Theoretical Background: Posttraumatic stress disorder (PTSD) occurs in response to a traumatic event or events. It is most likely to occur following an event that involves perceived personal threat, such as rape or physical assault (Breslau 1998). Approximately 10% to 30% of people who experience a major trauma go on to develop PTSD, giving it an estimated 8% prevalence in the general population (Kang and Hyam 2005; Kessler et al. 1995; Resnick et al. 1993). Criteria for PTSD include exposure to a significant traumatic event accompanied by an intense acute emotional response, persistent re-experiencing of the event or aspects of the experience, persistent avoidance of stimuli associated with the event, and/or withdrawal from some aspects of life, and persistent symptoms of increased arousal, with one month of persistence for acute PTSD and three or more months for chronic PTSD (DSM-IV). In the National Comorbidity Study, the median time to remission was 36 months with treatment and 64 months without treatment, but symptoms were documented as lasting up to 10 years (Kessler et al. 1995). In our ongoing study described above, treatment resistant subjects' symptoms have persisted for up to 43 years.
People with this disorder may experience impaired work productivity, difficulties with relationship maintenance and decline in overall health (Brady et al. 2000). Studies in humans and non-human animals suggest that ongoing symptoms and stress arising from untreated PTSD may be neurotoxic in hippocampal areas (Bremner 1999; Ling 1981; Rauch 1996; Sapolsky 1990; Shin 1997; Wolkowitz, 1990). Currently, there are two approved pharmacological treatments for PTSD, paroxetine (Paxil) and sertraline (Zoloft), and a small number of recognized psychotherapeutic treatments (Brady et al. 2000; Marshall et al. 2001; Montgomery and Bech 2000). Psychotherapeutic interventions for PTSD include cognitive-behavioral, exposure therapy, stress inoculation training, (including anxiety management), and insight-oriented psychotherapy (Foa et al. 1999; Jaycox et al. 2002; Krupnik 2002; Resick and Schnicke 1992; Resick et al. 2002). In November 2004, the American Psychiatric Association (APA) published Practice Guidelines for the treatment of PTSD. The three psychotherapeutic interventions recommended for established PTSD are cognitive and behavior therapies, eye movement desensitization and reprocessing (EMDR) and psychodynamic psychotherapy.
These procedures tend to share several elements in common, including exposure to trauma-related material, learning behavioral or cognitive strategies, anxiety management, and focusing on positive experiences occurring in the present. Although the APA endorses the above therapies in their Practice Guidelines, it is noteworthy that they also imply the need for research into more effective treatment techniques stating "there is a paucity of high-quality evidence-based studies of interventions for patients with treatment-resistant PTSD...." (Ursano et al. 2004).
PTSD is clearly a public health problem that causes a great deal of suffering and accounts for a significant portion of health care costs. A significant minority of people still experience some PTSD symptoms or retain the diagnosis even after receiving a recognized pharmacotherapy or psychotherapy treatment (Hamner et al. 2005; Resick et al. 2002), Resick et al (2002) reported that at posttreatment, 53% of women receiving Cognitive Processing Therapy, and 53% of the women in the Prolonged Exposure condition were PTSD negative on the CAPS in their intent to treat sample, with 47% still PTSD positive at the end of a course of treatment. Foa et al. (1999) report similar results with success ranging from 40% to 60%. People with PTSD may have to undergo more than one treatment, or combine treatments, before symptoms are reduced (Hamner et al. 2005). Developing treatments that work for a greater number of people will help reduce the suffering and public health costs of PTSD. Anecdotal reports (Adamson 1985; d'Otalora 2000) and preliminary findings from a current study suggest that MDMA-assisted psychotherapy may serve as an innovative treatment for PTSD, and that it might be helpful for people who have not responded well to the available therapies. MDMA-assisted psychotherapy may also be more strongly focused on dealing with and resolving issues of interpersonal trust and emotional numbing than psychotherapies that focus chiefly on resolving anxiety or avoidance both as a result of the subjective effects of MDMA and the therapeutic procedures used during MDMA-assisted psychotherapy. MDMA reportedly enhances access to emotionally charged material, feelings of closeness toward others and acceptance of the self and others (Greer and Tolbert 1986; Metzner and Adamson 2001), and the therapists support and encourage engagement in emotionally intense thoughts, feelings and memories throughout the course of therapy, and especially during MDMA- assisted sessions.
