3, 4- methylenedioxy ­ N ­ methylamphetamine (MDMA) produces an experience that has been described in terms of "inhibiting the subjective fear response to an emotional threat" (Greer & Tolbert, 1998, p. 371) and increases the range of positive emotions toward self and others (Adamson, 1985; Cami et al, 2000; Grinspoon and Bakalar, 1986). Though promising, reports of the benefits of MDMA-assisted psychotherapy remain anecdotal (Adamson, 1985; d'Otalora, http://www.maps.org/research/mdma/moaccount.html; Gasser 1994; Greer and Tolbert 1998; Metzner and Adamson, 1988, 2001; Naranjo, 2001; Styk, 2001; Wolfson 1986) or based on an uncontrolled study (Greer and Tolbert 1986). As a result, the Multidisciplinary Association for Psychedelic Studies (MAPS) is sponsoring a series of Phase II clinical trials to explore the potential risks and benefits of MDMA-assisted psychotherapy in treatment-resistant posttraumatic stress disorder (PTSD) patients. This manual will provide researchers with a method of MDMA-assisted psychotherapy to be used in conducting these trials.

PTSD is clearly a public health problem that causes a great deal of suffering and accounts for a significant portion of health care costs (Foa, Keane, & Friedman, 2003). PTSD is a complex biopsychosocial condition which is characterized by a combination of three types of symptoms: fear and hyperarousal, intrusive reexperiencing of traumatic experiences, and numbing and withdrawal. A combined treatment of MDMA and psychotherapy may be ideal for the treatment of PTSD because MDMA is considered to attenuate the fear response and decrease defensiveness without blocking access to memories or preventing a deep and genuine experience of emotion. (Metzner, et al 1988,). Participants seem to be able to experience and express fear, anger, and grief with a reduced likelihood of feeling overwhelmed by these emotions. MDMA appears to engender an awareness that such feelings are arising as an important part of the therapeutic process. In addition, feelings of empathy, love and deep appreciation often arise along with a clearer perspective of the trauma as a past event and with a heightened awareness of the support and safety that exists in the present. These effects are distinct from and go well beyond those of anti-anxiety drugs such as benzodiazepines. MDMA- assisted psychotherapy involves using the medicine in the context of a therapeutic session as opposed to the use of a daily dose of the medicine as in the case of the benzodiazepines. There is no evidence that MDMA creates a physical dependency as is the case with benzodiazepines.

Hence, the goal of MDMA-assisted psychotherapy for the treatment of PTSD is to enable the participant to restructure his/her intrapsychic realities and develop a wider behavioral and emotional repertoire with which to respond to anxiogenic stimuli. PTSD is also a disorder for which there are, to date, only two similarly acting FDA- approved medications, and about which there are still many unanswered questions regarding psychological and pharmacological interventions (Montgomery & Beck 1999).

One pharmacological approach has been to seek drugs that will directly decrease symptoms and/or reduce the adverse effects of trauma and chronic stress on the brain. Another approach to these problems is to develop drugs and/or psychotherapeutic treatments that will indirectly interrupt the destructive neurobiological changes associated with PTSD by decreasing or eliminating the stress reactions to triggers and the chronic hyperarousal of PTSD. In fact, the biological and the psychotherapeutic approaches overlap and re-enforce each other. Knowledge about the connections between the neurobiologic effects and the therapeutic effects of MDMA is far from complete, but it has been observed that MDMA acutely decreases activity in the left amygdala (Gamma, et al 2000). This action is compatible with its reported reduction in fear or defensiveness, and is in contrast to the stimulation of the amygdala observed in animal models of conditioned fear, a state similar to PTSD (Charney 1997, Davis 1999). A possible result of MDMA-assisted psychotherapy is the interruption of the stress-induced neurochemical abnormalities produced by the condition. This reduction in stress-induced activation of the amygdale may be supported and enhanced by interacting with the therapists during and after the MDMA experience. This manual will provide the researcher with a method of MDMA-assisted psychotherapy to be used in conducting a scientific study to investigate the possible risks and benefits of this treatment.

The purpose of this manual is to develop and test an investigational form of drug-assisted psychotherapy. Because this is research, by definition, the therapists in the studies are also investigators. In this document we refer to the experimental participants as "participants" rather than "patients". However when describing the investigators' roles as therapists, we have chosen to refer to them as "therapists", leaving implicit the fact that they are investigators in a research study.

The treatment described in this manual involves 13-14 sessions. Non-drug sessions will range from 1 to 1.5 hours of interaction with the co-therapists, and MDMA-assisted therapy sessions will range from 6 to 8 hours of interaction with the team of co-therapists. As is the case for the current research study, the treatment team will consist of two primary therapists, preferably one female and one male. For research purposes this manual includes two additional sessions in which a baseline neuropsychological assessment and a diagnostic clinical interview are conducted.