Alexander T. Shulgin

The Background and Chemistry of MDMA

This article will present the factual material that up to 1972, MDMA was entered with the phenethylamine exists in the literature representing the results of laboraname. Since then, the heterocyclic term benzodioxole-5i tory studies and scientific experimentation with ethanamine has been the root name. The common abbremethylenedioxymethamphetamine or MDMA, the comviation MDMA is based on the consideration of the stmcmon name applied to an organic compound, a secondary ture as a substituted methamphetamine. Other terms that amine. As a free base it is a white, musty smelling oil with have been used to refer to this drug include MDM, Ec_, a searing taste, insoluble in water but soluble in most stasy, XTC, Adam, and EA-1475 (the last, by the Edgeorganic solvents. It forms salts with several acids, and wood Arsenal). The computer searching of Chemical these are white solids or oils that are readily water soluble Abstracts employs the following registry numbers: _ and bitter to the taste. It has an empirical formula S-MDMA (+) 66142-89-0 Cl iHlsNO2, and its structural formula is given in Figure S-MDMA (+) HCI 69558-32-3

Inhibition of plasma membrane monoamine transporters by β-ketoamphetamines

Methcathinone and methylone, the beta-ketone analogues of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), respectively, were tested for neurotransmitter uptake inhibition in vitro. The beta-ketones were threefold less potent than the nonketo drugs at inhibiting platelet serotonin accumulation, with IC(50)s of 34.6+/-4.8 microM and 5.8+/-0.7 microM, respectively. Methcathinone and methylone were similar in potency to methamphetamine and MDMA at catecholamine transporters individually expressed in transfected glial cells. For dopamine uptake, IC(50)s were 0.36+/-0.06 microM and 0.82+/-0.17 microM, respectively; for noradrenaline uptake, IC(50) values were 0.51+/-0.10 microM and 1. 2+/-0.1 microM, respectively. In chromaffin granules, IC(50)s for serotonin accumulation were 112+/-8.0 microM for methcathinone and 166+/-12 microM for methylone, 10-fold higher than the respective values for methamphetamine and MDMA. Our results indicate that methcathinone and methylone potently inhibit plasma membrane catecholamine transporters but only weakly inhibit the vesicle transporter.

Psychotomimetic Drugs: Structure-Activity Relationships

The field of psychopharmacology has its sources in a number of different medical disciplines involved with the function of the brain. In the area of pharmacology, a major contribution has been made by the study of those drugs that are collectively known as psychotropic agents. The term “psychotropic” is used to describe a drug that turns or changes the mind, following quite literally from the Greek stemψυχη meaning soul, mind, or understanding, and τρeπeιν, to turn. A sizable proportion of our present pharmacopoea contains medicines designed to play a role in the changing or modification of a person’s mood or mental state. A classification of these materials into families defined by the nature of the mental state change evoked is a useful way of defining the subdivision known as “psychotomimetic drugs.” An historically interesting procedure was established by Lewin (1924), who characterized these drugs in five subdivisions according to the nature of their action.

Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter

N,N-dimethyltryptamine (DMT) is a potent plant hallucinogen that has also been found in human tissues. When ingested, DMT and related N,N-dialkyltryptamines produce an intense hallucinogenic state. Behavioral effects are mediated through various neurochemical mechanisms including activity at sigma-1 and serotonin receptors, modification of monoamine uptake and release, and competition for metabolic enzymes. To further clarify the pharmacology of hallucinogenic tryptamines, we synthesized DMT, N-methyl-N-isopropyltryptamine (MIPT), N,N-dipropyltryptamine (DPT), and N,N-diisopropyltryptamine. We then tested the abilities of these N,N-dialkyltryptamines to inhibit [3H]5-HT uptake via the plasma membrane serotonin transporter (SERT) in human platelets and via the vesicle monoamine transporter (VMAT2) in Sf9 cells expressing the rat VMAT2. The tryptamines were also tested as inhibitors of [3H]paroxetine binding to the SERT and [3H]dihydrotetrabenazine binding to VMAT2. Our results show that DMT, MIPT, DPT, and DIPT inhibit [3H]5-HT transport at the SERT with KI values of 4.00xa0±xa00.70, 8.88xa0±xa04.7, 0.594xa0±xa00.12, and 2.32xa0±xa00.46xa0μM, respectively. At VMAT2, the tryptamines inhibited [3H]5-HT transport with KI values of 93xa0±xa06.8, 20xa0±xa04.3, 19xa0±xa02.3, and 19xa0±xa03.1xa0μM, respectively. On the other hand, the tryptamines were very poor inhibitors of [3H]paroxetine binding to SERT and of [3H]dihydrotetrabenazine binding to VMAT2, resulting in high binding-to-uptake ratios. High binding-to-uptake ratios support the hypothesis that the tryptamines are transporter substrates, not uptake blockers, at both SERT and VMAT2, and also indicate that there are separate substrate and inhibitor binding sites within these transporters. The transporters may allow the accumulation of tryptamines within neurons to reach relatively high levels for sigma-1 receptor activation and to function as releasable transmitters.

[125I]-2-(2,5-Dimethoxy-4-Iodophenyl) aminoethane ([125I]-2C-I) as a label for the 5-HT2 receptor in rat frontal cortex

Recent studies of 5-HT2 receptor binding have involved the use of radiolabeled agonists. This report describes the use of [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for low-density 5-HT2 agonist binding sites. A nonhydrolyzable analog of GTP, GppNHp, was found to inhibit the high affinity binding of [125I]-2C-I. 5-HT and several 5-HT2 agonists and antagonists displayed high affinity for this site. In addition, a significant decrease in the Bmax value, but not the KD for [125I]-2C-I was observed at 37 degrees C as compared to that observed at 24 degrees C. Several structure-activity relationships were investigated for displacement of [125I]-2C-I, and the results are consistent with the importance of this receptor in the mechanism of action of hallucinogens. This study demonstrates the utility of [125I]-2C-I as a novel radioligand and provides further data that the 5-HT2 receptor is significantly linked to hallucinogenic activity for several compounds.

History of MDMA

There can never be a complete history of any intensely controversial topic whose proponents and skeptics state their beliefs with equal confidence. Some historical facts will rest uncontested. Many facts will be clothed in opinions that will color the way the facts are to be interpreted. Other facts will never be publicly known, for reasons of legality or privacy. And some facts may simply be irretrievably lost.

Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives.

Abstract Octanol-water partition coefficients (log P) were determined for a series of substituted psychotomimetic phenethylamine derivatives. A relationship was established between log P, steric bulk in the paraposition and the ability to stimulate serotonin (5-HT) receptors in an in vitro sheep umbilical artery preparation. It appears that Log P values and in vitro activity in this preparation.may be useful in predicting hallucinogenic potency in man.

Chemistry of Psychotomimetics

A presentation and discussion of the psychotomimetic drugs in a handbook concerned with psychotropic agents must, at the onset, emphasize the several properties that make this class of materials unique.

High pressure nucleophilic fluoride-ion substitution reactions: formation of fluoroalkylbenzenes

Abstract A series of 1-phenyl-2-tosyloxy- and 1-phenyl-3-tosyloxyalkanes was synthesized and then subjected to tetrabutylammonium fluoride in THF under 15 kbar (1.5 GPa), 8 kbar or 1 bar pressures. The resultant substitution and elimination reaction product distributions were analyzed. The application of pressure enhanced the progress of the fluoride-ion substitution reactions. The degree of selectivity of the one reaction over the other was found to be a function of tosylate substrate structure and the amount of pressure applied. The exclusive formation of fluoroalkanes from 1-phenyl-2-tosyloxyalkane substrates under 15 kbar pressure demonstrated the potential of the pressure method for prospective use in fluorine-18 radiolabelling applications.

Ecstasy analogues found in cacti.

Abstract Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobi vine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called “designer drugs.”