DMT - Nature's Ubiquitous Hallucinogen, by Dennis McKenna

Of the three major classes of hallucinogens, the simple derivatives of tryptamine bear the closest structural relationship to the brain neurotransmitter serotonin

Dennis J McKenna, PhD

Introduction

Of the three major classes of hallucinogens, the simple derivatives of tryptamine (Fig. 1) bear the closest structural relationship to the brain neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The classical hallucinogens are now thought to exert their effects through interactions with one or more 5-HT receptor subtypes, particularly 5-HT2 receptors, and the tryptamines present no exception to this generalization, although their pharmacological mechanism(s) of action and receptor interactions have not 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 Nature

The phylogenetic distribution of naturally occurring phenylethylamine or lysergamide hallucinogens is extremely 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 cactus species. Mescaline has not been found outside the Cactaceae. Similarly, the psychactive lysergamides are 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. Hallucinogenic tryptamines, by contrast, are among the most widely distributed psychoactive compounds in nature, and have been identified in over 19 higher plant families and higher fungi.

Hallucinogenic tryptamines have also been identified in animals, including humans. The compound bufotenine (5-hydroxy-N,N-dimethyltryptamine) was isolated from the venom of toads before its widespread occurrence in plants was recognized, and bufotenine and its derivatives are common in the genera Hyla, Leptodactylus, Rana, and Bufo. Bufotenine itself is not hallucinogenic, acting as a pressor amine rather than an hallucinogen in humans. The only species known to contain a hallucinogenic tryptamine is Bufo alvarius, which contains 5-methoxy-N,N-dimethyltryptamine at the rather staggering concentration 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, including humans. N-methyl transferases and other enzymes capable of catalyzing the biosynthesis of catabolism of 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 the possible neuromodulatory and/or neuroregulatory role of endogenous DMT in mammalian systems, and Callaway has presented an interesting hypothesis regarding the possible role of endogenous DMT and ß-carbolines in the regulation of REM sleep.

Human psychopharmacology

The available data on the human psychopharmacology of hallucinogenic tryptamines has been thoroughly 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 excess of 1 gram orally. The simplest tryptamine exhibiting unambiguous hallucinogenic activity in humans is DMT. Parenteral administration of DMT in the 25 to 135 mg range elicits an hallucinogenic episode characterized by rapid onset and short duration (15 - 30 min). 5-methoxy-DMT is also parenterally active, with a similar spectrum and duration of action as DMT, at doses of about one tenth that of the parent compound. The visual component of the experience triggered by this compound is somewhat attentuatedcompared to that of DMT.

Neither DMT nor 5-MeO-DMT are orally active, presumably due to peripheral degradation by monoamine oxidases (MAO) and possibly other enzymes in the liver and intestinal tract. These compounds may be rendered orally active by the simultaneous administration of ß-carbolines or other selective peripheral monoamine oxidase inhibitors. This mechanism may account for the oral hallucinogenic 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 isomer of 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 hallucinogenic response, and may result from the subject's reactions to peripheral autonomic phenomena (tachycardia, nausea, etc.) induced by the drug.

Structure/Activity Relationships

The substitution sites on the tryptamine nucleus that are important determinants of hallucinogenic activity 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 subtypes will be considered in the next section. This secton discusses some aspects of structure/activity relationships 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 and more 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 and qualitative 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 by approximately 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) effects while 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 hallucinogenic compounds. a-methyl tryptamine itself and its 5-methoxy- and 4-hydroxy congeners are orally active in humans at the 3 to 30 mg level. The a-substituted tryptamines are the only enantiomeric derivatives in this class that have been empirically investigated, and in general, the S-(+) enantiomers are more potent than 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 oral activity. The psychoactive properties of a-, N,N-dialkyl substituted tryptamines, if any, have apparently not been investigated.

Neuropharmacology

The neuropharmacology of psychoactive tryptamines has been studied in animal behavioral models, as well as in in vitro models such as receptor binding assays. One of the most useful animal models for studying hallucinogens has been the two-lever drug discrimination paradigm, in which an animal is trained to differentiate LSD or a similar active training drug from saline. The animal is administered a test drug and the degree of "LSD-appropriate" response is assessed; stereospecificity and significant correlations with receptor binding data can also be demonstrated.