Background and Review of Treatment Components: MDMA is a ring-substituted phenylisopropylamine derivative with a unique profile of psychopharmacological effects that make it well suited to intensive psychotherapy. Many researchers hypothesize that MDMA belongs to a new class of psychoactive agents, called entactogens (Nichols 1986), producing feelings of closeness to others, empathy, well being, and insightfulness, with little perceived loss of control (Nichols 1986; Shulgin and Nichols 1978). There is considerable previous human experience with MDMA in a psychotherapeutic context. Therapists have performed MDMA-assisted psychotherapy in the US and Europe (Gasser 1994; Greer and Tolbert 1986; Greer and Tolbert 1998; Widmer 1998). Prior to criminalization, some therapists employed MDMA in psychotherapy to treat a number of psychological problems and psychiatric disorders (Greer and Tolbert 1986; Widmer 1998). Though no well-controlled clinical trials were performed at the time, these therapists concluded that MDMA could be safely administered and was clinically useful in treating various sub-clinical or clinical psychiatric conditions, including PTSD (Greer and Tolbert 1986; Greer and Tolbert 1998; Stolaroff 2004; Widmer 1998). MDMA shares some psychological effects with stimulants and hallucinogens, but also seems to possess a unique pharmacological profile (Cami et al. 2000; Liechti et al. 2001; Mas et al. 1999; Tancer and Johanson 2003). MDMA reportedly increases rapport between patient and therapist and increases a sense of acceptance for the self and other (Greer and Tolbert 1998), though studies in healthy humans currently offer only tentative support for these effects (Harris et al. 2002; Tancer and Johanson 2003). An imaging study detected reduced activity in the left amygdala after 1.5 mg/kg MDMA (Gamma et al. 2000), suggesting that MDMA may reduce or alter either perception or attention to fear-inducing stimuli or the experience of fear (Adolphs 1999; LeDoux 1998), a potentially significant effect, because increased amygdalar activity differentiates people who developed PTSD after a traumatic event from people who did not develop PTSD (Shin et al. 2005). The subjective effects of MDMA specifically relevant to PTSD include increased recall, including recall of emotional material, specific increases and decreases in anxiety, altered perception of the meaning of objects or thoughts, and increased friendliness and closeness to others (Cami et al. 2000; Farre et al. 2004; Greer and Tolbert 1986; Grob et al. 1996; Harris et al. 2002; Liechti et al. 2001; Tancer and Johanson 2003; Vollenweider 1998). MDMA is associated with increased accessibility of intensely emotional thoughts, feelings and memories without a subsequent decline in recall for the experience or the emotionally intense material afterwards (Greer and Tolbert 1986; Greer and Tolbert 1998; Stolaroff 2004). These effects may be the direct result of pharmacological actions, as on serotonin release (Liechti et al. 2000; Liechti and Vollenweider 2000a) or they may arise indirectly through altering cognition, emotion, and social interaction. For instance, dopamine may increase arousal and positive mood (Liechti and Vollenweider 2000b), while activity at 5HT1A receptors, reduced learned associations that lead to adverse outcomes in rodents (Guimaraes et al. 1993).
Specific psychotherapeutic methods and procedures enhance and optimize the potentially therapeutic effects of MDMA. Helping people articulate goals for the MDMA-assisted session and discussing them with the patient beforehand, encouraging confrontation of emotionally intense material, creating a "safe space" where people will feel comfortable grappling with this intense material, discussing and offering techniques for making use of material from the MDMA-assisted session with particular attention in follow-up sessions to helping participants psychologically integrate the experience, and providing participants with recordings of MDMA-assisted sessions are all procedures or features of the therapeutic setting expected to support, enhance or stimulate the benefits of MDMA in combination with psychotherapy. By contrast, people who regularly consume "ecstasy" (material represented to be MDMA, often of unknown purity and dosage) do not typically experience improved psychological health (Lieb et al. 2002; Sumnall et al. 2004). Instead, these studies found an association between polysubstance use and psychological problems. While ecstasy use was not uniquely associated with these problems, using ecstasy didn't mitigate these problems either. These findings, along with the previously described reports and studies suggest that the effects of MDMA are most beneficial when given within a psychotherapeutic context.
Ecstasy use in uncontrolled settings has been associated with serious adverse events, though these occur rarely (Baggott 2002; Gore 1999; Henry and Rella 2001). These include hyperthermia, psychological distress, liver problems, hyponatremia, and other events (Baggott et al. 2001). By contrast, MDMA produces only a slight increase in body temperature in controlled settings (de la Torre et al. 2000; Liechti et al. 2000), and to date, elevated blood pressure is the only adverse event reported during clinical trials (Mas et al. 1999; Vollenweider et al. 1998). Studies of the brain serotonin system in ecstasy users have reported reduced amounts of brain serotonin transporter in current repeated ecstasy users when compared with controls (Buchert et al. 2004; Reneman et al. 2001), and studies have detected impaired memory and executive function (planning and decision-making) in repeated ecstasy users (see for example Gouzoulis-Mayfrank 2000; Halpern et al. 2004; Wareing et al. 2004). Impaired cognitive function seems to be associated with heavy ecstasy use and may also be associated with use of other drugs (Halpern et al. 2004; Thomasius et al. 2003). Comparisons of brain serotonin and cognitive function made before and after up to two doses of 1.5 to 1.7 mg/kg MDMA failed to find reductions in cognitive function or in amounts of brain serotonin transporter (Vollenweider et al. 2000; Ludewig et al. 2003). As well, findings from at least some studies suggest that changes in serotonin transporter availability are transient (Buchert et al. 2004; Reneman et al. 2001) and specific to heavy users (Reneman et al. 2001). These findings suggest that the risks of a few doses of MDMA in controlled settings are considerably lower than seen after repeated use of ecstasy and other drugs in uncontrolled settings. If MDMA-assisted therapy can help people repair relationships damaged by emotional numbing and distancing and return to activities they have shunned because of their PTSD, then these minimal risks are counterbalanced by PTSD symptom reduction.
