The protocol is a randomized, dose-response pilot study of 3,4- methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in twelve subjects experiencing anxiety associated with a diagnosis of advanced-stage cancer with one year or less of life-expectancy. Subjects will be randomized into one of two groups that differ only in the dosage of MDMA administered; group assignment is double-blind.
This initial pilot study is intended to allow the researchers to evaluate the safety of the intervention for individuals with advanced-stage cancer as well as evaluate the instruments used for outcome measures and the timing of these measures. Because no previous well-controlled studies have assessed the efficacy of MDMA-assisted psychotherapy, this pilot study will also be used to refine the experimental intervention itself. We recognize that this study is under-powered for all but large effects and that trends seen in this study must be interpreted with caution. A preliminary treatment manual has been written to describe the use of MDMA-assisted psychotherapy in subjects with advanced- stage cancer with anxiety (Ruse et al. 2004).
If data collected from this study 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 results of both of these pilot studies are favorable, the data gathered 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.
MAPS is currently sponsoring an ongoing, FDA-approved pilot study of MDMA-assisted psychotherapy in subjects with posttraumatic stress disorder (PTSD), with this study still in the early stages (Mithoefer 2004). A preliminary treatment manual has been written to describe the use of MDMA-assisted psychotherapy in subjects with PTSD (Ruse et al. 2002), with this treatment sharing common elements with the treatment of subjects with anxiety related to advanced-stage cancer (Ruse et al. 2004). The Heffter Research Institute is sponsoring a study on the use of psilocybin-assisted psychotherapy in advanced- stage cancer patients. This study is currently underway at Harbor- UCLA Medical Center, under the direction of Dr. Charles S. Grob.
The proposed study is primarily intended for two purposes. The first is to explore whether MDMA-assisted psychotherapy can safely be administered to cancer patients with a prognosis of less than 12 months who suffer from anxiety related to the advanced-stage cancer diagnosis who have either failed to respond adequately, if at all, to previous medications for anxiety or who have refused anxiolytic medications. The second purpose is to determine whether this therapy will produce improvements in symptoms of anxiety. Anxiety will be assessed prior to any intervention, immediately after the experimental intervention sessions, at a follow-up evaluation conducted two months after the second experimental session, and in review of a Daily Diary tracking use of anxiolytic and pain management medications. The STAI will serve as a primary outcome measure of anxiety. Improvement will be indicated by lower scores on established outcome measures of anxiety symptoms (STAI, (the primary outcome measure for anxiety), HAM-A, and SCL-90-R) (see Table 3 for the key to abbreviated test names), and reduced use of anxiolytic medications.
A secondary aim of this proposed study is to evaluate whether the experimental intervention translates into meaningful improvements in quality of life. Clinician and participant-rated measures on quality of life will be administered and assessed throughout the study (see Table 2 for the timeline). The EORTC-QLQ-C30 will serve as a primary outcome measure of quality of life. Additional measures assessing quality of life include hopelessness (BHS), suicidal ideation (SAHD), spiritual well-being (FACIT-Sp), self-expansiveness (SELF), depression (HAM-D and SCL-90-R), symptom prevalence and frequency and associated distress (MSAS), physical performance (KPRS), reductions in extent or intensity of experienced pain and resultant use of pain- relieving medications (VAPS, Daily Diary, and MSAS).
The specific hypotheses to be tested by the proposed study are:
1. MDMA can be administered to participants with advanced-stage cancer without serious adverse events.
2. Participants receiving MDMA-assisted psychotherapy will experience dose-dependent decreases in signs and symptoms of anxiety after each experimental session and at two months after the second MDMA session, as measured by the clinician-rated STAI, HAM-A, and the SCL-90-R anxiety-assessing components.
3. Participants receiving MDMA-assisted psychotherapy will experience dose-dependent decreases in use of PRN anxiolytic medications (for example, benzodiazepines) for treatment of symptoms of anxiety, as indicated by review of anxiolytic medication usage from the participant's Daily Diary.
4. Participants receiving MDMA-assisted psychotherapy will experience dose-dependent improvements in quality of life extending to the final follow-up two months after the second MDMA session, as measured by the BHS, EORTC QLQ-C30, FACIT- Sp, MSAS, KPRS, portions of the SCL-90-R, and the SELF. Participant's Daily Diary and VAPS will also provide data that measure potential improvement in quality of life.
5. Participants receiving MDMA-assisted psychotherapy will experience dose-dependent reductions in pain that will last for at least the duration of the study, as measured by the VAPS and through review of pain-control medication usage in the participant's Daily Diary, with dose and/or frequency of use expected to decrease after MDMA-assisted psychotherapy.