By the mid-1980s methylenedioxymethamphetamine (MDMA) had become a very popular recreational drug in the United States, as well as in various other countries, being widely used at all-night dance parties (raves). In the fall of 1984, I had been invited to a conference at the Esalen Institute, where a number of therapists were in attendance who had been using MDMA as an adjunct to their psychotherapy practice. I had largely been unaware of the use of MDMA by therapists and had primarily heard of its recreational use at parties and raves. The anecdotal reports offered by the conferees of the powerful effect of MDMA in therapy were eye-opening for me. Although their studies were not randomized and placebo-controlled but were only anecdotal, a typical report by a therapist who had been practicing for decades would go something like this, “this woman had been under my care for 10 years, and progress in her analysis had come to a standstill. But after being given MDMA, she suddenly opened up about traumatic events in her childhood. It was a breakthrough moment and since then we have made tremendous progress.” Such statements sounded rather unbelievable but the therapists who had been using MDMA in their practice seemed honest and sincere.

Also in attendance at this 1984 conference was Rick Doblin, a young student at New College. He had very ambitious plans to make MDMA into a medicine. At the time he had no professional credentials but was full of enthusiasm. I will come back to Rick later.

Although I had been convinced in 1984 that MDMA might have clinical utility, it seemed very doubtful that it would ever be commercialized because, in 1985, the Drug Enforcement Administration (DEA) proposed to use their emergency scheduling power to classify MDMA as a Schedule 1 controlled substance. A DEA spokesmen referred to MDMA as “just another hallucinogenic amphetamine.” Hallucinogenic amphetamines had already been relegated to Schedule 1 of the 1970 Controlled Substances Act (CSA), so logically, another “hallucinogenic amphetamine” would fall into that same category. The DEA justified the need for scheduling as related to the potential danger of MDMA use. They cited unpublished studies by Louis Seiden at the University of Chicago, who had demonstrated the loss of serotonin neurons in rodents given very high doses of MDMA (work published 2 years later by Commins et al. (1). Thus, they reasoned, the possibility of brain neuronal damage caused by MDMA use was so alarming that the drug should be immediately controlled. One could assume that MDMA would probably be relegated to the dustbin of history along with all of the other “hallucinogens” that fell into Schedule 1 of the CSA.

What I had heard at the Esalen conference, however, convinced me that MDMA had unique properties that put it outside of the structure-activity relationships known for hallucinogenic amphetamines with which I was very well versed. Earlier I also had become personally aware of the unique psychopharmacology of MDMA (2). I considered approaches that might prevent regulation of MDMA and allow its medical potential to be evaluated. My thinking was to prove that MDMA was not simply a hallucinogenic amphetamine. Here was where my expertise in the medicinal chemistry of small molecules and stereochemistry became important.

As we all know, every protein and peptide in our body, including receptors and transporters, is composed of L amino acids and is therefore chiral. Because of the chirality of these potential biological targets, it is a well-accepted tenet of pharmacology that if similar biologically active molecules have opposite stereochemistry, they almost certainly have different mechanisms of action.

To begin, the stereochemistry of the more active enantiomer of hallucinogenic amphetamines possesses the R absolute configuration at the alpha-carbon atom (3–6). Furthermore, as a graduate student I had discovered a simple way to prepare the enantiomers of substituted amphetamines (7) which made them more readily accessible for study. We used that method to prepare the enantiomers of MDMA and employed them to demonstrate that the clinical effects of MDMA resided largely in its S-(+) enantiomer (8).

In addition, Lyon et al. (9) showed that the in vitro affinity of (+)-MDMA for [³H]ketanserin-labeled rat brain 5-hydroxytryptamine (serotonin, 5-HT2) receptors was only about 16 micromolar, whereas the affinity of (−)-MDMA was about five-fold higher, at 3.3 micromolar. These authors suggested it was unlikely that the effect of MDMA could be attributed to a direct 5-HT2-mediated mechanism of action. Figure 1 illustrates the stereochemistry of the more active enantiomer of the classic psychedelic agent known as DOM. Also shown in Figure 1 is the more active enantiomer of MDMA. The reader will note that the stereochemistry of the more active enantiomer of S-(+)-MDMA is identical that that of the more active enantiomers of amphetamine or methamphetamine. From Figure 1 one can appreciate that the more active enantiomers of DOM and MDMA have opposite stereochemistry at their α-chiral carbon atoms. The divergent stereochemistries of these two molecules is strong evidence that they must have different mechanisms of action.

Also highlighted in Figure 1 by circles is the fact that DOM, and other classic phenethylamine psychedelics, are primary amines. N-methylation abolishes the psychedelic activity of phenethylamines (10), yet it is a structural feature of MDMA. Thus, both the stereochemistry at the α-carbon atom, as well as the secondary methylamine of MDMA provide strong arguments that MDMA is not simply another “hallucinogenic amphetamine.”

