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Version 4.1

August 22, 1995

A DOSE/RESPONSE HUMAN PILOT STUDY –

SAFETY AND EFFICACY OF

3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA)

IN MODIFICATION OF PHYSICAL PAIN

AND PSYCHOLOGICAL DISTRESS

IN

END-STAGE CANCER PATIENTS

Charles S. Grob, M.D.

Principal Investigator

Harbor-UCLA Medical Center

Introductory Statement

Protocol

Previous Human Experience

General Investigational Plan

Schedule of Tests

Pharmacology and Toxicology by Dennis J. McKenna, Ph.D.

Abuse Potential by Jerome Beck, Ph.D.

Additional Information

 

 

 

 

Introductory Statement

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This protocol is for a dose/response pilot study of the use of 3,4- methylenedioxymethamphetamine (MDMA) in modifying physical pain and psychological distress in patients with end-stage cancer. This study builds on research begun in the Phase 1 dose/response trial conducted at Harbor-UCLA Medical Center by Dr. Grob (in press,1995).

This pilot study will gather preliminary information about the safety and efficacy of MDMA when used as an analgesic in cancer pain, as a psychotherapeutic adjunct for the treatment of anxiety and depression related to terminal illness, and as a tool to facilitate psychoneuroimmunological stimulation of the immune system. Such information is vital in order to assess MDMA's risk/benefit ratio. This pilot study will take about one year to complete.

MDMA is a ring substituted phenylisopropylamine derivative invented by Merck in 1912 which bears structural and pharmacological similarities to both the stimulant amphetamine and the hallucinogen mescaline, yet has unique pharmacological and psychological properties (Shulgin,1990). Some investigators suggest MDMA be categorized as part of a new class of psychotropic agents (Nichols and Oberlender, 1990). The drug is a white, crystalline powder and will be administered orally in capsule form.

Assertions have been made that MDMA can reduce acute and chronic pain experienced by end-stage cancer patients (Greer and Tolbert,1990), perhaps that portion of total pain and suffering resulting from emotional, psychological, cognitive, and social variables (Foley,1985). To date, no study has attempted to evaluate the safety, efficacy or mechanism of action of MDMA as an adjunct to the reduction of pain in end-stage cancer patients, as a treatment of anxiety and depression, or as a tool to facilitate stimulation of the immune system.

This experiment will involve twelve subjects, all screened and referred by their oncologists to this study. All subjects will be trained in a guided imagery technique designed to ameliorate physical pain as well as psychological distress. The subjects in the experimental group will receive four sessions of MDMA, each separated by two to four weeks, within a tightly structured setting that includes guided imagery exercises. During the course of the four sessions, patients will first participate in a non-drug session with guided imagery and music alone. They will then receive an escalating sequence of dosages of MDMA from low to medium to high.

The subject population of end-stage cancer patients was selected both for the desperate life circumstance they encounter, for which conventional pain reduction treatments often offer limited assistance, as well as out of concern for the as yet unanswered question of long-term adverse sequelae of MDMA, which is largely obviated in patients with limited projected life spans.

Accurate information on both the risks as well as the clinical efficacy of MDMA is essential. As stated by Seiden, "The matter of putative or even established toxicity cannot be the sole criterion for the decision [to use a drug in humans]; efficacy must enter into the equation. Then one is left with the dilemma of assigning a weight to each factor." (Seiden, 1990).

 

The Protocol:

Experimental Design and Methods

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Type of Study

This is a dose/response pilot study investigating the safety, efficacy and mechanisms of action of MDMA and guided imagery in modifying psychological distress and physical pain and in stimulating the immune systems in patients with end-stage cancer.

Number of Patients Involved in Experimental Groups

Twelve subjects, all screened and referred by their oncologists to this study, will be included in the trial. All subjects will receive MDMA within an experimental setting (described below) designed to facilitate optimal trust, relaxation, and catharsis. Data from this initial set of twelve patients will be analyzed for preliminary information about safety and efficacy before any additional patients are treated in the context of a full-scale clinical trial.

Inclusion Criteria

Subjects must have chronic pain as a result of end-stage cancer that is incompletely remediated by standard therapies. Subjects must be between the ages of 18 and 75 years and have an anticipated life expectancy between three months and four years. Subjects must be willing to receive three doses of MDMA, along with several blood, urine, psychological and neuropsychological tests. In addition, subjects must be willing to refrain from taking any anti-depressant psychiatric drugs during the experiment. Female subjects of childbearing potential must have a negative pregnancy test and agree to use an effective form of birth control.

Exclusion Criteria

Subjects who have a history of schizophrenia, bipolar affective disorder, delusional disorder, paranoid disorder, or schizoaffective disorder will be excluded, as will any subjects who exhibit psychotic symptoms or have a history of epileptic seizures. Subjects who currently have a substance abuse disorder, or who have severe cardiovascular problems will also be excluded. Neurological exams will be conducted and any subjects who show evidence of brain metastasis will be excluded. Female subjects who are pregnant will be excluded.

Dosing Plan

All subjects will receive four individual treatment sessions, each separated by at least two weeks and at most four weeks from the previous session. The first session will be a non-drug session conducted without the administration of MDMA. Each subsequent session will involve the oral administration of an escalating sequence of dosages of MDMA beginning with the threshold dose for therapeutic effects (1 mg/kg). If no serious side effects are noted, the second MDMA session will involve a low-end therapeutic dose (1.5 mg/kg). If no serious side effects are noted with the second dose, the third and final MDMA session will involve the administration of a fully therapeutic dose (2 mg/kg).

Subjects and investigators will be aware that the MDMA doses will be given in a fixed order. Independent raters will be blinded as to which dose of MDMA, if any, was administered.

Prior to the experimental treatment sessions, all subjects will participate in several preliminary meetings with the investigator/psychotherapist. Each session will be used to facilitate the therapeutic alliance, identify the subject's significant issues and concerns, prepare for the guided imagery / pain reduction tasks and set goals for the treatment. The experimental treatment sessions themselves will be supervised and facilitated by the investigator/psychotherapist, roughly following the guidelines already developed for MDMA-assisted psychotherapy (Greer and Tolbert, 1990) and guided imagery (Achterberg,1985). Except for the administration of different doses of MDMA or no drug at all, the treatment protocols will be exactly the same for each session.

