6.1 Risks and Discomforts Associated with Drawing Blood

Blood specimens will be obtained from the subjects during the screening ("Day -1") evaluation. Temporary discomfort may arise as a result of sampling blood. Blood samples will be used to assist in the investigator's determination of whether or not the participant can safely take part in the study. A risk-benefit analysis suggests that the temporary discomfort from providing blood samples is outweighed by the need to ensure that participants are healthy enough to meet all inclusion criteria at screening.

6.2 Risks and Discomforts Associated with Screening Procedure Medical data will be collected via history and physical examination, and via measurement of vital signs. Submitting to a full medical examination may be time consuming, and may be distressing or uncomfortable for some. Because medical examinations are part of the screening procedure, they cannot be omitted from the study design.

Psychological data will be obtained through interviews and SCID testing. Because these interviews require individuals to discuss their condition, interviews may prove upsetting for some. Because psychiatric interviews and discussion of symptoms of anxiety are used during screening, they cannot be avoided. The investigators, however, will seek as much as possible to reduce anxiety and distress during these interviews.

6.3 Risks and Discomforts Associated with Non-Experimental and Experimental Psychotherapy

During non-drug and experimental sessions, participants will be asked to think about and discuss their thoughts and emotions relating to their medical condition. They may experience intense emotional responses to speaking about this material. Psychotherapy is conducted as part of the research study, including the experimental intervention (MDMA-assisted psychotherapy), and individuals undergoing psychotherapy are expected to confront unpleasant thoughts, feelings and memories in the process of therapy. Because psychotherapy is an integral part of the research study design, the potential distress arising from psychotherapy is unavoidable.

6.4 Risks and Discomforts Associated with the Experimental Intervention

In doses similar to those proposed for this study, MDMA produces sympathomimetic effects similar to the effects of a moderate dose of methamphetamine or other stimulants (Cami et al. 2000; Grob et al. unpublished; Grob et al. 1996; Harris et al. 2002; Lester et al. 2000; Liechti et al. 2001a; Mas et al. 1999; Tancer and Johanson 2003; Tancer and Johanson 2001; Vollenweider et al. 1998). The amount of MDMA used in this study is not likely to produce changes in blood pressure or heart rate greater than 40% of resting values. These changes should last no more than six hours, with peak effects occurring 1 to 3 hours after drug administration (Liechti et al. 2001a; Tancer and Johanson 2003). These changes have been well-tolerated by volunteers in previous studies and should not pose large risks to participants enrolled in this study, who will be carefully screened for cardiovascular and related problems. In less than 5% of volunteers, increases in blood pressure were higher. Clinical intervention was not required in any of these cases. Nonetheless, careful monitoring of participants and predefined contingency plans will allow the researchers to rapidly identify and manage any related toxicity.

MDMA also may produce mild alterations in perception and altered perception of time (Cami et al. 2000; Hernandez-Lopez et al. 2003; Vollenweider et al. 1998). Women may be more sensitive to these effects of MDMA (Liechti et al. 2001a). Some participants receiving MDMA report experiencing periods of increased anxiety (Harris et al. 2002; Liechti et al. 2001a; Tancer and Johanson 2003; Tancer and Johanson 2001; Vollenweider et al. 1998). Psychological distress could arise at any time after the onset of the effects of MDMA, from the first indications of drug effects until the last effects have dissipated (approximately 3 to 5 hours after drug administration). Anxiety or distress is liable to occur in 40% to 70% of subjects, and may last for as little as 15 minutes or for as long as 5 hours or longer. In previous Phase I studies, these symptoms have been modest, self-limiting, and responded well to reassurance from investigators. Anxiety may be greater in participants already experiencing anxiety. In the proposed study, participants 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 as part of the psychotherapy to be conducted during the experimental treatment sessions (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. If significant anxiety persists more than two hours after the expected end of the experimental session, contingency plans (described in the below appendix) include the continued presence of the investigators, support and assistance provided by an individual close to the participant, and the possibility of administering anxiolytic agents as a rescue medication as a last resort. Hospitalization will be considered in cases of extreme psychological distress in individuals who are judged to be a danger to themselves or others.

