Dear Dr. Kavanaugh,

We are happy to respond to Dr. Mithoefer and colleagues' comments and queries, which are paraphrased below, in the order they appear in their letter.

1. "It appears that Dr. Ricaurte et. al underestimate by 100% the mortality rate of their primates... A total of 10 monkeys and 5 baboons received the sequential dosing regimen of MDMA described in our paper. Of the 10 monkeys treated with this regimen, one (10%) died, as stated in our letter. Data from the surviving monkeys were used for neurochemical, immunocytochemical, autoradiographic and/or motor studies described in our paper. As described in our paper, one baboon (not monkey) also died during the course of our study.

2. "The number of test animals that died is an important issue since it can be used to evaluate whether the regimen employed in the study represents a "common recreational dose..." As previously stated, it is inappropriate to estimate mortality rates on a small number of test cases. Imagine, for example, that this practice was employed in the famous case of Leah Betts and her small group of friends who took single doses of MDMA to celebrate her 18th birthday. It would be erroneously concluded that MDMA has a high mortality rate in humans who ingest single doses of MDMA. As already indicated in our first response, we believe it is inappropriate and potentially highly misleading to use small samples to arrive at epidemiological estimates.

3. "Mortality rates can be used to evaluate whether the dose used by Ricaurte et al is a common recreational dose regimen..." Mortality rates and dosing regimens are distinct issues. It can not be argued that many people who use MDMA often take repeated dosages over several hours. Further, the dosages used in our study are actually lower than typical doses used by humans, when intraspecies dose scaling is taken into account.

4. "Furthermore, the paper reports behavioral toxicity in two animals after two doses of MDMA..." Having experienced the unanticipated deaths of two animals (one monkey and one baboon), we were extremely vigilant for the potential emergence of further problems in all animals tested. As a result, the final dose was held for one baboon and one monkey when they appeared to exhibit some gait instability. Of note, both animals recovered within hours, and in retrospect, the gait instability might have merely been evidence of the pharmacological effects of MDMA, possibly related to sequential dosing. Notably, gait instability has been reported in humans given MDMA in experimental settings (Greer and Tolbert, 1986; Downing, 1986) and occurred in one third of subjects in one study (Downing, 1986).

5. "Dr. Ricaurte's team can't just sweep under the carpet the death of a second monkey..." One monkey and one baboon in our study died, as clearly stated in our paper. The letter that we wrote in response to Dr. Mithoefer and colleagues was intended to address questions and comments that they raised in their letter to the editor. Our response did not mention baboons, because no questions or comments had been raised regarding baboons, not because we were attempting to "sweep data under the carpet." Our effort to be forthcoming about the MDMA's adverse effects in our study should be obvious, since the deaths of two animals were prominently featured in our paper.

Greer G and Tolbert R. Subjective reports of the effects of MDMA in a clinical setting. J. Psychoactive Drugs 1986;18(4):319-327.

Downing J. The psychological and physiological effects of MDMA on normal volunteers. J Psychoactive Drugs 1986;18(4):335-340.