Clinical MDMA research using healthy volunteers has been conducted by at least six research groups, including three in the United States. Double-blind placebo-controlled MDMA studies have been published in peer-reviewed journals. To date, the most extensive studies have been carried out by Franz Vollenweider of the University of Zurich and his colleagues. They have administered up to two doses of 1.5 to 1.7 mg/kg MDMA to 74 subjects. These researchers have published studies of brain imaging, EEG, cardiovascular, neuroendocrine and subjective effects of MDMA (Frei et al. 2001; Gamma et al. 2000; Liechti et al. 2000a; Liechti et al. 2000b; Liechti et al. 2001a; Liechti et al. 2001b; Liechti and Vollenweider 20001a; Liechti and Vollenweider 2001b; Vollenweider et al. 1998; Vollenweider et al. 1999). The Zurich researchers have also published a review of the data that notes gender differences in MDMA effects (Liechti et al. 20001a), and they have presented data at conferences investigating the effects of up to two doses of 1.5 to 1.7 mg/kg MDMA on levels of serotonin transporter or cognitive function (Ludewig et al. 2003; Vollenweider et al. 2000). A team of researchers in Spain have measured the subjective, cardiovascular, and immunological effects of 50, 75, 100, 125 and 150 mg MDMA, alone and, in some studies, in combination with ethanol (Cami et al. 2000; Hernandez-Lopez et al. 2002; Mas et al. 1999; Pacifici et al. 1999; Pacifici et al. 2001; Pacifici et al. 2002; Pacifici et al. 2004). This same team of researchers has investigated the effects of repeated doses of 100 mg MDMA, with the second dose given four or 24 hours after the initial dose (Farre et al. 2004; Pacifici et al. 2002), and they have published countless pharmacokinetic and drug detection studies (e.g. de la Torre et al. 2000; Navarro et al. 2001; Pichini et al. 2002; Pichini et al. 2003; Pizarro et al. 2002; Pizarro et al. 2003; Segura et al. 2002). While it appears that the researchers reported data form the same sample in several studies, they have administered MDMA to 42 to 54 subjects. A team of researchers at Wayne State University in Detroit has assessed cardiovascular, subjective, and neuroendocrine effects of about 1.1, 1.6, and 2.1 mg/kg MDMA, as compared with the psychostimulant d-amphetamine and the serotonin releaser and serotonin receptor agonist mCPP in 22 men and women with prior use of ecstasy (Tancer and Johanson 2001). This team has also performed a similar study of 1 and 2 mg/kg MDMA in 12 men and women that also measured rewarding effects (Tancer and Johanson 2003). The Wayne State researchers have also presented data from studies of ambient temperature and 2 mg/kg MDMA in four subjects, and co-administration of fluoxetine with 1.5 mg/kg MDMA in eight subjects (Tancer and Johanson 2004; Tancer et al. 2003). Researchers at UCLA-Harbor Medical Center assessed cardiovascular, neuroendocrine and some subjective effects of ascending doses of MDMA that varied from 0.25 to 2.5 mg/kg MDMA in 18 men and women who had reported some ecstasy use (see IND #63,384, pp. 44-48 and pp. 52-70 for more details; Grob et al. 1996). A team of researchers in the Netherlands has studied the cardiovascular and subjective effects of 75 mg MDMA in 12 men and women reporting ecstasy use (Lamers et al. 2003; Samyn et al. 2002), focusing on acute effects of MDMA on skills related to driving. Researchers at the University of California-San Francisco have studied the cardiovascular, subjective and neuroendocrine effects of MDMA in eight men and women with past experience with ecstasy (Harris et al. 2002; Lester et al. 2000). Lastly, researchers in England studied the neuroendocrine effects and pharmacokinetics of 47.6 mg MDMA (equivalent to 40 mg freebase) in eight drug-naive men, specifically examining changes in arginine vasopressin release (Fallon et al. 2000; Forsling et al. 2001; Henry et al. 1999). Up to 2.5 mg/kg MDMA was well tolerated in these clinical trials, and no serious adverse events were reported in any of the published or unpublished reports. More information on the acute effects of MDMA can be found in the Investigator's Brochure (Baggott et al. 2001) and the two successive revisions to the IB (Jerome and Baggott 2003; Jerome 2004).