Using this model, Koerner and Appel investigated the stimulus generalization effects of psilocin, LSD, and mescaline in rats trained to discriminate psilocybin from saline. They reported that the psilocybin cue generalized to psilocin (the dephosphorylated congener of psilocybin) and LSD, but not to the phenylethylamine hallucinogen mescaline. Their results suggested that the hallucinogenic effects of the three drugs in humans may not be identical to their discriminative stimulus properties in animals, and indicate that the drug discrimination assay may be inadequate as a model of "hallucinogenicity" in humans. A further implication of their findings is that mescaline may not belong to the same drug class as LSD and psilocin.

There is a paucity of data on the interactions of tryptamine derivatives with 5-HT receptor subtypes, and relatively few receptor binding studies have used the more subtype-selectie radioligands, which have only recently become available. Lyon, et al. compared the binding characteristics of 21 indolealkylamines in competition experiments using [3H]-ketanserin to label 5-HT2 receptors in rat cortex. They reported that 4- or 5-methoxy substitution results in a higher affinity than 6- or 7-methoxy-substitution, while 7-hydroxy substitution abolishes affinity, and 7-bromo- or 7-methyl substitution enhances affinity.

The most recent investigation to focus on the subtype selectivity of tryptamine derivatives in radioligand competition assays is that of McKenna et al. These workers compared the rela tive affinities of 21 indolealkylamines having various ring and N,N-dialkyl substitutions, for the 5-HT1A receptors labeled with [3H]-8-OH-DPAT, the 5-HT2A receptor labeled with [125I]-R-(-)DOI, and the 5-HT2B receptor labeled with [3H]-ketanserin. They found that derivatives lacking lacking ring substituents displayed lower affinities for all of the recognition sites compared to derivatives having a 4- or 5-substituent on the ring. Affinity of all the derivatives at the 5-HT2B site was greater than 300 nM. The nature and position of the ring substituent was the primary determinant of affinity and selectivity. While the size of the N,N-dialkyl substituent was of secondary importance, groups larger than N,N-diisopropyl resulted in a dramatic reduction of affinity at both the 5-HT1A and 5-HT2A sites. The 5-substituted derivatives displayed approximately equal potencies at the 5-HT1A sites and 5-HT2A sites, but the 4-hydroxy-substituted compounds displayed 25 to 380-fold selectivity for the 5-HT2 site over the 5-HT1A site. The authors noted that 4-hydroxy-substituted tryptamines, e.g., psilocin, are qualitatively similar to "classical" hallucinogens such as LSD, while in 5-substituted tryptamines, e.g., 5-MeO-DMT, a visual hallucinatory component is generally lacking or attenuated and an amphetamine-like central stimulatory component is prominent. Therefore, the selectivity of the 4-hydroxytryptamines for the 5-HT2A site further implicates these receptors in mediating the action of hallucinogenic agents.
The nature of the 5-HT2-like binding site labeled by [125I]-R-(-)DOI is a matter of continued controversy. On one hand, the low density of the binding site relative to the total 5-HT2 bidnign site labeled by [3H]-ketanserin, coupled with its sensitivity to guanyl nucleotides, supports the interpretation that the [125I]-R-(-)DOI binding site represents an agonist "state" of the 5-HT2 receptors. On the other hand, Peroutka and co-workers have argued that these radioligands label a novel subtype of the 5-HT2 receptor, which they term the 5-HT2A receptor to distinguish it from the [3H]-ketanserin binding site in bovine cortex, which they term the 5-HT2B receptor. The ultimate resolution of this controversy will require further investigations. With regard to relative affinities of hallucinogenic tryptamines for the two subtypes, or states, the data of the two groups are in agreement. Most of the tryptamine derivatives dispaly 10 to 100-fold higher affinities for the [125I]-R-(-)DOI binding site versus the [3H]-ketanserin site.