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

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

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

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

To date, several Phase I trials have been conducted in the United States, Spain, Switzerland, and the Netherlands; MDMA has been administered to over 112 participants in controlled studies conducted within the United States, and to over 133 more individuals in controlled studies conducted in Europe. When MDMA is used in therapeutic doses in a controlled setting, the risk/benefit ratio is favorable (Cami et al. 2000; Chang et al. 2000; de la Torre et al. 2000a; de la Torre et al. 2000b; Grob et al, In Preparation, data presented to FDA; Grob et al. 1996; Harris et al. 2002; Hernandez- Lopez et al. 2003; Lester et al. 2000a; b; 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). By and large, MDMA appears to have risks that are similar to those of other structurally-related sympathomimetic compounds (Mas et al. 1999; Tancer and Johanson 2003), such as amphetamine (marketed in the United States as Adderall, Dexedrine, and others), that have been used clinically for many years.

Since the late 1970s, MDMA has been used by a growing number of individuals in non-medical settings. Illicit use of ecstasy (material sold as MDMA) is most commonly reported at dance events, such as "rave" parties and at nightclubs, but is not confined to these situations or subcultures. In the United States, prevalence of ecstasy use reported in 2002 was estimated to be 4.3% for persons aged 12 and up, and 15.1% for 18-25 year old adults (Office of Applied Studies, Substance Abuse and Mental Health Services Administration, 2003; tables online at www.oas.samhsa.gov/nhsda/2k2nsduh/html/Sect1peTabs1to110A.htm#tab1.1a ). While a number of serious adverse events, including fatalities, have been reported after illicit use of ecstasy in uncontrolled conditions, such events are relatively rare when considering the prevalence of ecstasy use (Gore 1999; Baggott 2002; Henry and Rella 2001).

There has been no evidence of significant or lasting toxicity in Phase I studies of MDMA. This is noteworthy because animal studies have indicated a possibility of long-term serotonergic brain changes after high dose MDMA regimens (e.g., Hatzidimitriou et al. 1999; Lew et al. 1996; Sabol et al. 1996) and some studies suggest clinically subtle neurocognitive impairments may occur in a subset of repeated users of illicit MDMA and other drugs (e.g., Croft et al. 2000; Gouzoulis- Mayfrank et al. 2003; Gouzoulis-Mayfrank et al. 2000; Thomasius et al. 2003). In contrast, all available Phase I data indicate that it is unlikely that the MDMA exposures proposed in this protocol cause persisting measurable reduction in serotonin function or lasting neurocognitive deficits. This data has not yet been published in peer- reviewed journals but has been presented at several conferences in the United States and Europe. Tests of neurocognitive function have found that performance is not affected by participation in clinical trials with MDMA (Boone et al., unpublished data supplied to MAPS; see also Table 2.5 in Investigator's Brochure; Ludewig et al. 2003, data presented at the 58th Annual Conference of the Society for Biological Psychiatry; Vollenweider et al. 2001; Vollenweider et al. 2000). Vollenweider and colleagues (2000) presented positron emission tomography (PET) data at the 2000 conference of the German Society for Psychiatry, Psychotherapy and Neuromedicine that found no change in estimated serotonin transporter binding sites four weeks after a dose close to 125 mg MDMA was given to MDMA-naive volunteers. The same team of researchers failed to detect any differences in performance on a measure of executive function and memory in 15 drug-naive volunteers given two doses of 1.5 to 1.7 mg/kg MDMA (Ludewig et al. 2003, data presented at the 58th Annual Conference of the Society for Biological Psychiatry, San Francisco CA). Moreover, our own laboratory has investigated the question of neurocognitive deficits; we have already tested, in a pilot study, 23 "pure" illicit MDMA users versus 16 non-using matched controls. Initial results (Halpern et al. 2004) found no significant differences between users versus non-users on any measure, but a post-hoc median split of users revealed some impaired performance on strategy application tests and on tests of perseverations in those individuals reporting 60 or more exposures to MDMA. No significant differences were found between non-users and those who reported more than 20 but less than 60 MDMA exposures. Our laboratory intends to expand this pilot study: the revised R01 grant application to do so with the National Institute on Drug Abuse recently scored 161 (14.4 percentile) and is expected to be funded starting January 2005.

Based on these data and on an extensive review of the MDMA literature, we conclude that MDMA-assisted psychotherapy may have the potential to serve as a novel treatment for anxiety disorders associated with advanced-stage cancer, and that the modest risks of administering MDMA within a therapeutic context are outweighed by the possibility that this treatment may offer significant benefits.

2.1 Previous Clinical Experiences with MDMA

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).

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

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

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

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