While there are a number of available means for the treatment of anxiety related to diagnosis with serious life-threatening illnesses such as advanced-stage cancer, the search for a wider array of potential treatments is crucial. Not all individuals with anxiety due to a medical condition that is associated with an expectation of less than 12 months of remaining life will respond to currently available treatments. MDMA- assisted psychotherapy may prove to be yet another treatment option for individuals experiencing anxiety as they face their own near-term mortality. If MDMA is found to be safe and efficacious in this population, then a potentially greater number of individuals will be able to increase their quality of life through the reduction or alleviation of these symptoms. If this pilot study demonstrates improvement in anxiety symptoms, then future research may assist in the development of MDMA as a novel treatment that supports a better quality of life than otherwise would be possible for those individuals facing their own death from advanced-stage cancer.

Even currently available methods of reducing anxiety in people with advanced-stage cancer, such as use of benzodiazepines, have drawbacks such as over-sedation. MDMA-assisted psychotherapy may increase quality of life by reducing need for daily anxiolytic or pain control medication in this population. MDMA-assisted psychotherapy may also improve other aspects of quality of life not addressed by currently available treatments, such as reducing fear in the face of impending death and greater interpersonal connection with loved ones or friends.

There is good evidence that administering MDMA in a clinical setting poses a low risk to subjects. Previous studies examining the effects of MDMA in humans found that it has been well-tolerated, and no lasting toxicity has been reported in clinical trials with MDMA (Cami et al. 2000; Grob et al. unpublished; Grob et al. 1996; Harris et al. 2002; Lamers et al. 2004; Lester et al. 2000; Liechti et al. 2000a; Liechti et al. 2000b; Liechti et al. 2001; Liechti et al. 2000; Mas et al. 1999; Pacifici et al. 2004; Pacifici et al. 2002; Pacifici et al. 2001; Pacifici et al. 2000; Tancer and Johanson 2003; Tancer and Johanson. 2001; Vollenweider et al. 1998). There is no evidence for reduced serotonin transporter site density or neurocognitive function after a small number of MDMA administrations conducted during a clinical trial (Boone et al., unpublished; Ludewig et al. 2003, data presented at 58th Conference for the Society for Biological Psychiatry, Vollenweider et al. 2001; Vollenweider et al. 2000, data presented at the 2000 conference of the German Society for Psychiatry, Psychotherapy and Neuromedicine). Case reports of therapeutic work carried out before the scheduling of MDMA indicate that MDMA can be safely administered (Adamson 1985; Gasser 1994; Greer and Tolbert 1986; Grinspoon and Bakalar 1986). In conclusion, MDMA has been safely administered in numerous Phase I and II studies around the world (including in the United States) and in therapeutic settings.

Subjects receiving low (25 mg MDMA followed by 12.5 mg MDMA) in the course of this pilot study are not expected to improve as much as those receiving higher doses. Use of a low dose as an active placebo is recognized as a means of investigating the effects of an intervention, allowing for clearer evidence concerning safety and efficacy. Low doses of MDMA produce feelings of tension and some mild physical discomforts (Grob et al. unpublished; Harris et al. 2002), but also mild feelings of relaxation (Harris et al. 2002). Otherwise, risks associated with these doses are unlikely to be greater than those associated with an inert placebo. All subjects in the study will receive 5 non-drug therapy sessions as well as experimental treatment sessions.

Previous accounts and an uncontrolled study indicate that an additional dose of MDMA that is approximately one half the size of the initial dose was used in therapy conducted prior to the scheduling of MDMA in the US (Greer and Tolbert 1986; Stolaroff 1988), and that this procedure was well-tolerated. There is less information concerning the risks associated with the addition of a second smaller dose of MDMA, but studies of the effects of repeated doses of MDMA in humans (Farre et al. 2004; Pacifici et al. 2001) suggest that one additional dose administered four hours later, and equal to the initial dose, slightly enhanced subjective and physiological effects without increasing most side effects. Prolonging the therapy session is expected to have a greater chance of improving symptoms of anxiety, since there will be more time to rely on the anxiolytic and insight-fostering effects of MDMA.

The possibility of developing a novel means of reducing or alleviating symptoms of anxiety associated with the diagnosis of advanced-stage cancer with a less than 12 month prognosis of remaining life outweighs the low risks of administering MDMA in a controlled laboratory setting. The advantages of a prolonged working period provided by an additional dose of MDMA are predicted to more than compensate for any slight increase in risk of acute or long-term adverse effects resulting from this slight increase in dosage.

An examination of the risks and benefits of the study, both with respect to risks and benefits faced by study participants and arising from conducting the study, indicate that the proposed study has an acceptable risk-benefit analysis.