Side effects of MDMA are modest and generally have not been associated with serious discomfort among volunteers in previous studies (Cami et al. 2000; Harris et al. 2002; Liechti et al. 2001a; Tancer and Johanson 2001; Vollenweider et al. 1998). Decreased appetite, jaw clenching, dry mouth, difficulty concentrating, and impaired gait or balance are commonly reported during peak MDMA effects, while fatigue may be felt up to several days afterward. Less commonly, mild anxiety and depressed mood are reported one to three days after MDMA administration (Harris et al. 2002; Liechti et al. 2001a; Liechti et al. 2000b; Liechti and Vollenweider 2000a; Liechti and Vollenweider 2000b; Vollenweider et al. 1998). Some of these effects are very likely to occur, but proper preparation and follow-up support will reduce the difficulties participants might have with acute or sub-acute side effects, so that they will not be unduly troubled by them.

MDMA may produce modest changes in immune functioning, lasting up to two days after drug administration. A research team in Spain has studied the immunological effects appearing after the administration of one or two doses of 100 mg MDMA (Pacifici et al. 2004; Pacifici et al. 2002; Pacifici et al. 2001; Pacifici et al. 2000). They reported a decline in CD4 cells, smaller CD4/CD8 ratio, attenuated lymphocyte proliferation in response to mitogen, and an increase in natural killer (NK) cells, with effects diminishing but still detectable 24 hours after drug administration. MDMA decreased production of pro-inflammatory cytokines, including IL-2 and interferon-Gamma and increased production of anti-inflammatory cytokines, including IL-4 and IL-10. Generally, MDMA appeared to decrease the concentration of Th1 cytokines and increase the amount of Th2 cytokines measured in blood. A second dose of 100 mg given four hours after an initial dose of 100 mg enhanced the immunological effects produced by the first dose (Pacifici et al. 2001) without increasing the duration of these effects. The mechanism of this MDMA-induced immunomodulation is unclear, but may involve MDMA-induced glucocorticoid release or sympathomimetic activity. Serotonin release may play a direct or an indirect role in producing immunological changes, since paroxetine pretreatment in humans attenuated or eliminated most of the changes described above (Pacifici et al. 2004). Changes of similar magnitude and duration have been previously noted after ingestion of other psychoactive agents, such as alcohol or cocaine (Pacifici et al. 2000; Pacifici et al. 2001). Because of their limited duration, these changes are not likely to have clinical significance beyond a possibly increased risk of the common cold or similar illness for several days. Previous Phase I studies have not reported any indication of increased risk of illness occurring after MDMA administration.

MDMA may cause modest changes in cerebral blood flow lasting several weeks after drug exposure. These changes have been hypothesized to be the result of short-term down-regulation of serotonergic receptors controlling cerebral vasodilatation (Reneman et a. 2002a; Reneman et al. 2000). MDMA induced decreased regional and global cerebral blood flow (CBF) 10 to 21 days after administration (Chang et al. 2000), as reported in a study of 10 ecstasy users given two separate ascending doses of MDMA at a two-week interval, with comparisons made at baseline and after the administration of both doses. Doses per administration in this study ranged from approximately 17 mg (0.25 mg/kg) to approximately 175 mg (2.5 mg/kg). The authors did not find differences in regional or global CBF when 21 MDMA-experienced volunteers (with a reported 211 340 exposures) were compared to 21 non-users (data are presented in the same paper), suggesting that effects on CBF do not last indefinitely. There are no known consequences of these changes and neurocognitive performance was not altered in these volunteers.

