This protocol is for a randomized, dose-response, Phase II pilot study of ( )-3,4- methylenedioxymethamphetmaine (MDMA)-assisted psychotherapy in twelve subjects with anxiety related to advanced-stage cancer. Subjects will have less than a year of estimated life expectancy and will either not have adequately responded to anxiolytic treatments or will have refused to take anxiolytic medications. The study is being conducted in order to develop our treatment method and to gather preliminary evidence about whether this treatment may be safe and efficacious in this population. Eight of twelve participants will be assigned to the Experimental Intervention dose condition, and four of twelve will be assigned to the Low Dose condition. Participants enrolled in the study will receive two sessions of MDMA-assisted psychotherapy separated by a two to three week interval, and they will be assessed for up to two months after the second experimental (MDMA) session. Anxiety, quality of life, life function, and pain will all be assessed regularly for the duration of this study. It is expected to take around one year to complete this study.

MDMA is a ring-substituted phenylisopropylamine derivative invented by the E. Merck of Darmstadt, Germany pharmaceutical company in 1912 that bears structural and pharmacological similarities to both the stimulant amphetamine and the hallucinogen mescaline. It has the chemical name N,-alpha-Dimethyl-1,3-benzodioxole-5-ethanamine, and is described by the chemical formula C11H15NO2. The drug is a white, crystalline powder and will be administered orally in capsule form (see also FDA Drug Master File 6293). Some investigators have categorized MDMA as belonging to a novel drug class, the "entactogens" (Greer and Tolbert 1998; Nichols and Oberlender 1990; Shulgin 1990). This term refers to MDMA and similar substances possessing a unique set of pharmacological and psychological effects, including increased feelings of rapport with others, increased sensitivity to emotions and increased insights about the self, especially in the context of interpersonal relationships. These effects make MDMA an attractive adjunct in psychotherapy.

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

This pilot study is part of a program of research to evaluate and develop procedures for using MDMA as an adjunct in psychotherapy. This program of research will include studies intended to further develop and standardize MDMA-assisted psychotherapy in people with posttraumatic stress disorder (PTSD), anxiety related to a diagnosis of advanced-stage cancer or other terminal illnesses, and potentially other patient populations. If it is found that MDMA-assisted psychotherapy seems safe and efficacious in one or more of the patient populations studied, then MAPS will seek to conduct Phase III studies of MDMA-assisted psychotherapy in larger populations. This is part of a plan to develop MDMA into a prescription medication.

In a teleconference meeting conducted on June 24, 1999, Dr. Cynthia McCormick, Director of the Division of Anesthesia, Critical Care and Addiction Drug Products, stated that the FDA supported a proof of principle study of MDMA-assisted psychotherapy in people with cancer (Memorandum of Telecon Meeting Minutes, July 23, 1999). The meeting was conducted in relation to a study proposed in 1999 by Dr. Charles Grob of UCLA-Harbor Medical Center. Dr. Grob has subsequently obtained FDA permission for his on-going study of psilocybin-assisted psychotherapy in subjects with anxiety associated with cancer.

If data collected from the proposed study of MDMA-assisted psychotherapy in people with advanced-stage cancer indicates that the experimental intervention shows promise of meaningful improvements or significant benefits and can be administered with an acceptable risk/benefit ratio, we will design a second pilot study. This second pilot study will be conducted with a larger sample to increase the statistical power of our findings. In addition, the second pilot study will be used to further refine and standardize MDMA- assisted psychotherapy in these patients. The second study will also aid the further development of an operationalized treatment manual that can be used to evaluate investigator adherence to the principles and practices of MDMA-assisted psychotherapy. If the results of these pilot studies in people with cancer-related anxiety produce favorable results, the data gathered from these studies will be used to inform the design of two large (N = at least 280) multi-site Phase III studies. MAPS' Clinical Plan (Doblin 2002) estimates that this process will require at least 5 years and will involve at least 600 subjects.