Dmt Nature's Ubiquitous Hallucinogen - Dennis Mckenna

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DMT - Nature's Ubiquitous Hallucinogen, by Dennis McKenna What's Related >>Of the three major classes of hallucinogens, the simple derivatives of tryptamine bear the closeststructural relationship to the brain neurotransmitter serotonin--------------------------------------------------------------------------------DMT - Nature's ubiquitous hallucinogenDennis J McKenna, PhDIntroductionOf the three major classes of hallucinogens, the simple derivatives of tryptamine (Fig. 1) bear the closeststructural relationship to the brain neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Theclassical hallucinogens are now thought to exert their effects through interactions with one or more 5-HTreceptor subtypes, particularly 5-HT2 receptors, and the tryptamines present no exception to thisgeneralization, although their pharmacological mechanism(s) of action and receptor interactions havenot been as extensively characterized as LSD and the phenylethylamine hallucinogens.This article presents a summary overview of the natural distribution, neuropharmacology, and structure/ activity relationships of N,N-dimethyltryptamine (DMT) and its close structural relatives.Occurrence in NatureThe phylogenetic distribution of naturally occurring phenylethylamine or lysergamide hallucinogens isextremely limited. The only natural hallucinogenic phenylethylamine so far identified is mescaline,which is an alkaloid of the peyote cactus (Lophophora williamsii) and approximately 20 other cactusspecies. Mescaline has not been found outside the Cactaceae. Similarly, the psychoactive lysergamidesare rare in nature; they have been identified in the ergot fungus, Claviceps purpurea, and the related C.paspali, and in one higher plant family, the Convolvulaceae or morning-glory family. Hallucinogenictryptamines, by contrast, are among the most widely distributed psychoactive compounds in nature, andhave been identified in over 19 higher plant families and higher fungi.Hallucinogenic tryptamines have also been identified in animals, including humans. The compoundbufotenine (5-hydroxy-N,N-dimethyltryptamine) was isolated from the venom of toads before itswidespread occurrence in plants was recognized, and bufotenine and its derivatives are common in the

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genera Hyla, Leptodactylus, Rana, and Bufo. Bufotenine itself is not hallucinogenic, acting as a pressoramine rather than an hallucinogen in humans. The only species known to contain a hallucinogenictryptamine is Bufo alvarius, which contains 5-methoxy-N,N-dimethyltryptamine at the rather staggeringconcentration of 50 - 160 mg/g of skin.Bufotenine, 5-methoxy-N,N-dimethyltryptamine, and DMT, as well as tryptamine and N-methyl-tryptamine, have been identified as endogenous metabolites in rats and other mammals, includinghumans. N-methyl transferases and other enzymes capable of catalyzing the biosynthesis of catabolismof hallucinogenic tryptamines have been characterized in human lung, brain, blood, cerebrospinal fluid,liver, and heart, as well as in these and other tissues in other species. Barker et al. have speculated on thepossible neuromodulatory and/or neuroregulatory role of endogenous DMT in mammalian systems, andCallaway has presented an interesting hypothesis regarding the possible role of endogenous DMT and ß-carbolines in the regulation of REM sleep.Human psychopharmacologyThe available data on the human psychopharmacology of hallucinogenic tryptamines has beenthoroughly reviewed by Shulgin and Nichols and Glennon and will only be summarized briefly here.Tryptamine itself and N-methyltryptamine are both without central effects in humans at doses in excessof 1 gram orally. The simplest tryptamine exhibiting unambiguous hallucinogenic activity in humans isDMT. Parenteral administration of DMT in the 25 to 135 mg range elicits an hallucinogenic episodecharacterized by rapid onset and short duration (15 - 30 min). 5-methoxy-DMT is also parenterallyactive, with a similar spectrum and duration of action as DMT, at doses of about one tenth that of theparent compound. The visual component of the experience triggered by this compound is somewhatattentuatedcompared to that of DMT.Neither DMT nor 5-MeO-DMT are orally active, presumably due to peripheral degradation bymonoamine oxidases (MAO) and possibly other enzymes in the liver and intestinal tract. Thesecompounds may be rendered orally active by the simultaneous administration of ß-carbolines or otherselective peripheral monoamine oxidase inhibitors. This mechanism may account for the oralhallucinogenic activity of several plant-derived hallucinogens used by Amazonian peoples.Ring hydroxylation of DMT at the 4-position of the indole nucleus results in the compound psilocin,which is orally active as a hallucinogen at threshold doses of 4 - 8 mg. Bufotenine, the 5-hydroxy isomerof psilocin, is hallucinogenically inactive, probably due to an inability to cross the blood/brain barrier.Bufotenine can induce a subjective reaction, but the effects are not those of the typical hallucinogenicresponse, and may result from the subject's reactions to peripheral autonomic phenomena (tachycardia,nausea, etc.) induced by the drug.

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Structure/Activity RelationshipsThe substitution sites on the tryptamine nucleus that are important determinants of hallucinogenicactivity are the indole ring, the side-chain carbons, and the side-chain nitrogen (fig. 1). The relevance of structure/activity relationships to the interactions of tryptamine derivatives with 5-HT receptor subtypeswill be considered in the next section. This secton discusses some aspects of structure/activityrelationships that bear on the human psychopharmacology of these compounds.The N-alkyl homologues of DMT in which the N,N-dimethyl substituents are replaced with longer andmore hydrophobic aliphatic moieties include N,N-diethyltryptamine (DET), N,N-dipropyltryptamine(DPT), N,N-diisopropyltryptamine (DIPT), N,N-diallyltryptamine (DAT), and N,N-dibutyltryptamine.All of these derivatives, except for DBT, are psychoactive in humans, and all are orally active.Qualitatively, homologation of the N,N-dialkyl substituents attenuates the intensity of the experience,and prolongs the course of action. Nonsymmetrical alkyl substitution of the side-chain nitrogen, e.g., N-methyl-N-isopropyl substitution, also yields orally active compounds with threshold doses andqualitative actions similar to those of the N,N-dimethyl derivatives.In general, hydroxylation at the 4-position of the indole nucleus, as in the prototype compound psilocin,enhances the potency of N,N-dialkyl homologues and nonsymmetric N-alkylated derivatives byapproximately an order of magnitude, compared to the unsubstituted derivatives. Methoxylation at the 5-position of the ring similarly increases potency but enhances the simulant (amphetamine-like) effectswhile attenuating the visual effects. Derivatives with 6-methoxy, 7-methoxy, 5,6-dimethoxy, or 5,6-methylenedioxy substituents display greatly attenuated activity.Methyl substitution of tryptamine at the side-chain a-carbon also results in orally active hallucinogeniccompounds. a-methyl tryptamine itself and its 5-methoxy- and 4-hydroxy congeners are orally active inhumans at the 3 to 30 mg level. The a-substituted tryptamines are the only enantiomeric derivatives inthis class that have been empirically investigated, and in general, the S-(+) enantiomers are more potentthan the R-(-) enantiomers in both animal and human experiments. a-methyltryptamine and a-ethyltryptamine are competitive inhibitors of MAO, and this property may contribute to their oralactivity. The psychoactive properties of a-, N,N-dialkyl substituted tryptamines, if any, have apparentlynot been investigated.NeuropharmacologyThe neuropharmacology of psychoactive tryptamines has been studied in animal behavioral models, as

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