Serious MDMA toxicity has not been documented in controlled research experiments with human subjects, but it has occurred in settings outside of research. When considering the millions of users taking ecstasy of unknown identity, potency, and purity (Baggott, 2002; Gore 1999; Henry and Rella 2001, in Holland 2001), serious toxicity appears to rarely occur. Many such users routinely consume estimated MDMA doses higher than those proposed in the current protocol without any apparent toxicity. Under unsupervised and non-medical conditions, the most common serious adverse event involves hyperthermia, which often appears to be influenced by prolonged physical exertion (dancing) and other unsafe conditions of use, such as high ambient room temperature. In addition to hyperthermic syndromes, other adverse events include dysphoric responses, hyponatremia, and hepatotoxicity, though, again, none of these serious adverse events have occurred in the reported clinical research of human subjects administered pure MDMA. In the proposed clinical study, volunteers will be carefully monitored for signs and symptoms of these unlikely events and temperature and liquid intake will be controlled. Contingency plans for responding to these unlikely events are described in the appendix.

MDMA may interact with pain management medication. Currently, there are no systematic published studies of the effects of co- administration of MDMA and pain management medication, such as opiates. However, there are two anecdotal, non-peer-reviewed accounts that indicate that MDMA can be safely administered along with opiates used in pain management (Anonymous 1999; Doblin, 2004, personal communication). A study in rodents comparing analgesia after MDMA with morphine-induced analgesia did not see any changes in MDMA effects on analgesia when given with the opioid antagonist naloxone (Crisp et al. 1989), suggesting that the two drugs affect pain independently. MDMA should not interfere with the effects of opioid-based pain control medication. The investigators will monitor vital signs and respond accordingly to any clinically significant changes. Weighing the risks of combining pain control medication and MDMA with the risks of abstaining from pain control medication, which will increase suffering and may in some cases produce symptoms of opiate withdrawal, we conclude that it is preferable to allow continued medication for pain control.

Risks posed by MDMA to pregnant women are not known. One of two studies of ecstasy users suggests that use of ecstasy and other drugs during pregnancy may be associated with some abnormalities at birth, but the validity of these findings are in dispute (McElhattan et al. 1999). Studies in mice and rats have detected changes in serotonin neurons and some behavioral changes when repeated doses of MDMA were given at certain times during pregnancy or infancy (Broening et al. 2001; Williams et al. 2003; Won et al. 2002), suggesting that exposure to MDMA during pregnancy could pose a developmental risk. However, doses used in these studies were higher than those used by humans. Women who are able to bear children will be required to use effective contraception during the study (barrier-type contraceptives, oral contraceptives, or long-acting injection or implanted contraceptives), with pregnancy tests performed before administration of MDMA on each of the two experimental session days. Pregnant women will be excluded from participation.

MDMA is classified as a Schedule I compound, largely on the basis of its growing popularity at nightclubs and parties in the early to mid- 1980s, the concern of known toxicity from the compound methylenedioxyamphetamine (MDA), and the reports of MDMA abuse or dependence (Jansen 1995). A study of a representative sample of young people found dependence in up to 6% of those reporting use of ecstasy (Lieb et al. 2002). There are no reports of MDMA-naive healthy volunteers exposed to MDMA in previous Phase I clinical studies being motivated to seek out and use MDMA in non-medical settings. For example, Liechti et al. (2001a) reviewed the effects of MDMA in 54 male and 20 female volunteers who had participated in clinical studies. Liechti and colleagues stated that "none of the participants expressed any interest in taking MDMA as a recreational drug" after participation in an MDMA study.

In the currently proposed study, diversion is not an issue because MDMA will only be administered under supervision of a psychiatrist and no take-home doses will be permitted. MDMA will be handled in accordance with all DEA and Massachusetts Department of Public Health regulations pertaining to the handling and dispensing of Schedule I substances within research studies.

