Drug Dependence and Abuse Potential

As noted above in the Introductory Statement and in "Monitoring for Toxicity", MDMA is classified as a Schedule I drug with a high potential for abuse. Studies in non-human animals and retrospective studies of humans confirm the presence of abuse potential. However, clinical trials of MDMA do not suggest that drug-naive participants given MDMA in controlled settings are likely to seek out ecstasy in uncontrolled settings. Features of MDMA-assisted psychotherapy are expected to lessen the likelihood that participants will seek out or use ecstasy outside the confines of the study.

Recreational use of MDMA started possibly as early as the 1960s (see Shulgin 1991) and is known to have occurred during the late 1970s and early 1980s. Instances of abuse and dependence in users have been reported (Jansen 1995; Topp et al. 1999). While studies using non-representative samples, including samples of drug users, have reported diagnosing up to 30% of users with abuse or dependence (Topp et al. 2002; Cottler et al. 2001), a survey of a representative sample of young Munich residents found that about 6% of people reporting ecstasy use had signs of abuse or dependence on the drug. This suggests that some people who take ecstasy may develop substance abuse or dependence on the drug. It is important to note that people begin using ecstasy only after they have begun using cannabis or other illicit substances (Pedersen and Skrondal 1999; see also age of onset in Daumann et al. 2004, for example). Measuring reward value by finding the point at which people would switch from receiving drug to either giving up or receiving money, Tancer and Johanson (2003) found that 2 mg/kg MDMA and 20 mg d- amphetamine had higher reward value than placebo, and that 1 mg/kg MDMA and 10 mg d-amphetamine did not significantly higher reward value than placebo. However, participants in this study were selected for past use of ecstasy and minimal use of other substances, so seems likely that study participants would assign high reward value to MDMA.

Studies in rodents (e.g. Cornish et al. 2003; Robledo et al. 2004; Schenk et al. 2002; Wakonigg et al. 2004) and non-human primates (Beardsley et al. 1987; Fantegrossi et al. 2002; Fantegrossi et al. 2004; Lamb and Griffith 1987) suggest that animals will self- administer MDMA. Conditioned place preference, referring to the tendency to spend more time in a chamber associated with an injection of the drug, was reported to occur in rats given MDMA (Bilsky et al. 1990; Cole and Sumnall 2003; Meyer et al. 2002). A study that examined the rapidity with which a drug-naive rat descended a runway to obtain an injection of MDMA also found that animals descended the runway more rapidly when MDMA was available (Wakonigg et al. 2004). All of these findings suggest that MDMA possesses some reward value for rats, usually considered a sign of human abuse potential.

A number of studies have found that non-human primates self-administer MDMA, though to date, all studies have employed animals previously experienced with the self- administration of other substances, such as cocaine or methamphetamine. Rhesus monkeys self-administered an average of 2 to 4 mg/kg MDMA in one study (Fantegrossi et al. 2004) during twice-daily hour-long sessions occurring approximately three times a week. Less self-administration was seen at the end of an eighteen-month period, suggesting that when repeatedly self-administered, MDMA loses some reward incentive. However, overall findings in non-human primates support the presence of at least some abuse liability. Baboons that had previously self-administered cocaine also self- administered MDMA (Beardsley et al. 1987)

MDMA given within the context of psychotherapy will be associated with both pleasant and unpleasant emotional experiences. It is expected that some participants will be confronting thoughts, feelings, and memories that provoke negative emotions such as fear, anger, and grief. The investigators will encourage participants to explore these deeply emotional thoughts and experiences. While MDMA is expected to have an anxiolytic effect during these explorations, it is not expected that experimental sessions will be carefree events. As noted, even healthy participants taking part in research studies did not express a desire to use MDMA outside of laboratory settings when asked about future behavior (Liechti et al. 2001).

The abuse potential of MDMA is acknowledged but appears to be no greater than the abuse liability of conventional anxiolytics. The investigators will include only study participants who have not received a diagnosis of substance abuse or dependence on any substances save caffeine or nicotine in the sixty days prior to screening. Prospective participants and participants will be encouraged to voice concerns about abuse or dependence issues with the investigators.