After reviewing previous accounts of MDMA-assisted therapy, we concluded that this treatment has promise for people with PTSD (Adamson 1985; Gasser 1994; Greer and Tolbert 1998; d'Otalora 2000; Widmer 1998). Therapists reported using MDMA to help patients confront and work with upsetting thoughts, feelings or memories while remaining relatively calm and clear-headed, and without eliminating emotional impact or inhibiting later recall (Greer and Tolbert 1998). The qualities that have been associated with MDMA in anecdotal reports (i.e. decreased defensiveness and enhanced therapeutic alliance) have the potential to be particularly useful in the treatment of this disorder. Subjective effects of MDMA reported in Phase I studies (e.g. Cami et al. 2000; Grob et al. 1996; Harris et al. 2002; Liechti et al. 2001; Tancer and Johanson 2003; Vollenweider et al. 1998), include positive mood, increased recall for emotionally intense material, and changed perceptions of meaning, may also hold significant roles in PTSD treatment. PTSD is a condition that involves prominent fear responses, social withdrawal, and distance from feelings (emotional numbing). Revisiting traumatic experiences in psychotherapy is recognized to be of therapeutic value, and MDMA may facilitate this process. The sense of increased closeness to others, self-acceptance and interpersonal trust may help people with PTSD reduce social withdrawal and strengthen their social relationships or networks. Patients receiving MDMA-assisted psychotherapy can use the experience of increased self-acceptance and interpersonal trust as an alternative point of reference that can be carried over into everyday life. The combination of setting and pharmacological effects may help dissociate feelings of anxiety with intrusive thoughts or memories while at the same time increasing acceptance of unusual and disturbing somatic sensations as not necessarily threatening in and of themselves. Unlike other anxiolytic drugs, MDMA does not prevent or dampen emotions, nor does it interfere with later recall of the MDMA-assisted session. Furthermore, rather than eliminating anxiety altogether, previous reports and controlled studies suggest that MDMA produces moderate increases in anxiety with respect to losing control of oneself while reducing anxiety in response to emotionally upsetting thoughts or memories (Adamson 1985; Greer and Tolbert 1998; Vollenweider et al. 1998). The principal investigator is currently conducting a randomized, placebo-controlled, double-blind, sponsor-supported pilot study of two sessions of MDMA-assisted psychotherapy as part of course of 12 psychotherapy sessions in 20 individuals with treatment-resistant PTSD to test the safety and efficacy of MDMA-assisted therapy in this population. The sponsor will be supporting other studies of MDMA- assisted psychotherapy in people with PTSD to take place in Israel, Spain and Switzerland. To summarize, MDMA is a psychoactive compound with a unique pharmacological profile that was previously used as a psychotherapeutic adjunct prior to being made illegal, and an examination of anecdotal reports and research studies, including the study currently being conducted by the principal investigator, suggest that the subjective effects of MDMA within a psychotherapeutic environment can serve to treat PTSD. This new intervention differs from the use of anxiolytics in psychotherapy, enhancing emotional experience and maintaining full recall of psychotherapeutic sessions. If further research confirms its safety and efficacy, MDMA-assisted psychotherapy may serve alongside other therapies as a means of treating PTSD.
Significance of the Proposed Study: There is currently no systematic, standardized formulation of MDMA- assisted therapy. Further research into the efficacy of MDMA-assisted therapy is hampered by the lack of standardized treatment. Specifically, conducting studies in larger samples or at several sites is not possible without a standardized model of the therapy or a means of training therapists to perform the standardized therapy. This project is intended to develop a treatment manual and accompanying measures of therapist adherence and competence that will allow for more thorough investigations of this innovative treatment. The completion of the treatment manual will support the long-term goal of conducting Phase III studies of MDMA- assisted therapy, and if findings continue to be promising, then these studies will lead to the development of another treatment option for people with PTSD.