6.4.1 Potential Neurotoxicity Associated with Ecstasy Use

Extensive studies in animals indicate that high or repeated dose MDMA exposure can damage serotonergic axons originating in the dorsal raphe nucleus of the brainstem, probably as a result of oxidative stress, and this damage is associated with decreases in serotonin, serotonin metabolites, and serotonin transporter site density (See Baggott and Mendelson 2001; Green et al. 1995; O'Callaghan and Miller 1994; Chapters 4 and 5 in the Investigator's Brochure, Chapter 3 in the 2002 Update to the Investigator's Brochure, and Chapter 3 in the 2003 update to the Investigator's Brochure). Although some regrowth occurs, seemingly permanent redistribution of axons was noted in a study with squirrel monkeys (Hatzidimitriou et al. 1999). Similar changes can be induced by methamphetamine and some other psychostimulants (Miller and O'Callaghan 1996; Molliver et al. 1990; O'Callaghan and Miller 1994; Sabol et al. 1995; Seiden and Kleven 1989; Seiden and Sabol 1996).

There is controversy over the extent to which analogous changes occur in humans. Imaging studies comparing ecstasy users with non-users have found evidence of lower binding to serotonin transporter re- uptake (SERT) sites (Buchert et al. 2003; McCann et al. 1998; Obrocki et al. 2000; Reneman et al. 2001a; Reneman et al. 2001b; Reneman et al. 2002c; Semple et al. 1999). The degree of reduction in SERT varies widely across studies (e.g. Buchert et al. 2003 versus McCann et al. 1998). Many researchers interpret reduced serotonin transporter sites as indicative of damage to serotonin axons, but others note that there may be other reasons for these findings. In preliminary findings reported at several conferences, there has been no evidence of these changes occurring in volunteers enrolled in clinical trials of MDMA. Vollenweider and colleagues measured serotonin transporter density using positron emission tomography (PET) with the same radioligand (radioactively labeled drug) employed in one of the previous studies [11 C]McN5652 (McCann et al. 1998) before and after a clinical administration of approximately 105-120 mg (1.5-1.7 mg/kg) MDMA (Vollenweider et al. 2001, in letter to Neuropsychopharmacology; Vollenweider et al. 2000, data at the 2000 conference of the German Society for Psychiatry, Psychotherapy and Neuromedicine). Comparisons were made in a pilot study with six MDMA-naive healthy volunteers, and later in a second study with additional volunteers (n = 8), so that the two investigations examined a total of 14 subjects. Vollenweider and colleagues failed to find any lasting differences in scans made before and after MDMA administration. These findings indicate that it is unlikely that MDMA will produce significant serotonergic toxicity at the dosage that will be used in the proposed study.

Structural imaging of ecstasy users' brains has generally failed to find significant changes (Chang et al. 1999; Obergriesser et al. 2001; Reneman et al. 2002b; Reneman et al. 2001c; Reneman et al. 2000). Recently, researchers imaging brains of ecstasy user and polydrug user controls with structural magnetic resonance imaging with voxel based morphometry (VBM) detected reduced gray matter in selected brain areas in frontal, occipital and temporal cortex, and in the brainstem (Cowan et al. 2003). While provocative, drawing conclusions from these findings is difficult, due in part to the retrospective study design and the novelty of the imaging technique used. As well, the researchers found associations between use of a number of different drugs, including cannabis and hallucinogens, and reductions or changes in gray matter. One report detected elevated amounts of a substance associated with injured neurons (Reneman et al. 2001c), while another study failed to find such indicators, finding instead an increase in an indicator of stress and repair (Chang et al. 1999), and the third study failed to detect any signs of neuronal injury and did not assess the marker for stress and repair (Obergriesser et al. 2001). Findings from structural imaging studies remain inconclusive, and their significance at present remains unclear. However, these studies have only been conducted so far in ecstasy users, and so reflect the effects of repeated ecstasy use and use of other drugs, and not the effects of MDMA administered in controlled settings.