All treatment sessions will begin at 10:00 am and will take place in the Harbor- UCLA Clinical Research Center or the patients' home. After the session begins, subjects will recline in a comfortable position with eyes closed or wearing blindfolds if preferred. For the first hour, subjects will listen to a guided imagery tape following a standardized script recorded with their own voice. For the next several hours following the tape, subjects will be given instructions to focus on their experiences of feelings, thoughts and associations, except when asked to complete rating scales or give blood or saliva. Depending on their readiness and willingness, the subjects will be encouraged to have verbal interaction with the therapist, discussing the content of the experience with an emphasis on how it relates to the goals of the therapy. During the session clinically appropriate music will be played to help elicit images, thoughts and feelings and to tap deep unconscious levels of emotional processes (Unkefer, 1990; Bonny and Savary, 1990).

The investigator/psychotherapist and a research assistant will be present and available throughout the session to tend to each subject's needs and handle any difficulties that might arise. A variety of psychological and physiological tests (discussed below) will be administered during the sessions. All sessions will be audiotaped in their entirety. Sessions will last from six to eight hours, depending on the subject's feeling of completeness with the process and the therapist's determination of the mental and physical state of the subject. For outpatient subjects, rides home will be pre-arranged so that subjects will not have to drive after the sessions. A psychiatrist will be on call 24- hours a day, seven days a week to handle any concerns or emergencies related to the protocol. After the last experimental session, subjects will continue to meet with their psychiatrist at least once a month for at least six months for follow-up.

 

Methods of Evaluating Safety

A) Neurotoxicity

In order to assess the effect of MDMA on serotonin neurons, a battery of neuropsychological tests to include the Wechsler Adult Intelligence Scale (WAIS-R), the paragraph and figural sections of the Wechsler Memory Scale, the Boston Naming test, the multiple choice form of the Benton Visual Retention Test (revised), the Tokens tests, the Trail Marking Test, the Manual Performance Test, the Finger Oscillation Test, the Lafayette Pegboard Test, and Grip Strength test will be administered two weeks before the first session and two weeks after the last session.

B) Organ and Immune System Function

In order to assess the effect of MDMA on organ function and the immune system, subjects will have blood drawn immediately before each session begins and twenty-four hours later, and two weeks after the last treatment session. During the first and third sessions, blood will also be drawn at 1, 2, 4, and 6 hours. Complete blood workups will be conducted including hematologic, immunologic, hepatic and renal analysis.

All subjects will be given physicals and an EKG upon entering the study and two weeks after the last treatment session. During the sessions, vital signs will be monitored every two hours.

C) Pharmacokinetics

During the third session only, subjects will have blood drawn through an intravenous catheter fifteen minutes before the session begins and then every fifteen minutes for the next two hours. Blood will then be drawn every hour for the next four hours, and then six, eight, twelve, twenty-four, thirty-six and forty-eight hours after session.

D) Acute Psychological Effects

The acute psychological effects of the treatments will be measured through the use of the Brief Profile of Mood States-SR (POMS-SR) (McNair et al, 1971) and the State-Trait Anxiety Inventory (STAI) (Spielberger, 1983). These tests will be administered to all subjects before each treatment session begins and at the first, third and sixth hours of the sessions. The Hallucinogenic Rating Scale (HRS), developed by Dr. Strassman, will be administered the day after each session.

Methods of Evaluating Efficacy

A) Pain

MDMA's efficacy in reducing pain in end-stage cancer patients will be examined through the use of the McGill Pain Questionnaire, Dallas Pain Questionnaire, and the Memorial Sloan Kettering Pain Card. The McGill and Dallas Pain questionnaires will be administered two weeks prior to the first treatment session, the day before and the day after the each treatment session, two weeks after the last session, and then every month for the next six months. The Memorial Sloan Kettering Pain Card will be self- administered by the subjects every day from two weeks before the first session until two weeks after the last experimental session, before and after each treatment session, and every hour of each session. In addition, the continued need for conventional medications (eg. narcotics) to alleviate pain will be monitored.

B) Psychological Treatment Efficacy

Psychological treatment efficacy will be measured through the use of standardized tests. The tests include the Beck Depression Inventory (BDI), Brief Symptom Inventory (BSI), Brief Profile of Mood States-SR (POMS-SR) (McNair et al, 1971), Questionnaire Measure of Emotional Empathy (QMEE) (Mehrabian and Epstein, 1972), State-Trait Anxiety Inventory (STAI) (Spielberger, 1983), and Symptom Distress Scale (SDS) (McCorkle and Young,1978). All subjects will have all tests administered the day before each treatment, two weeks after the last treatment session and then every month for the next six months. The day after each treatment all tests will be administered except the BDI and the BSI.

C) Immune System Function

Measures of tumor size and location and Ig A will be conducted two weeks before the first session and two weeks after the last. Ig A will be measured in saliva immediately before each session, at one, three and six and twenty-four hours after the session began.

 

References

Achterberg, J, Imagery in Healing, Boston, New Science Library, 1985.

Bonny, HL and Savary, LM: Music and Your Mind. Tarrytown, New York, Station Hill, 1990.

Foley, KM: The treatment of cancer pain. New Eng J Med 313:84-95, 1985.

Greer, G and Tolbert, R: The Therapeutic Use of MDMA. In S.J. Peroutka (Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Holland, Kluwer, 1990.

Grob C, Poland R, Chang L, Ernst T. Psychobiological effects of 3,4-methylenedioxy- methamphetamine (MDMA) in humans: Methodological considerations and preliminary observations. BrainBehavior Research. (In Press, 1995)

McCorkle and Young, Development of A Symptom Distress Scale, Cancer Nursing, Oct.1978, p.373-378.

