimental Session 2 administering 125 mg in the first dose and then supplementing this dose with 62.5 mg as a second dose. This will allow researchers to examine dose-dependent differences in safety and efficacy both across sessions and between groups, with active placebo serving as control. Data collection and experimental sessions will be completed according to the timeline contained in Table 2 and the test measures are listed in Table 3. One day after each experimental session, a non-drug psychotherapy session will occur at McLean Hospital ("Day 15" and "Day 29"). Also at McLean Hospital, additional non-drug psychotherapy sessions will be conducted and data will be collected between the two experimental sessions (on Day 21) and one week after the second experimental session ("Day 35"). A follow-up medical examination including physical and other measures of physical functionality will also follow one week from the second experimental session (on Day 36). This follow-up medical examination will be performed at the Lahey Clinic Medical Center by co-investigator oncologist Dr. Shuster. A final data-collection session ("Day 84") will take place at McLean Hospital two months after the second experimental session and the participant will also have a final psychotherapy review hour with the co-therapists.
The timeline for participation in the study is outlined below in Table 2. Visits are to be scheduled within the week that the below numbered days fall within.
Table 2. Schedule of Visits Timeline
| STUDY MEASURE | DAY | ||||||||||
| -1 | 0 | 7 | 14 Sa |
15 | 21 | 28 Sa |
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 Hospitalb | x | x | x | x | x | x | x | x | x | ||
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 Questionnairea | 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 Inventorya | 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 |
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 symptomatology, mood state, and global functioning ("Day -1" and "Day 0"). All study measures described above will be administered during baseline assessments. The baseline assessment should last from 1.5 to a little over 2 hours.
3.5 Non-Experimental Psychotherapy Sessions
Following the initial screening and data collection at baseline, all participants will receive one sixty-minute introductory psychotherapy session with the co-therapist investigators (Drs. Halpern and Naidoo) ("Day 7"). There will then be two individual experimental sessions conducted 2-3 weeks apart, each lasting approximately six to eight hours depending upon the participant's response ("Day 14" and "Day 28"). One sixty-minute non-drug psychotherapy session will be conducted in the time intervening between the two experimental sessions ("Day 21"). Outcome measures will be completed at McLean Hospital on the same day as the scheduled psychotherapy sessions, with completion of outcome measures taking approximately ninety minutes. Participants will also see the investigators in a sixty-minute follow up session a day after each experimental session ("Day 15" and "Day 29"). Outcome measures will not be completed on the day after the experimental sessions. Participants will meet with the investigators in one more psychotherapy session conducted after the second experimental session but before the study has been completed ("Day 35"). If a participant requests an additional psychotherapy session and the co-therapists agree, then additional sessions may be scheduled as well, with these sessions also lasting sixty minutes. If any additional psychotherapy sessions are conducted, participants will complete outcome measures before that session as well. The final research follow-up session will take place two months from the second experimental session ("Day 84"). 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.
MDMA will be supplied by David Nichols, Ph.D., Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University. This MDMA is of confirmed identity and purity and has been used in all Phase I and II clinical trials of MDMA conducted in the United States. Dr. Nichols only produced one lot of MDMA, and all material used for this study will come from this lot, Lot #1. Analytic data has been filed with the FDA in MAPS' MDMA Drug Master File # 6293. After obtaining from the Commonwealth and the DEA a Schedule I license for administering MDMA specific to this study, power-of-attorney will be signed over from Dr. Halpern to the Director of the McLean Hospital Pharmacy, the pharmacist Mr. Stanley Rosen, so that the pharmacy can order 5 grams of MDMA from the manufacturer, Dr. Nichols.
This supply of MDMA will be stored in the key-locked drawer within the separately alarmed research safe located within the alarmed and locked facilities of the McLean Hospital Pharmacy. Direct control of MDMA will be maintained within the pharmacy as per the procedures and methods already established between the McLean Hospital Pharmacy and the local DEA Branch Office. Since Dr. Halpern and colleagues will not have independent access to the pharmacy, or ever be in possession of the research safe combination or the key to the locked-drawer within this safe, MDMA will not at any time be maintained in a location directly available to the PI or any co- investigator. MDMA will be requested from the pharmacy using the research study drug order form and will be picked up from the pharmacy by the principal investigator on the morning of the study day. The McLean Hospital Pharmacy research form for tracking study drug use will be returned to the pharmacy stating relevant subject number or name, the time and location of administration of the first and second doses of MDMA, and will be signed by both the principal investigator and a witness (the co-investigator therapist, Dr. Naidoo). All unused doses of MDMA will be returned to the Pharmacy. In the event that the second dose is not administered to the participant, the investigators will follow current pharmacy protocol to document proper disposal of this second MDMA capsule.
Participants will receive MDMA on two experimental sessions spaced 2- 3 weeks apart ("Day 14" and "Day 28"). 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. The two doses of MDMA chosen for the Low 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 serving as an active placebo. Even 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 in Mithoefer and Wagner, 2001). With participants carefully monitored for any indicators of adverse events, this dose should still prove tolerable and will produce the full array of subjective and physiological effects.