Clinically significant hypertension has occurred in a approximately 5% of individuals enrolled in controlled studies of MDMA (Grob et al., Unpublished, see also pp. 45 in IND #63,384; Vollenweider et al. 1998), and significant hypertension has occurred in at least one participant in the study of MDMA-assisted therapy in people with PTSD (Mithoefer, 2004a, personal communication to R Doblin and L Jerome, Nov 4, 2004). However, hypertension subsided without clinical intervention in all cases. Plans for monitoring and treating hypertension are described in detail below in "Monitoring for Toxicity."

A study of the effects of two separate sessions of MDMA-assisted therapy in people with posttraumatic stress disorder (PTSD) is underway (Mithoefer 2004c). This study is described in IND #63,384 and uses two doses of 125 mg MDMA or placebo given three to five weeks apart. So far, five participants have completed the study without occurrence of any serious adverse events (Mithoefer, 2004b, personal communications to R Doblin Nov 12, 2004). Because the study is still operating and the blind has not been broken, it is not known how many of these subjects have received MDMA, but it can be assumed given the study design that between one and three individuals have received the experimental intervention. A team of researchers in Spain have administered 50 mg, 75 mg MDMA, or placebo to women with PTSD arising from a sexual assault. This study also reported no serious adverse events. However, this study has since been halted due to political concerns expressed by the local anti-drug authority (Bouso, 2003, communication to R Doblin and L Jerome, January 15, 2003 ). Since the study was halted without being discontinued, the blind was not broken and it is not known whether participants received the experimental intervention or placebo. MDMA has been tolerated by participants in both the ongoing and the halted study, assuming that one or more participant received MDMA.

There also exists an extensive history of using MDMA as an adjunct to psychotherapy prior to scheduling (Adamson 1985; Greer and Tolbert 1986; Greer and Tolbert 1998; Grinspoon and Bakalar 1986; Metzner and Adamson 2001; Stolaroff 1997; Widmer 1998). Narrative accounts and case reports of MDMA given in these circumstances indicated that MDMA was tolerated and that no serious adverse events occurred. Two uncontrolled studies of MDMA (Downing 1986; Greer and Tolbert 1986), including one performed in a psychotherapeutic context (Greer and Tolbert 1986) also found that study participants tolerated MDMA and reported no serious adverse events. Lastly, during a period lasting from 1988 to 1993, psychotherapists in Switzerland were permitted to administer MDMA to patients (Gasser 1994; Widmer 1998). These therapists reported that MDMA-assisted psychotherapy was tolerated and did not report any serious adverse events occurring after MDMA administration.

In summary, researchers have measured the cardiovascular, physiological, neuroendocrine, neurofunctional (PET and EEG), psychiatric, and subjective effects of MDMA at doses ranging from 0.25 to 2.5 mg/kg, and researchers are currently studying the effects of 125 mg MDMA given as an adjunct to psychotherapy in people with posttraumatic stress disorder. MDMA has been generally well tolerated in these studies, and we are aware of no serious adverse events. Participants with and without previous experience with MDMA reported that the effects of MDMA were mostly pleasant and otherwise tolerable (Cami et al. 2000; Farre et al. 2004; Grob et al. 1996; Harris et al. 2002; Hernandez-Lopez et al. 2002; Liechti et al. 2001; Tancer and Johanson 2001; Tancer and Johanson 2003; Vollenweider, 1998). Occasionally, dysphoric responses to MDMA have occurred, but have always resolved within several hours, and transient changes in thought processes are reported (Harris et al. 1998; Vollenweider et al. 1998). Clinically significant hypertension has occurred in several volunteers; these cases are discussed above. To date, there is no indication that administration of MDMA in controlled settings has any adverse effects on cognitive function (Grob et al. Unpublished; Ludewig et al. 2003; Vollenweider et al. 2000). As shown in Table 2.5 of the Investigator's Brochure, Grob et al. did not detect any change in neurocognitive function in their volunteers. Similarly, Vollenweider and colleagues (Ludewig et al. 2003; Vollenweider 2001; IND #63,384 pp. 189-190; Vollenweider et al. 2000) report that retrospective analysis of their studies did not detect any lasting effect of MDMA on psychological and neuropsychological measures, cerebral blood flow (H215O-PET), and electrophysiological indices of information processing such as prepulse inhibition of the startle reflex (PPI) and brain wave activity (EEG/ERP). Most importantly, preliminary analysis using positron emission tomography (PET) and the radioligand McN-5256 revealed no significant changes in estimated serotonin transporter density four weeks after a single dose of MDMA (1.5-1.7 mg/kg) in MDMA-naive volunteers (Vollenweider et al. 2001). This data and the history of past use of MDMA in psychotherapy prior to scheduling indicate that MDMA can be safely administered to humans.