McNair, DM, Lorr, M and Droppleman, LF: EITS Manual for the Profile of Mood States. San Diego, Educational Testing Service, 1971.

Mehrabian,A and Epstein, E: A measure of emotional empathy. J Personality 40:525- 543, 1972.

Nichols, DE and Oberlender, R: Structure-activity relationships of MDMA and related compounds: A new class of psychoactive agents? In S.J. Peroutka (Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Holland, Kluwer, 1990.

Seiden, LS: MDMA and related compounds: Summary. Ann NY Acad Sci 600:711-715. 1990.

Shulgin, AT: History of MDMA. In SJ Peroutka (Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA. Holland, Kluwer, 1990.

Spielberger, CD: Manual for the State-Trait Anxiety Inventory. Palo Alto, CA, Consulting Psychologists Press, 1983.

Unkefer, RF: Music Therapy in the Treatment of Adults with Mental Disorders: Theoretical Bases and Clinical Interventions. New York, Schirmer Books, 1990.

 

 

Previous Human Experience

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Efficacy

There have been no previous studies exploring the efficacy of MDMA in the treatment of chronic pain and distress in cancer patients. The data that does exist comes from anecdotal reports gathered during the early 1980’s prior to the DEA scheduling of MDMA. The theoretical basis for using MDMA in the treatment of chronic pain in cancer patients evolved from the psychedelic and psycholytic therapies of the 1950's, 1960's, and early 1970's (Grinspoon and Bakalar, 1986).

Reports suggesting MDMA may be a useful adjunct in the treatment of intractable pain associated with end-stage cancer were noted in a survey of 17 psychiatrists and 3 clinical psychologists (Harlow and Beck, 1990). The sample consisted of 15 therapists in the United States who employed MDMA as a therapeutic adjunct before its scheduling in 1985 and 5 psychiatrists in Switzerland had been permitted by the Swiss government to use MDMA in therapy. In one case reported by Greer, the debilitating pain associated with multiple myeloma spontaneously remitted during an MDMA session in which the patient practiced visualization techniques for pain control. Greer notes that "it was the first time he [the patient] had really been pain free in the four years since the current relapse of his myeloma had begun. In a letter written two weeks after his session, he stated that his pain had returned, but that his ability to hypnotically re-anchor his pain-free experience greatly assisted him in reducing the pain by himself. He had four MDMA sessions spaced over the course of nine months; each time he achieved relief from his physical pain, and he had greater success in controlling painful episodes in the interims by returning himself to an approximation of the MDMA state" (Greer and Tolbert, 1990).

Safety

An FDA-approved Phase 1 study into the physiological and psychological effects of MDMA is currently being conducted by Dr. Charles Grob and Dr. Russell Poland at Harbor-UCLA Medical Center. This is the only study in the United States in which MDMA is being administered to human volunteers. Preliminary results have not yielded any evidence to suggest that MDMA is too dangerous to administer to cancer patients, though final conclusions can only be made after the completion of the entire Phase 1 study.

There is only one study in the literature in which MDMA was administered to humans and neurophysiological and laboratory data were collected (Downing, 1986). The study, conducted in 1984, involved a single exposure to MDMA in 21 healthy volunteers all of whom had previously been exposed to MDMA in non-research settings. Measurements were taken of blood chemistry, pulse and blood pressure in all subjects. Ten subjects received neurological exams and five received electrocardiograms. Downing reported "there were moderate, consistent biochemical, cardiovascular and neurobehavioral changes within normal limits that peaked between one and two hours following ingestion, returning to pre-drug levels within 24 hours. This experimental situation produced no observed or reported psychological or physiological damage, either during the 24-hour study period or during the three month follow-up period."

In 1988, the Swiss government sanctioned several members of the Swiss Association for Psycholytic Psychotherapy (SAEPT) to conduct clinical investigations of MDMA- facilitated psychotherapy. Although a rigorous research methodology was not applied in their studies, the Swiss psychiatric investigators reported a positive degree of treatment response in several hundred patients with a variety of psychiatric indications including some cancer patients (Zanger, 1989; Harlow and Beck, 1990; Gasser, 1995). No significant deleterious health consequences have been reported as a result of the use of MDMA. A Swiss psychiatrist who is not a member of SAEPT concluded in his Ph.D. thesis that "All members of the SAEPT are of the opinion that MDMA in a standard dose of up to 150 mg. is... non-toxic" (Benz, 1989).

Standard 28-day toxicity studies in dogs and rats provide no evidence to suggest that MDMA has harmful physiological effects outside the brain (Frith et al, 1987). Investigators of rodent and non-human primate populations have demonstrated neuronal changes to the serotonergic neurotransmitter system following administration of MDMA in amounts exceeding those used in therapeutic contexts, (Ricaurte et al,1988; Schmidt, 1987; Schmidt and Taylor,1987; reviewed by McKenna and Peroutka, 1990). More recent data demonstrates partial regeneration of serotonin nerve terminals with hyperinnervation in some areas of the brain and hypoinnervation in others (Fischer, 1995). The pre-clinical literature up to 1992 is comprehensively reviewed in this protocol's Pharmacology and Toxicology section, pages 36-45.

Because of animal neurotoxicity data, retrospective investigations searching for central serotonergic abnormalities in heavy MDMA users have been conducted. One human study failed to show any effect on CSF 5-HIAA (Peroutka et al, 1987) while another study (Ricaurte et al, 1990) does report a significant difference in CSF 5-HIAA in chronic MDMA users compared to a control population of patients with chronic low back pain who had received lumbar punctures for clinical purposes. These data may be indicative of some degree of serotonergic neurotoxicity in the MDMA population. However, this interpretation needs to be qualified in several respects. One concern is directed at the choice of control group selected, patients with chronic low back pain. Though one study suggests that low back pain does not affect CSF 5-HIAA levels (Hyyppa et al,1985), there is a known serotonergic mechanism involved in pain and pain control (Crisp et al, 1989; Nencini et al, 1988; Messing et al, 1976). Several studies have demonstrated increased levels of CSF 5-HIAA in patients suffering from chronic non-malignant and malignant pain (Costa et al,1984; Ceccherelli et al, 1989).