A report appearing in 2002 that claimed that MDMA damaged dopamine neurons in non-human primates (Ricaurte et al. 2002) was later retracted after it was discovered that the monkeys and baboons in the study had received methamphetamine, and not MDMA (Ricaurte et al. 2003). To date, no studies in humans have found reduced numbers of dopamine transporter sites in ecstasy users (Kish et al. 2000; Reneman et al. 2002c; Semple et al. 1999). Furthermore, the researchers responsible for the study of dopamine toxicity in non- human primates failed to replicate the findings reported in the retracted paper (Ricaurte 2004). Ricaurte did not detect dopamine neurotoxicity after three oral (intragastric) doses of up to 8.6 mg/kg MDMA to monkeys within a six-hour period (25.8 mg/kg total), or after three 4 mg/kg injections given within six hours (12 mg/kg total) (Ricaurte 2004), suggesting that even high doses of MDMA are unlikely to change dopamine function in primates.

If reduced SERT is indicative of MDMA neurotoxicity in humans, it is not known if there are any clinically significant consequences resulting from it. Studies of ecstasy users have suggested that repeated MDMA use may be associated with lowered neurocognitive performance, including measures of verbal memory (Alting Von Geusau et al. 2004; Bhattachary and Powell 2001; Bolla et al. 1998; Curran et al. 2003; Dafters et al. 2003; Gouzoulis-Mayfrank et al. 2003; Gouzoulis- Mayfrank et al. 2000; Hanson and Luciana 2004; McCardle et al. 2004; McCann et al. 1999; Morgan 1999; Reneman et al. 2000; Rodgers 2000; Thomasius et al. 2003; Alting Von Geusau et al. 2004; Zakzanis and Young 2001a), visual memory (Fox et al. 2002; Wareing et al. 2004) and executive function (Gouzoulis-Mayfrank et al. 2000; Hanson and Luciana 2004; McCardle et al. 2004; Verkes 2000; Wareing et al. 2000; Zakzanis et al. 2001b). There is continuing controversy over whether these findings reflect pre-existing differences or the effects of other drug use (particularly cannabis) (Croft et al. 2000; Dafters et al. 2003: Simon et al. 2002) as well as or instead of the effects of repeated ecstasy use. The decreases are clinically insignificant, and do not appear to disrupt the lives of most ecstasy users examined in these studies. Our own laboratory's findings in an initial pilot study of neurocognitive performance of essentially "pure"/exclusive illicit MDMA users failed to replicate decreased performance on most measures, including tests of verbal memory (Halpern et al. 2004). Subtle deficits that were statistically significant were, however, observed by us on some measures of impulsivity and mental processing speed - but only in users reporting 60 or more separate exposures to illicit MDMA preparations.

Conclusions drawn from examining regular ecstasy users may be inappropriately applied in estimating risks of one or two doses of MDMA in a controlled environment, since a number of studies have found neurocognitive deficits only in heavy ecstasy users, and not in moderate users. An early comparison of ecstasy users and drug-using controls (Bolla et al. 1998) found that after accounting for gender and estimated verbal intelligence, monthly ecstasy dose was correlated with impaired performance on some measures of memory. A study failed to find decreased memory in ecstasy users reporting a lifetime dose of under 80 tablets (mean = 39.5 18 tablets), with decreased memory function appearing only in ecstasy users reporting a lifetime dose of 80 or more tablets (Gouzoulis-Mayfrank et al. 2003). Another study comparing a sample of 22 regular ecstasy users with 28 archival controls only found lower scores on some tests of visual memory in individuals with a lifetime dose of over 50 tablets (Back-Madruga et al. 2004). A Phase I study comparing 14 ecstasy users (similar sample to that appearing in Back-Madruga et al. 2004) at baseline and again after two separate administrations of MDMA, at doses per administration ranging from 0.25 mg/kg (approximately 17 mg) to 2.5 mg/kg (approximately 175 mg) (combined dose of 0.75-4.75 mg/kg, or approximately 52.5-332.5 mg) in a controlled setting failed to find differences between performance on an extensive battery of neurocognitive tests given at baseline and after MDMA administration (Boone et al. Unpublished, also see Table 2.5 in Investigator's Brochure). Measures employed in this study included assessments of verbal recall and executive function. It would thus appear that while regular ecstasy use may be related to subtle decline in some areas of cognitive function, administration of MDMA at doses similar to those proposed for this study does not appear to produce differences in neurocognitive function. For further discussion of the methodological limitations of prior MDMA neurocognition studies, see Halpern et al., 2004.

