Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated

In this paper (2022), David Nichols discusses how he coined the term ‘entactogen’ for the pharmacological class of drugs that includes MDMA and other substances with similar psychopharmacological effects. Nichols details the chemistry underlying entactogens and how they differ from classical psychedelics such as psilocybin and LSD as well as how the effects of MDMA differ from these psychedelics.

Abstract

“At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an N-methyl attached to its amino group, and methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines that N-methylation of hallucinogenic amphetamines attenuates or abolishes hallucinogenic activity. Nevertheless, MDMA is biologically active and has a potency of only slightly less than its MDA parent. Importantly, it is the Ievo-isomer of hallucinogenic phenethylamines that is more biologically active, whereas it is the dextro isomer of MDMA that is more active. This reversal of stereochemistry for the activity of two very closely related molecules is a very powerful clue that their mechanisms of action differ. Finally, extension of the alpha-methyl of hallucinogenic amphetamines to an alpha-ethyl moiety completely abolishes their hallucinogenic activity. Ultimately, we extended the alpha-methyl group of MDMA to an alpha-ethyl to afford a molecule we named (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) that retained significant MDMA-like psychoactivity. Hence, there are three structural features that distinguish MDMA from the hallucinogenic amphetamines: (1) the N-methyl on the basic nitrogen, (2) the reversal of stereochemistry and, (3) tolerance of an alpha-ethyl moiety as contrasted with the alpha-methyl of hallucinogenic phenethylamines. Clearly, MDMA is distinct from classical hallucinogenic phenethylamines in its structure, and its psychopharmacology is also unique. Thus, in 1986 I proposed the name “Entactogen” for the pharmacological class of drugs that includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect. The name is derived from roots that indicate that entactogens produce a “touching within.” Rather than having significant psychostimulant, or hallucinogenic effects, MDMA powerfully promotes affiliative social behaviour, has acute anxiolytic effects, and can lead to profound states of introspection and personal reflection. Its mechanism of action is now established as involving the transport of MDMA by the neuronal serotonin reuptake carrier followed by the carrier-mediated release of stored neuronal serotonin.”

Author: David E. Nichols

Summary

INTRODUCTION

By the mid-1980s, MDMA had become a popular recreational drug in the United States and was widely used at all-night dance parties (raves). I had heard of its recreational use, but was unaware that therapists were using MDMA as an adjunct to their psychotherapy practice.

In 1985, the Drug Enforcement Administration proposed to classify MDMA as a Schedule 1 controlled substance. They justified this action by citing unpublished studies that demonstrated the loss of serotonin neurons in rodents given very high doses of MDMA.

MDMA has unique properties that make it outside of the structure-activity relationships known for hallucinogenic amphetamines. I considered approaches that might prevent regulation of MDMA and allow its medical potential to be evaluated.

STEREOCHEMICAL AND STRUCTURAL ARGUMENTS FOR A NOVEL DRUG CLASS

The more active enantiomer of hallucinogenic amphetamines has the R absolute configuration at the alpha-carbon atom, and we were able to demonstrate that the clinical effects of MDMA reside largely in its S-(+) enantiomer.

Lyon et al. (9) showed that (+)-MDMA had a low affinity for 5-HT2 receptors, whereas ()-MDMA had a high affinity, suggesting that MDMA may not have a 5-HT2 mediated mechanism of action.

Figure 1 highlights the fact that DOM and other classic phenethylamine psychedelics are primary amines, and that MDMA is a secondary methylamine.

A third structural feature of DOM was worth examination, as the -ethyl congener of DOM had no significant CNS activity at doses up to 270 mg.

We prepared the enantiomers of MDMA and MBDB and examined their discriminative stimulus properties in rats trained to discriminate LSD from saline. Neither isomer of MDMA nor either of its enantiomers substituted for the LSD stimulus.

The Shulgin group carried out an uncontrolled clinical study in 14 subjects, and found that MBDB had effects similar to MDMA, with certain differences.

Based on stereochemical and steric arguments, as well as anecdotal reports of users, we proposed that MDMA and compounds with a related psychopharmacology should be considered in a new drug classification. We called this category “entactogens” because these substances allow or promote a touching within or reaching inside to retrieve repressed memories.

Consistent With a Novel Drug Class

We identified a new pharmacological class of psychoactive substances with MDMA, and we needed to define its mechanism of action. This brief review will touch on a few key publications from around the time we first proposed this.

Early studies had found that substituted hallucinogenic amphetamines could possess either a direct or an indirect mechanism of action. The 2,5-dimethoxy aryl substitution caused only a direct action and did not cause the indirect release of neuronal transmitters.

MDMA is a potent releaser of neuronal serotonin, with the S-(+)-isomer being more active. This pharmacology is distinct from the direct stimulation of 5-HT receptors by 2,5-dimethoxy-substituted amphetamines.

Racemic MDMA had highest affinity at serotonin uptake sites, followed by 2 -adrenergic sites and 5-HT2 sites.

Steele et al. (23) found that the S-(+) isomers of amphetamine, MDA, MDMA, MBDB, and DOM inhibited 5-HT uptake into rat brain synaptosomes, but the DOM had no inhibitory activity against any of the three uptake sites.

A study by Steele et al. (23) found that removal of the ortho-methoxy of DOM afforded a compound that was nearly as potent as DOM in its ability to disrupt mouse behavior, with a comparable duration of effect.

Carlsson’s reports led us to examine the O-methyl derivative 3-methoxy-4-methylamphetamine (MMA) and its two stereoisomers. We found that racemic MMA was a potent and selective inhibitor of [3 H]-5-HT uptake into rat brain synaptosomes and that both enantiomers of MMA fully substituted in MDMA-trained rats.

Dimpfel et al. (28) found that the in vivo pharmacology of MDMA and MBDB is distinct from the classic hallucinogenic amphetamines, at least in rats.

MDMA, MMA, and several other amphetamine derivatives inhibited imipramine binding to serotonin transporters and released serotonin from nerve terminals by a process of exchange.

Nash et al. (30) found that (+)-MDMA was completely inactive at the 5-HT2 A receptor, but produced about 60% of the maximal stimulation of serotonin at the 5-HT2 C receptor.

Recent Validations for a Novel Class

Subsequent clinical studies confirmed the early preclinical hypotheses that MDMA’s psychoactive effects depend on carrier-mediated release of 5-HT. The effects of MDMA were also reduced by pretreatment with fluoxetine, paroxetine, and duloxetine.

MDMA produces distinct effects that are distinguishable from psychostimulants across several social domains, including increased self-reported feelings of trust and generosity, increased empathy, and increased social and emotional themes in spontaneous speech.

In a recent mouse study, Heifets et al. (38) demonstrated that MDMA’s prosocial and rewarding properties were due to its action at the serotonin transporter within the nucleus accumbens.

In 1986, Rick Doblin completed a Phase 3 clinical trial using MDMA-assisted therapy to treat PTSD. The results were robust, durable, and unprecedented.

CONCLUSION

Entactogens are phenethylamines that are structurally different from classic psychedelic phenethylamines, but have clinical psychoactive properties that are clearly distinct from psychostimulants. The mechanism of action of entactogens involves the release of neuronal serotonin, which is mediated by the serotonin reuptake carrier.