Caution should be exercised in extrapolating Ricaurte’s data to the proposed study because the patient population in his study differs in several important respects from this protocol. For one thing, the frequency and acute exposure to MDMA in the proposed study is quite moderate by comparison. Another factor is the wide range of doses the subjects in Ricaurte’s study received from self-experiments. While the average dose was 0.98 to 2.6 mg/kg, the daily dose ranged from 150 to 700 mg; in addition, while the mean frequency of use was 3.4 1.8 weeks between doses, a significant number (13 of 33) reported brief periods (5 to 7 days) of daily use. Hence both the range of administered doses and the frequency differs markedly from the projected dose regime for this protocol. Even given the wide range of acute doses and frequency of exposure, no correlation could be found between either of these parameters and the level of CSF 5- HIAA. A 72 year old subject who had used MDMA in excess of 100 times had one of the highest values of CSF 5-HIAA recorded (Doblin, personal communication, 1992). In addition, virtually all of the patients in Ricaurte’s study (1990) were polydrug users, having a history of exposure to marijuana, hallucinogens, and other ring substituted amphetamines and stimulants such as cocaine and possibly methamphetamine. The effect of polydrug exposure on CSF serotonin levels has not been assessed but may be significant.

A more extensive and well-controlled study funded by NIDA to assess potential serotonergic dysfunction in heavy MDMA users has recently been completed (McCann, 1994a). This study found that the MDMA users had, on average, roughly 15% lower levels of 5-HIAA than controls, possibly due to exposure to MDMA. However, because this study used a matched control group design instead of pre- and post- measures on the same subjects, the difference in serotonin levels could also be due to uncontrolled for factors resulting from an imprecise matching process.

In any case, there were no harmful observable functional or behavioral differences between the subjects in the MDMA or control groups. On the contrary, the MDMA users exhibited less hostile and impulsive personality traits, and greater constraint and control than the members of the control group. This finding raises doubts about the theory that MDMA caused the differences in the serotonin levels because previous research has associated lower levels of serotonin with violent and impulsive behavior, not the reverse.

Sleep EEG data (McCann,1994) indicated that MDMA users experienced about 18 minutes less total sleep per night than members of the control group, possibly suggestive of lowered levels of serotonin. Alternative explanations are that the MDMA group was disproportionally from the West Coast, and the time-zone changes may have caused a disruption in normal sleep patterns. Furthermore, this finding could be considered a beneficial effect. MDMA users had about 33 minutes less of Stage 2 non-REM sleep, generally considered to have no important restorative function. MDMA users actually spent about 15 minutes more than controls in the stages of sleep considered essential for physical and biological restoration, Stages 3 and 4 non-REM sleep, and REM sleep. The sleep patterns of MDMA users could thus be considered more efficient and more restorative than those of the control group. There was no evidence of increased sleep problems in the MDMA subjects.

One study demonstrated statistically "non-significant" differences in prolactin levels between heavy MDMA users and controls utilizing the L-Tryptophan challenge test (Price et al, 1989). However, any conclusions are premature due to an unreported selection bias of subjects who had been previously identified by a prior study (Ricaurte et al, 1990) as having among the lowest CSF 5-HIAA levels from a larger group of tested MDMA users (Doblin, personal communication). Other methodological shortcomings raise uncertainty as to whether prior MDMA use was the actual etiological basis for the observed biochemical findings (Grob et al, 1990; Grob et al,1992). Furthermore, the average cumulative dose per subject substantially exceeded the amount to be administered in the present protocol. Subjects in this group were also administered neuropsychological tests, with some minor abnormal findings in a few subjects (Krystal, 1992). However, attributing these findings to MDMA is impossible given the many confounding variables.

Dr. Price commented about this IND application: "I have previously come out on record as opposing the use of MDMA in clinical studies with humans because of the potential for neurotoxicity. I believe that this protocol adequately addresses my concerns. In particular, the possible risk of serotonergic neurotoxicity following administration of MDMA would not appear to constitute an unacceptable risk in your proposed sample of terminally ill cancer patients in grave distress." (Price, personal communication, 1992)

A recent study (Strassman, personal communication, 1992) found no evidence of physiological or psychological differences between "MDMA Positive" and "MDMA Negative" subjects exposed to i.v. DMT. There were no significant differences in ß-endorphin, ACTH, prolactin, corticol, growth hormone, baseline and maximum rise temperature responses across all four doses of DMT and placebo, nor in the Profiles of Mood States test (POMS) or the Hallucinogen Rating Scale (HRS) developed specifically by Strassman for his experiment.

Expected clinical sequelae of a "damaged" serotonergic neurotransmitter system, which would include disturbances to mood, sleep, appetite, aggression or sexual regulation, have been reported (Ricaurte et al,1990). In that study, 30 out of 33 heavy MDMA users reported no functional complaints while one complained of depression, one of "poor memory" and "difficulty concentrating," and one of "diminished creativity" and mood swings. All three subjects were poly-drug users and all "believed their difficulties were related to their MDMA use but recognized other factors might be involved." No evidence was presented discerning whether such concerns were attributable to either the psychological or physiological effects of MDMA.

Further elucidation of the term "neurotoxicity" as it applies to the serotonergic system is also necessary. Evidence from animal studies showing actual regeneration of neuronal terminals damaged by large amounts of MDMA (Battaglia et al, 1988) should be considered. New findings examining the effect of the highly potent serotonergic neurotoxin 5,7-dihydroxytryptamine may also be relevant. 5,7-DHT seems to reactivate dormant developmental signals in the brain which encourage sprouting of serotonergic fibers as well as stimulation of an astrocytic growth factor. To activate these mechanisms, postulated to have a role in healthy regeneration and treatment of the aged brain, serotonergic neurons first must be "damaged or blocked" (Azmitia and Whitaker-Azmitia,1991). Such findings show that speculations as to the meaning of MDMA "neurotoxicity" are preliminary (O'Callaghan et al, 1990).