Group assignment will be randomized using a table of random numbers generated by the McLean Hospital Pharmacy. The table will be placed on file at 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.
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 above). 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 Acute 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.
3.6.2 Measures During Experimental Session
Participants will complete outcome measures on the day of the experimental study, but prior to the start of the experimental session. Measures made during the experimental sessions are primarily made for safety monitoring and are described below in "3.8 Monitoring for Toxicity." In addition, 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 all 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, the participant's immediate personal supports, and the participant's outside therapist.
3.6.3 Psychotherapeutic Procedures during Experimental Session
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; see accompanying Treatment Manual). 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 "3.8 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.
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 any 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.
3.7 Post-Session Monitoring and Data Collection
Psychotherapy follow-up sessions ("Day 15" and "Day 29" - see Table 2 above) will be conducted in the morning on the day after the experimental sessions at McLean Hospital. Seven days after each experimental session (on Day 21 and Day 35), outcome measures will be obtained and then a psychotherapy session will also occur. A final research follow-up ("Day 84") will be conducted two months after the second experimental session. Outcome measures will also be administered during the final meeting, and the participant will have a final opportunity to review participation in the study with Drs. Halpern and Naidoo. Participants may contact the investigators at any time throughout the study. 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. The investigators will schedule one or more additional hour-long psychotherapy sessions if requested by the participant and the investigators deem it necessary.
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. 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. Daily diaries will also be reviewed at these meetings. Outcome measures will be completed at McLean Hospital prior to each psychotherapy session (except for those conducted the day after the experimental session days - "Day 15" and "Day 29"). Participants will complete outcome measures on days when any additional sessions are scheduled.
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"). 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.
One day after each experimental session ("Day 15" and "Day 29" - see Table 2 above), participants will meet with the therapist co- investigators, Dr. Halpern and Dr. Naidoo, for an hour-long non-drug psychotherapy follow-up session. During these follow-up sessions, participants will be encouraged to describe their experiences of the MDMA-assisted sessions and to freely express any thoughts, feelings, questions or concerns they have. Participants will also be asked to indicate whether they believe they received Low or Experimental Intervention doses of MDMA during the day-prior's experimental session. Participants will not complete any outcome measures, other than continuing to keep their Daily Diary, on this next day following the experimental session. After completion of these day-after psychotherapy sessions, the participant will be discharged to home and will be driven from McLean Hospital either by pre-arrangement with a designated support person to the participant or by a study- provided taxi. The participant will again be instructed to not drive a motor vehicle or operate heavy machinery during this day. 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. 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).
Follow-up sessions ("Day 21" and "Day 35") at McLean Hospital will be scheduled for participants one week after each experimental session. These research follow-up sessions will occur at an appropriate research facility of or made available to the Biological Psychiatry Laboratory. After participants complete the outcome measures (approximately 90 minutes), hour-long non-drug psychotherapy with Drs. Halpern and Naidoo will immediately follow. During these psychotherapy sessions, participants will be encouraged to continue to review their symptoms and problems related to their management of anxiety and how the prior week's experimental treatment session may have affected their anxiety. Participants will be encouraged to describe their experiences of the MDMA-assisted session(s), including their experience of reviewing their videotapes, and to freely express any thoughts, feelings, questions, or concerns they have. If this is the first follow-up session ("Day 21"), participants will be scheduled for their second experimental treatment session ("Day 28"). If this is the second follow-up session ("Day 35"), participants will be scheduled for the final follow-up session ("Day 84"). The repeat medical examination ("Day 36") to be conducted by co-investigator oncologist Dr Shuster at the Lahey Clinic will also have been scheduled for one week after the second experimental session ("Day 28").
Participants will need approximately 1.5 hours to complete outcome measures during the final follow-up session ("Day 84") scheduled two months after the second experimental session ("Day 28"). After the participants have completed all outcome measures, they will have a final meeting with the co-therapist investigators. This session will take place at an appropriate research facility of or made available to the Biological Psychiatry Laboratory at McLean Hospital. If the participant requests an additional psychotherapy session and the co-therapists agree, then additional sessions occurring prior to the final follow-up may be scheduled as well, with these sessions also lasting sixty minutes. If any additional psychotherapy sessions are conducted, participants will complete outcome measures before that session as well. All such sessions will be held at McLean Hospital.
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 in Mithoefer and Wagner 2001). 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. Dr. Halpern has been board certified in general psychiatry, has completed a multi-year research fellowship at McLean Hospital's Alcohol and Drug Abuse Research Center (ADARC), and is Associate Director of Substance Abuse Research at the Biological Psychiatry Laboratory. Dr. Halpern will have Advanced Cardiac Life Support (ACLS) certification prior to the first experimental session. Dr. Naidoo is a board-eligible psychiatrist who has completed a Fellowship in Psychosocial Oncology at the Dana Farber Cancer Institute. She is currently Acting Medical Director of the Erich Lindemann Mental Health Center. In addition, 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.
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. 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.
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 other 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 within 72-hours to the FDA. 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 resident (as well as the principal investigator) during their overnight period of observation if necessary.