Finally, there was a third structural feature that was worth examination. It had been demonstrated that extending the α-methyl of DOM to an α-ethyl dramatically attenuated or even abolished hallucinogenic activity (11, 12). Indeed, the R-(−) enantiomer of the α-ethyl congener of DOM, BL3912A (Figure 2), was taken into clinical trials and found to have no significant CNS activity at doses up to 270 mg (13), whereas DOM is orally active in the 5–10 mg range.

We therefore prepared the enantiomers of the α-ethyl analog of MDMA, which we called (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) (14) (Figure 3). Although we believed that the α-ethyl moiety would abolish any hallucinogenic activity, we had no foreknowledge of its effect on MDMA-like psychopharmacology. We first examined the discriminative stimulus properties of the enantiomers of MDMA and MBDB in rats trained to discriminate Lysergic acid-N,N-diethylamide (LSD) (0.08 mg/kg) from saline. As anticipated, neither isomer of MDMA substituted in LSD-trained rats. Similarly, neither racemic MBDB nor either of its enantiomers substituted for the LSD stimulus. [Somewhat later we carried out two lever drug discrimination studies in rats trained to discriminate MDMA, where MBDB fully substituted, and in (+)-MBDB-trained rats, where MDMA fully substituted, ultimately demonstrating symmetrical substitution between the two drugs (15)].

At about the same time the Shulgin group carried out an uncontrolled clinical study in 14 subjects, using methods described by Shulgin et al. (16). Oral doses between 150 and 200 mg of the racemic hydrochloride salt of MBDB were administered to the subjects, all of whom had prior experience with a range of psychotropic drugs, including MDMA. No hallucinogenic effects were experienced, and there was a general consensus among the subjects that MBDB had effects very similar to MDMA, with certain differences. Specifically, the onset of action for MBDB was slower and more subtle than with MDMA, and also there was less euphoria and CNS stimulation with MBDB than with MDMA (14).

In a separate double-blind experiment, four subjects were administered either a lactose placebo, or 125 mg of the hydrochloride of either the R or S enantiomer of MBDB. Subjects could readily distinguish between the two enantiomers and found the S-(+)-enantiomer to be active.

Based on our stereochemical and steric arguments, as well as the anecdotal reports of users, we proposed that MDMA and compounds with a related psychopharmacology should be considered in a new drug classification. The late Ralph Metzner also reached a similar conclusion and proposed to call MDMA an “empathogen.” We found that term undesirable for several reasons. First, when considering their potential use as aids to psychotherapy, we did not envision that it was empathy in the patient for the therapist that was the goal. Empathy for the patient, however, is an emotion that should be expressed naturally by a competent therapist, yet the therapist is not the one who takes the medicine. Perhaps more important, however, is that these substances do not simply evoke empathy, although recent studies document that MDMA does enhance empathy (17, 18). Rather, discussion with therapists indicated that MDMA allowed subjects to retrieve repressed and often traumatic memories. If these elements were normally not available for conscious processing, MDMA must have allowed the subjects somehow to have gone within their own psyche to retrieve these events. Thus, MDMA seemed to allow or facilitate a process of internal retrieval. Therefore, we proposed the word “entactogen” as a category for this type of psychoactive drug. The word is composed of the Greek roots en and gen meaning within and to generate, respectively, and tactus, the Latin root for touching. Hence, entactogens are substances that allow or promote a touching within or reaching inside to retrieve repressed memories.

Structural and stereochemical arguments were definitive in distinguishing entactogens from classic psychedelic phenethylamines. There are fewer structural elements to distinguish entactogens from psychostimulants such as methamphetamine but entactogens have clinical psychoactive properties that are clearly distinct from psychostimulants. Early in vitro pharmacology studies indicated that a necessary, but perhaps not sufficient component of action for entactogens was the release of neuronal serotonin, which today we recognize as resulting from a reverse transport of serotonin from the neuron terminal following uptake of the entactogen molecule through the SERT. The potential role of NE release in the action of entactogens has not been sufficiently investigated but also may play some role in the psychopharmacology of entactogens. Clinical studies have demonstrated that drugs that block the serotonin reuptake carrier can block or attenuate most of the psychoactive effects of entactogens, so we hypothesize that an action at the SERT is a necessary, but perhaps not entirely sufficient explanation for the pharmacology of entactogens. Extensive investigation of MDMA-induced social affiliation in mice has been demonstrated to result from serotonin release and stimulation of serotonin 5-HT_1B receptors in the nucleus accumbens. In essence, one can envision that entactogens are the serotonergic counterparts of psychostimulants, where the mechanism of action of entactogens involves carrier-mediated release of serotonin [and norepinephrine? (40)], whereas psychostimulants act by carrier-mediated release of catecholamines from neuronal stores.

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