In spite of a rapidly growing literature on MDMA's effects on the neurochemistry and histopathology of animal brain, clinical reports of deleterious MDMA-related syndromes are rare given the amount of MDMA reportedly used recreationally (Whitaker-Azmitia and Aronson,1989; McGuire and Fahy, 1991; Creighton et al, 1991, McCann and Ricaurte, 1991; Benazzi and Mazzoli,1991; Schifano, 1991). While MDMA is by no means innocuous, particularly when used by vulnerable and unprepared individuals in uncontrolled settings, most case reports suggest complicating factors in addition to MDMA. One report in the literature of MDMA-related neuropsychiatric sequelae discusses two subjects who ingested large dosages of MDMA (McCann and Ricaurte,1991). Both subjects had a preexisting history of clinical depression and polysubstance use, making impossible any conclusion about the causal role of MDMA. Whitaker-Azmitia and Aronson (1989) associated MDMA use with two transient anxiety episodes but may not have given sufficient attention to the highly adverse setting for the experiences (the New York City subway system). Similarly, one of the three flashback cases cited by Creighton et al (1991) involved a woman who was abducted and raped while on MDMA. The other two cases involved prolonged use of cannabis and LSD-like symptoms that Creighton et al speculates may have been due to impure MDMA adulterated with contaminants.

Deleterious idiosyncratic reactions to MDMA, including fatalities, have been reported (Chadwick et al,1991; Sucret and Reimerzmc,1988; Vereby et al,1988; Henry et al, 1992), though such reactions are "exceedingly rare" and most always involve complicating factors (Dowling, 1990). In this protocol, the administration of a relatively low initial dose of pure MDMA to pre-screened subjects in the presence of medical personnel minimizes this risk.

Additional uncertainty over MDMA's capacity to inflict injurious clinical outcomes in humans comes from the case of fenfluramine. Fenfluramine is a currently accepted FDA- approved prescription drug which causes findings greater than MDMA in its toxic effects on the serotonergic neurotransmitter systems of animals in basic research studies (Schuster et al, 1986; Wagner and Peroutka,1990; Ricaurte et al, 1991, McCann,1994b) and has an established abuse potential (Levin,1973). Despite such findings, fenfluramine has accepted clinical indications in adults and children, a history of widespread use (50,000,000 people have been clinically treated with fenfluramine over the last 25 years [Derome-Tremblay and Nathan,1989] ), and is without the known induction of neurological side effects or adverse clinical sequelae (Schechter,1990).

A NIDA-funded study has been conducted on the sociological effects of MDMA in humans (Beck et al, 1989, Beck 1990). Though not explicitly looking for evidence of MDMA neurotoxicity, the study reported that "there were few mentions of critical physical or psychological problems associated with MDMA use, even among frequent or binge users. Although some of our respondents knew or had heard of other users who had experienced serious reactions such as panic attacks or possible overdoses, such problematic consequences were usually regarded as uncommon."

A comprehensive retrospective evaluation of the experiences of twenty psychiatrists with a mild to moderate degree of first-hand experience with MDMA reported virtually no significant adverse clinical sequelae over both short and long term periods of time (Leister, 1992).

 

General Investigational Plan

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Rationale

A) Pain and psychiatric morbidity in end-stage cancer patients

Major advances in the medical and surgical treatments of patients with cancer have occurred over the last century. However, even with increasingly effective interventions, quality of life for patients, now often with expanded longevity, remains a vexing problem. As patients live longer with their cancers, they must contend with cancer treatments which in addition to combating the underlying illness may also produce severe adverse effects which further detract from the patients' quality of life (Barofsky and Sugarbaker, 1990).

Studies have demonstrated an unfortunate world wide trend of undertreatment of cancer pain (Marks and Sachar, 1973; Swerdlow and Stjernsward, 1982). Estimates have ranged from 25% to 50% of end-stage cancer patients dying without relief from "unendurable" pain (Foley, 1985; Tunca and Yelken, 1991; Ventafridda et al, 1990). This condition is also strongly associated with a sense of hopelessness and fear of impending death, which further exacerbates the patients' suffering and experience of cancer pain (Breitbart, 1989; Foley, 1985).

Not surprisingly, psychiatric morbidity in the end-stage cancer patient has been found to be high. One study indicates that between 23% and 56% of patients diagnosed with cancer have a coexistent clinical psychiatric syndrome (Derogatis et al, 1983). The incidence of anxiety and depressive disorders in particular were found to be considerably higher among cancer patients with pain than among those without pain. Severe depression has been assessed to affect 25% of all cancer patients and as many as 77% of those with advanced end-stage disease (Bukberg et al, 1984). Psychosocial treatments, however, have been shown to be of value, by improving quality of life (Spiegel et al, 1981), reducing the pain associated with cancer (Spiegel and Bloom, 1983) and even prolonging life span for the end-stage cancer patient (Spiegel et al, 1989).

B) MDMA in the treatment of pain

Investigations of novel psychoactive drugs in cancer patients began in the early 1960's, with initial attempts directed at reducing the chronic, intractable pain associated with malignant disease with low doses of LSD (Kast and Collins, 1964). Findings not only included the efficacy of pain reduction, superior to that achieved by conventional narcotic regimens, but the additional observation that the depression frequently associated with cancer noticeably declined. The reduction of pain as well as the improved psychological status was attributed to an "attenuation of anticipation" and a decrease in associated anxiety and fear of loss of control through death (Kast, 1970). Considerable enthusiasm was generated that psychedelics might potentially hold the key to a new technique for profoundly altering the experiencing of dying. As one prominent researcher at the time expressed his belief of the importance of pursuing such research: "Death must become a more human experience. To preserve the dignity of death and prevent the living from abandoning or distancing themselves from the dying is one of the great dilemmas of modern medicine" (Cohen, 1965).