Lastly, findings from several recent publications suggest that use of cannabis and other drugs may play a role in reduced memory or executive function. Some recently published studies failed to find reduced memory function in ecstasy users when compared with cannabis user controls (Dafters et al. 2003; Simon et al. 2002). Other studies have found that when samples are well-matched for polydrug use, current ecstasy users perform similarly to polydrug user controls, and former ecstasy users, who reported more cannabis and amphetamine use, performed less well than non-drug user controls (Thomasius et al. 2003). Based on the above data, and additional data listed in the Investigators Brochure, it appears very unlikely that sessions with two doses with a cumulative dose ranging from 37.5 to 187.5 mg MDMA will have any lasting untoward effect on neurological functioning.

Researchers have detected decreased psychological well-being (either as depressed mood, dysphoria, increased aggression, or increased impulsivity) in illicit MDMA users (Bond et al. 2003; Daumann et al. 2004; Daumann et al. 2001; Gamma et al. 2000; Gerra et al. 2001; Gerra et al. 2000; Hanson and Luciana 2004; MacInnes et al. 2001; McCardle et al. 2004; Morgan et al. 2002; Parrott et al. 2002; Thomasius et al. 2003). These changes include elevated scores on measures of depression (Hanson and Luciana 2004; MacInnes et al. 2001; McCardle et al. 2004) and on self-reported psychological symptoms (Daumann et al. 2004; Morgan et al. 2002; Thomasius et al. 2003). However, other studies have failed to detect decreased psychological well-being in ecstasy users (Curran et al. 2003; Simon et al. 2002), and a number of researchers who found decreased psychological well-being in ecstasy users also found that decreased psychological well-being was equally or more strongly related to cannabis use (Dafters et al. 2003; Daumann et al. 2004; Daumann et al. 2001) or polydrug use (Bond et al. 2003; de Win et al. 2004; Thomasius et al. 2003). A prospective examination of a representative sample of Munich residents aged 14 to 24 found that psychiatric problems are more likely to precede onset of ecstasy use than to follow it (Lieb et al. 2002). An examination of the literature and a consideration of the methodological flaws inherent in retrospective studies suggests that while an association between exposure to MDMA and changes in psychological health or personality cannot be ruled out, this association, if it exists, is weak and influenced by other factors. Given the findings reported in studies of ecstasy users, estimated risk of decline in psychological well-being after the administration of two doses of MDMA in the course of this study is likely to be extremely low.

Estimating the risk of reductions in memory, cognitive function or psychological well-being associated with 187.5 mg MDMA is more difficult, as only one study employing doses in this range has also studied cognition (Boone et al., unpublished), who failed to find any differences in neurocognitive function after the administration of two doses of MDMA, including two separate doses greater than 187.5 mg and three doses only slightly lower (two single doses of 175.5 and one single dose of 172.8 mg. No one has yet assessed psychological well- being after larger doses of MDMA. If there is a relationship between dose and these long-term effects, then it is possible that using higher doses of MDMA increases the likelihood of their occurring. It is notable that at least two studies did not detect reduced memory in ecstasy users reporting average doses per use equal to or above 187.5 mg (Curran et al. 2003; Thomasius et al. 2003), assuming an average of 60 to 80 mg per tablet, as estimated in recent analyses of ecstasy pill contents (Baggott et al. 2000; Cole et al. 2003). Another study of cognitive function in ecstasy users failed to find lower performance in subjects reporting an estimated monthly dose of 440 mg used approximately twice a month (Bolla et al. 1998). Given these figures, it is possible that some of these individuals used equivalent or greater doses of MDMA without it affecting performance on measures of memory. Likewise, one of these studies failed to detect notable differences in psychological well-being, and the other only found differences in one measure of depressed mood in the same samples (Curran et al. 2003; Thomasius et al. 2003). These findings suggest that risks to cognitive or psychological function associated with doses of 187.5 mg MDMA or higher are minimal.