The most diligent investigations into the role psychedelics might have in easing the suffering of end-stage cancer patients were conducted at the Maryland Psychiatric Research Center (Kurland et al, 1968; Kurland, 1982; Pahnke, 1969). Rating scales were devised to assess a variety of parameters, including degree of depression, psychological isolation, anxiety, difficulty in management, fear of death, and physical pain. Dramatic positive change in a variety of clinical parameters was noted in many of the end-stage cancer patients who were provided psychedelic facilitated treatment, ranging from improvement of depression, anxiety, tension, insomnia and restricted social communication, through relief of physical pain, to a profound shift in attitude toward impending and inevitable death. Global rating indexes indicated that greater than 70% experienced dramatic or moderate improvements in their psychiatric status (Grof et al, 1973).

The precise mechanism of action of MDMA in the modulation of pain has yet to be established but is presumed to be a modification of higher level interpretation of lower level perception of pain stimuli. However, studies of MDMA in animals do suggest a direct serotonergic-mediated analgesic effect. Experimental animal models designed to test antinociceptive, or analgesic, effects have provided evidence suggestive of a role for MDMA in the control of pain. Crisp et al (1989) have examined the antinociceptive effects of MDMA by use of the tail-flick and hot-plate analgesiometric tests. Their findings revealed that MDMA in the dosage range of 1.5-6.0 mg/kg IP produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. The analgesic effects of MDMA on the hot-plate test, however, was reversed by the serotonergic antagonist methysergide, thus implying that the antinociceptive effects of MDMA are serotonergically mediated. Further evidence of MDMA's acute and long-term antinociceptive capacity was provided by Braun et al (1980) who demonstrated MDMA's analgesic potency in experimental mice, and by Nencini et al (1988) who have reported that the analgesic effect of morphine was enhanced in experimental rats that had previously received repeated sub-cutaneous injections of MDMA, after the MDMA had cleared the system.

C) MDMA's Acute Psychological Effects

No research to date has been conducted into the acute psychological effects of MDMA. MDMA has been described as having significant advantages over the classical psychedelics because it acts as a relatively mild, easily controlled and short acting drug which enhances the capacity within the psychotherapy setting for introspection and intimacy, noticeably reducing depression and anxiety yet without the distracting alterations in sense of self, body image and perceptions which had complicated earlier treatment efforts with psychedelics (Grinspoon and Bakalar, 1986) Numerous anecdotal reports have discussed MDMA's purported ability to produce feelings of peacefulness and acceptance, enhance the capacity for guided imagery and facilitate the experience and expression of emotions. These characteristics may contribute to the reported ability of MDMA to enhance psychotherapy by improving the therapeutic alliance and promoting abreaction and catharsis.

MDMA has been reported in anecdotal accounts of clinical use to have the rather unique pharmacological effect of facilitating states of empathy and emotional intimacy. Grinspoon and Bakalar (1986) have reported on one patient many months following an MDMA-assisted psychotherapy session, who described "feelings of closeness and sharing with others - evaporation of the usual barriers to intimate communication", and another who stated "I would say this is a heart drug, but not in the way I would have expected. I did not feel romantic love ... I felt attention toward (the therapists) and a concern for them and how they were. This feeling was one of compassion for their needs ... this feeling I have been able to carry over after the immediate MDMA effects have gone." A third patient, describing the degree to which the capacity for communication, intimacy and trust was strengthened said "it was characterized by warmth ... although I was intellectually lucid and clear, the chief impact of the experience for me was in the heart, and not in the head. Fundamentally it seemed to facilitate intimacy. I found I could give and receive at very intimate levels without embarrassment or defensiveness."

The concept of the therapeutic alliance has received increasing attention since the 1950's as a critical determinant and predictor of psychotherapy outcome (Hartley, 1985; Gaston, 1990). Numerous studies have unequivocally established that the therapeutic alliance is essential in creating a dynamic therapeutic process and crucial to the ultimate treatment outcome (Luborsky and Auerbach, 1985; Frieswyk et al, 1986). The quality of empathic rapport between therapist and patient has been identified as a particularly important feature of the therapeutic alliance (Mitchell et al, 1977). Indeed, the degree to which an empathic approach has been observed to facilitate the development of a positive therapeutic alliance has become a cornerstone of contemporary psychotherapeutic theory and technique (Baker and Baker, 1987). Empathy has been defined as "that unique capacity of the human being to feel the experiences, needs, aspirations, frustrations, sorrows, joys, anxieties, hurt, or hunger of others as if they were his or her own", and "as the very opposite of rigid egocentricity" (Clark, 1980). MDMA has been proposed as a pharmacological facilitator of conscious, empathic rapport, and as such may strengthen the therapeutic alliance and increase the probability of a positive therapeutic outcome.

D) MDMA's Therapeutic Efficacy

Over the last four decades the advent of psychopharmacological treatments has transformed the theory and practice of psychiatry, yet their impact upon psychotherapeutic technique and efficacy has been marginal (Bakalar and Grinspoon, 1990). Although the 1950's and 1960's saw a flurry of activity centered on the utilization of psychedelics as adjuncts to psychotherapy, such investigations were terminated because of strong socio-cultural pressures and public health concerns. Interest in pharmacologically-assisted psychotherapy has revived over the past decade, however, with reports that MDMA has been utilized within psychotherapeutic contexts as a potent facilitator of positive treatment outcomes. Contributing to this interest are previous reports that MDA and MMDA, two compounds structurally related to MDMA, had therapeutic utility as an adjunct to psychotherapy (Naranjo,1973; Yensen, 1975; Yensen et al, 1976).

A series of relatively unstructured and anecdotal clinical case studies with MDMA, performed prior to its designation as a Schedule I controlled substance, reported that subjects experienced a significant alleviation of a variety of forms of psychological distress following treatment with MDMA. Clinical presentations responding positively to MDMA treatment intervention have included the physical pain and emotional distress associated with end-stage illness, post-traumatic stress disorders, depression, phobias, substance abuse disorders, psychosomatic disorders and relationship (marital) problems (Greer, 1985; Greer and Tolbert, 1986; Downing, 1986, Harlow and Beck,1990, Gasser, 1995). In reviewing their work with 80 patients treated with MDMA-augmented psychotherapy, Greer and Tolbert (1990) have noted long lasting benefits in symptom reduction, particularly in regards to diminishing the pathological effects of prior traumatic experience, as well as sustained improvement in effective and empathic communication skills with family members.