Some researchers believe that MDMA is neurotoxic in humans even at doses used in clinical trials (McCann et al. 2001). Relying on a commonly used calculation for estimating pharmacological effects across species and data from studies in rats and monkeys, the researchers claim that humans should be even more sensitive to the effects of MDMA than smaller animals with higher metabolisms. However, their use of interspecies scaling may be inappropriate in this case. Interspecies scaling models may not be suited for estimating effects of extensively metabolized drugs, and there is some evidence that calculations using less than three different species are not as accurate as those using three or more species (Mahmood and Balian 1996). A recent study in rhesus monkeys challenges the use of interspecies scaling with respect to MDMA (Bowyer et al. 2003), finding instead that plasma levels of S-(+)-MDMA after 10 mg/kg to be ten times levels seen in human clinical trials. In a letter sent to the journal Neuropsychopharmacology, Vollenweider et al. (2001) compared published pharmacokinetic data for humans and rats and conclude that human exposure to MDMA after 125 mg is significantly less than the lowest known consistently neurotoxic MDMA dose in Sprague-Dawley rats, 20 mg/kg, sc, (Battaglia et al. 1988; Commins et al. 1987). At these doses, human MDMA plasma AUC is approximately 30% of the rat AUC. Similarly, human Cmax are approximately 10% of rat Cmax. The same research team that has used interspecies scaling to calculate a neurotoxic dose in humans has found no signs of neurotoxicity when 2.5 mg/kg was administered once every two weeks to squirrel monkeys over a period of four months, at a total of eight doses (Vollenweider et al. 1999b, citing personal communication from Ricaurte to the Swiss Federal Ethical Committee). Another recent study in rhesus monkeys failed to detect signs of serotonin or dopamine toxicity in animals that had self- administered MDMA over an 18-month period (Fantegrossi et al. 2004), with monkeys self-administering, on average, 2 to 4 mg/kg MDMA, though sometimes up to 15 mg/kg was administered during a session. When comparing monkeys that had self-administered MDMA with monkeys that had not had the opportunity to self-administer MDMA, Fantegrossi and colleagues failed to detect any changes in markers of axonal health, no changes in brain dopamine levels, and insignificantly lower brain serotonin levels. Taken together, these findings suggest that the dose of 125 mg MDMA is very unlikely to produce serotonergic neurotoxicity in humans.

It is possible that MDMA neurotoxicity to serotonin axons, if it occurs in humans, will only produce significant psychological or neuropsychological difficulties later on in life. To date, no studies in non-human animals or in humans have examined this hypothesis. Studies have found abnormalities in serotonin innervation in squirrel monkeys given repeated doses of MDMA (Haztidimitriou et al. 1999), this study did not report on any behavioral or cognitive differences after MDMA administration. Brain serotonin neurons show some decline with age, but they appear to decline at a lesser rate than brain dopamine cells (Martin and Rubin 1997). There are no studies examining delayed effects of ecstasy use or exposure to MDMA in humans. It is possible that long-term effects of MDMA will only be apparent after ageing, but the occurrence or likelihood of this occurrence remains unknown.

We have carefully considered the risks of such neurotoxicity and conclude that they are minimal in the proposed study with the proposed population. This conclusion is supported by empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported in previous clinical MDMA studies. Similar conclusions have been drawn by the FDA, which has permitted three Phase I and one Phase II clinical trials by other research groups in the United States.

Nevertheless, the risks of neurotoxicity arising from MDMA administration will be discussed with all potential participants prior to and during the informed consent process.