Psychopharmacological modification of psychotherapy is a treatment modality with pre-historic roots in the shamanic healing application of psychedelic plants within a societally sanctioned and ritualized context (Bravo and Grob, 1989). Evidence has accumulated that the controlled utilization of psychedelics for therapeutic purposes has played a vital role in aboriginal and pre-industrial societies from pre-recorded history to the present (Dobkin de Rios, 1984). After the discovery of the synthetic psychedelic, lysergic acid diethylamide (LSD), in 1943 by Albert Hofmann of Sandoz Pharmaceuticals in Basel, Switzerland, considerable interest was directed to these substances. Between 1950 and the mid-1960's more than one thousand papers appeared in the psychiatric literature encompassing the clinical experience of 40,000 patients treated with psychedelics (Grinspoon and Bakalar, 1979). Treatment with psychedelics was applied to a wide variety of clinical problems, including the physical pain and psychological distress associated with dying, alcoholism and substance abuse, psychosomatic disorders,

childhood autism, post-traumatic stress disorder, and refractory antisocial behavior.

Using psychotropic medication as an adjunct to psychotherapy requires a modification of existing psychopharmacological paradigms. Specifically, the medication is not given daily nor is it necessarily to correct underlying pathophysiological mechanisms (at least through currently known neurochemical means). Rather, it is administered in special sessions usually separated by weeks or months with considerable attention to a therapeutic environment and ample preparation of the patient to maximize a set and setting that will promote therapeutic goals (Bravo and Grob,1989; Grinspoon and Bakalar, 1986; Greer and Tolbert, 1990).

E) MDMA and the Immune System

MDMA may have a useful role in the treatment of patients with a variety of several medical illnesses. Therefore, gathering data to help answer the question of whether or not MDMA has an effect on the immune system will help to determine the relative risks and benefits involved in the administration of MDMA to patients whose immune systems are already complicated by their underlying illness.

A comprehensive review of both the preclinical and clinical literature on MDMA reveals no investigation, observation or commentary of possible immunologic effects. Nevertheless, increasing attention has been given to a growing body of evidence that psychological stress and psychiatric illness can compromise functional immunocompetence (Calabrese et al 1987, Schleifer et al, 1989). Studies have demonstrated blunted mitogen stimulation of T lympocyte response in subjects experiencing severe psychosocial stressors ( Bartrop et al, 1977, Schleifer et al , 1983). A considerable scientific literature exists that supports the theory that cancer growth may be significantly augmented by acute and chronic psychosocial stressors coupled with the subjective experience of helplessness (Sklar and Anisman, 1981; Calabrese et al, 1987). Severe depression in particular has been implicated as exerting a deleterious effect on immune response (Schleifer et al, 1989; Kronfol et al, 1989; Kronfol et al, 1983), yet which may be modulated by standard somatic treatments of mood disorder ( Eisen et al, 1989; Albrecht et al, 1985; Shenkman et al, 1980; Kaspar et al, 1991). Futhermore, non-somatic psychosocial treatments have also recently been demonstrated to exert a positive effect on immune function ( Pennebaker et al, 1988; Kennedy et al, 1988; Fawzy,1994).

Indications To Be Studied

The proposed dose/response pilot study is primarily designed to gather preliminary information about the safety and efficacy of MDMA and/or guided imagery in subjects suffering from intractable pain and psychological distress as a result of end-stage cancer.

General Approach To Be Followed

The primary aim of the experiment is to gather preliminary safety and efficacy data regarding the use of MDMA to reduce physical pain and psychological distress, and to stimulate the immune system, in end-stage cancer patients. The first and third sessions will involve frequent blood draws. The second and fourth sessions are designed without such intrusive measures so as to maximize the emotional experience that MDMA can facilitate.

The general approach to be followed is:

1) In order to determine if MDMA produces detectable changes in the human serotonergic system, subjects will receive a battery of neuropsychological tests. These tests will be administered twice, two weeks before the first treatment session and two weeks after the last treatment session.

2) The question of how MDMA effects various organ systems in the body will be studied primarily through various laboratory tests involving blood samples. Physical examinations will be conducted and vital signs will be monitored. Blood samples will be taken immediately before the each session begins and twenty-four hours later, and two weeks after the last treatment session. Blood will be drawn frequently during the first and third sessions. Complete blood workups will be conducted including hematologic, immunologic, hepatic and renal analysis.

3) Pharmacokinetic data will be gathered from the third session only.

4) Efficacy in reducing chronic pain will be examined through the use of pain intensity differentials, patient global indexes, visual analogue scales and quality of life inventories during the course of treatment. Efficacy in reducing acute pain will be examined through the hourly measurement of pain during each treatment session. In addition, the continued need for conventional medications (eg. narcotics) to alleviate pain will be monitored.

5) MDMA's hypothesized mechanism of action as a therapeutic adjunct will be examined. Psychological instruments will be utilized to quantify acute variation in mood state, anxiety and state of consciousness.

6) Efficacy in the relief of psychiatric symptoms will be examined through psychological tests. Correlation between pain reduction and therapeutic outcome will be explored.

7) The effect of the treatments on immune system function will be evaluated through a series of blood and saliva tests administered before, during and after each session. In addition, tumor size and location will be evaluated two weeks before the first treatment session and two weeks after the last treatment session.

Clinical Trials to be Conducted in the Year Following Submission

The clinical trial described in this IND application is the only clinical trial currently planned for the year following this submission. If the results are promising, a subsequent full-scale clinical trial will be conducted.

Estimated Number of Patients to be Given the Drug in the Study

The total number of patients who will be given MDMA is twelve.

Anticipated Risks

There is a possibility that long-term neurochemical changes may be produced by MDMA and that these changes may be associated with functional alterations as manifested by 5-HT-coupled neuropsychological responses. However, subjects will be exposed to cumulative and single dose mg/kg levels below the no-effect levels in primates, doses for which there is no evidence in humans or animals of any harmful neurotoxicological or neuropsychological effects. Based on the toxicological data in animals and prior studies in humans with MDMA or related drugs, the risk to the subjects of long-term neurochemical changes and/or harmful functional alterations as manifested by 5-HT-coupled neuropsychological responses is estimated to be very small.

Another possibility is that the subjects will experience lasting psychiatric sequelae related to their therapeutic sessions with MDMA. While there are no reports of lasting psychiatric sequelae resulting from the therapeutic use of MDMA, there are several anecdotal reports of lasting psychiatric disorders related to the recreational abuse of MDMA (Whitaker-Azmitia and Aronson,1989; McGuire and Fahy, 1991; Creighton et al, 1991, McCann and Ricaurte, 1991; Benazzi and Mazzoli,1991). While some cases involved people with pre-existing psychiatric conditions, a few did not. The risk to the subjects in this protocol of lasting psychiatric sequelae is reduced by the use of pure MDMA in pre- screened subjects under controlled, supervised therapeutic conditions. Before administration of MDMA, patients will have been prepared for the experience and will have built a therapeutic alliance with the therapists. In addition, subjects with major preexisting psychiatric syndromes will be excluded from participating in the study. Furthermore, the dose/response nature of the study will help to gradually prepare the subjects for the psychological effects of MDMA.

There is also a possibility that subjects will experience deleterious idiosyncratic reactions to MDMA. Though such reactions are "exceedingly rare" and most always involve complicating factors (Dowling, 1990), they have been noted in the literature (Chadwick et al,1991; Sucret and Reimerzmc,1988; Vereby et al,1988). The administration of a relatively small initial dose of pure MDMA to pre-screened subjects and the presence of medical personnel minimizes this risk.

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Yensen, R, Di Leo, FB, Rhead, JC,Soskin, RA, Turek, I and Kurland AA, MDA-assisted psychotherapy with neurotic outpatients: a pilot study. J. of Nerv. Ment. Dis. 163 (4):233- 245.

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SCHEDULE OF TESTS

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Two Weeks Before First Treatment Session

Complete Physical Exam, Blood Tests, EKG

Neuropsychological Tests

Pain Evaluation Measures

Immune System Tests

Guided Imagery Training

 

Daily From Two Weeks Before the First Session Until Two Weeks After the Last Session

Memorial Sloan Kettering Pain Card

 

Day Before the First Treatment Session

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

 

Day of First Treatment Session

Vital Signs Monitored Before Session Begins and Every Two Hours

Blood Drawn Before Session Begins, and 1, 2, 4, and 6 Hours

Acute Psychological Tests (POMS-SR and STAI) Before Session Begins and 1, 3 and 6 Hours

Memorial Sloan Kettering Pain Card Before Session Begins and Each Hour

Immune System Tests Before Session Begins and 1, 3, and 6 Hours

Guided Imagery Tape from 30 Minutes to 1 Hour

 

Day After First Treatment Session

Pain Evaluation Measures

Psychological Tests (expect BDI and BSI) and Hallucinogenic Rating Scale

Blood Drawn 24 Hours After Beginning Of Session

Immune System Test At 24 Hours After Beginning Of Session

 

Day Before Second Treatment Session

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

 

Day of Second Treatment Session

Vital Signs Monitored Before Session Begins and Every Two Hours

Blood Drawn Before Session Begins

Acute Psychological Tests (POMS-SR and STAI) Before Session Begins and 1, 3 and 6 Hours

Memorial Sloan Kettering Pain Card Before Session Begins and Each Hour

Immune System Test Before Session Begins and 1, 3, and 6 Hours

Guided Imagery Tape from 30 Minutes to 1 Hour

 

Day After Second Treatment Session

Pain Evaluation Measures

Psychological Tests (expect BDI and BSI) and Hallucinogenic Rating Scale

Blood Drawn 24 Hours After Beginning Of Session

Immune System Test At 24 Hours After Beginning Of Session

 

Day Before Third Treatment Session

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

 

Day Of Third Treatment Session

Pharmacokinetic Study -Intravenous Catheter and Numerous Scheduled Blood Draws

Vital Signs Monitored Before Session Begins and Every Two Hours

Acute Psychological Tests (POMS-SR and STAI) Before Session Begins and 1, 3 and 6 Hours

Memorial Sloan Kettering Pain Card Before Session Begins and Each Hour

Immune System Tests Before Session Begins and 1, 3, and 6 Hours

Guided Imagery Tape from 30 Minutes to 1 Hour

 

Day After Third Treatment Session

Blood Drawn Twenty-Four, Thirty-Six and Forty-Eight Hours After Experimental Session

Pain Evaluation Measures

Psychological Tests (expect BDI and BSI) and Hallucinogenic Rating Scale

Immune System Test At 24 Hours After Beginning Of Session

 

Day Before Fourth Treatment Session

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

 

Day of Fourth Treatment Session

Vital Signs Monitored Before Session Begins and Every Two Hours

Blood Drawn Before Session Begins

Acute Psychological Tests (POMS-SR and STAI) Before Session Begins and 1, 3 and 6 Hours

Memorial Sloan Kettering Pain Card Before Session Begins and Each Hour

Immune System Tests Before Session Begins and 1, 3, and 6 Hours

Guided Imagery Tape from 30 Minutes to 1 Hour

 

Day After Fourth Treatment Session

Pain Evaluation Measures

Psychological Treatment Efficacy Tests (except BDI and BSI) and Hallucinogenic Rating Scale

Blood Drawn 24 Hours After Beginning Of Session

Immune System Test At 24 Hours After Beginning Of Session

 

Two Weeks After Last Treatment Session

Complete Physical Exam, Blood Tests, EKG

Neuropsychological Tests

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

Immune System Tests

 

Every Month Thereafter For Six Months

Pain Evaluation Measures

Psychological Treatment Efficacy Tests

Immune System Tests

 

 

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