Psychedelics indoles

The family Zygophyllaceae is made up of 30 genera and 250 species of shrubs known to have the tendency to elaborate a series of serotonin-like psychedelic indole alkaloids such as harmine, harmol, and harmaline, notably found in the seeds of a medicinal... 

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a psychedelic indole, as is its active metabolite, psilocin. It is found in about 200 species of fungi, including those of the genus Psilocybe, such as Psilocybe semilanceata (the liberty cap) and Psilocybe cubensis (golden top or golden cap), also called magic mushrooms or simply shrooms (1). 

P. viridis grows naturally in Amazonian tropical forests in Central and South America, and the leaves are used as one of the main components in the preparation of the hallucinogenic drink ayahuasca. This plant is a rich source of the psychedelic indole-alkaloid DMT [94] in the mixture that also contains jS-carboline alkaloids provided by Banisteriopsis caapi (Malpighiaceae), mainly harmine, harmaline, and tetrahydroharmine, that besides psychoactive properties, act as reversible MAOIs. MAO acts as a detoxifying enzyme [105], and when inhibited by MAOIs, DMT inactivation is prevented in the gut [106] enabling it to reach the CNS site of action, affording significant psychotropic effect. DMT biosynthesis is relatively simple and is summarized in Scheme 5.2. 

Orders for certain chemicals used to make psychedelics (especially large orders in suspect areas) are sometimes checked by narcs. Indole, lithium aluminum hydride, trimethoxybenzaldehyde, phenyl-2-propanol, diethylamine, olivetol and ergotamine are among those watched. The vast majority of the homologs and analogs described here are, however, legal to manufacture and use. 

If the alkyl side chain at the 3 position of the indole nucleus is shortened (e.g., gramine) or lengthened (e.g., 3-(3-dimethylamino)-propyl indole) activity seems to decrease strikingly. Also, as the substituents are moved around the benzene ring of indole, activity decreases greatly in the order 4,5,6,7. For example, whereas 4-OH-DMT(psilocin) is active at about 5 mg orally (i.e., about as active as STP), 5-OH-DMT(bufotenin) is not psychedelic at all. 

Convert indole to indolyl-3-methyl-ketone (I) by treating indolyl-Mg-Br (preparation already described) with acetyl-Cl, by treating indole in POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole with diketene (ACS 22,1064(1968)). 15.9 g (1) in 50 ml methanol cool, stir and add dropwise 16 g Br2. Reflux 1 Vi hours on water bath cool, filter, wash with ether and recrystallize-methanol to get 18 g indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (II) in 60 ml warm isopropanol and add 11 g 3 8% aqueous DMA (or equimoiar amount other amine) reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g indolyl-3-dimethylamino-methyl ketone (III). Add 4.6 g (0.02 M) (III) in 30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml tetrahydrofuran, stir one-half hour at room temperature and reflux two hours. Add a little water dropwise and extract the precipitate with acetone. Dry, evaporate in vacuum the combined organic phases to get an oil which will precipitate with ether-petroleum ether to give DMT. (Ill) should be tested for psychedelic activity. Dialkyltryptamines BCSJ 11,221 (1936), BSC 2291 (1966)... 

Replacement of one or more of the C or N atoms of the indole nucleus by atoms of N, C, O or S will result in dialkyltryptamine analogs some of which are very likely to be psychedelic. Among the indole analogs are isoindole, indene, indazole, diazindoles, benzo-furan, benzothiophene and benzimidazole. The syntheses of several such compounds follows. 

By the fifth hour, I was mending the physical zombie is not there anymore. I can ignore the crawling. At the ten hour point I am still dilated, and teeth rubby, and hypoxic. Something is still poisonous. Sleep not satisfactory. Restless, with strange mental interpretations. The next day, I am clear and totally without residues. This a,0-DMS is probably the most potent indolic psychedelic yet uncovered, at least via the oral route. Any higher dose would require a babysitter, and I must remember that there is a big toxic component that is part of this trip."... 

A case in point. What happens when you put a methyl group on the two-position of the indole ring of a tryptamine. In the three examples, examples of the best studied tryptamines that were not active orally, they all became orally active. DMT, DET and 5-MeO-DMT, the three major parenterally-only active psychedelics, all blossomed into orally active compounds with the addition of a simple methyl group to that indole 2-position. As I had smugly argued, in the discussions of 2-Me-DMT, 2-Me-DET and Indapex, it is as if that bit of bulk got in the way of the destructive amine oxidases, and protected the molecule from its expected first-pass metabolic destruction. 

EXTENSIONS AND COMMENTARY This base, a-ET or etryptamine, was a promising antidepressant, explored clinically as the acetate salt by Upjohn under the name of Monase. Its central stimulant activity is probably not due to its monoamineoxidase inhibition activity, but appears to stem from its structural relationship to the indolic psychedelics. It was withdrawn from potential commercial use with the appearance of an unacceptable incidence of a medical condition known as agranulocytosis, but the extra mural research into its action, among the lay population, goes on. 

EXTENSIONS AND COMMENTARY TMA was the very first totally synthetic psychedelic phenethylamine that was found to be active in man, for which there had been any attempt to describe such drug effects in any detail. This was the report of research done in Canada, and it appeared in 1955, six years before my own report on the material. There was an earlier report on TMPEA which is mentioned in the appropriate recipe, but there were few details given. Also there had been interest in reports that adrenalin that had become old and discolored seemed to elicit central effects in man. The oxidation products were identified as the deeply colored indolic compound adrenochrome and the colorless analogue adrenolutin. The controversy that these reports created just sort of died away, and the adrenochrome family has never been accepted as being psychedelic. Noone in the scientific community today is looking in and about the area, and at present this is considered as an interesting historical footnote. But, in any case, they are not phenethylamines and so not part of this book. 

The belladonna alkaloids are much more toxic than the indoles and phenethylamines. Furthermore, they are just plain dangerous, and the experiences they give are, at best, difficult to integrate with ordinary consciousness. Kava-kava seems to me more like alcohol than like the psychedelics, as does nitrous oxide, a general anesthetic with similar depressant qualities. PCP and ketamine are pharmacological curiosities, not related to other recreational drugs. Many users like the "dissociative" states they provide, but few find them truly psychedelic. Their toxicity and abuse potential are significant. 

On top of the indolic nucleus, there are two additional rings in the structure of the LSD molecule. These are typical of the LSD family of chemicals to synthesize LSD and its analogues, one has to obtain the preformed lysergic acid "skeleton first and then manipulate its chemistry through quite difficult processes. Such is not the case with the one- and two-ring psychedelic compounds, which can be synthesized more readily and altered to a much greater extent. 

The sixty or so alkaloids in Lophophora williamsii fall mainly into two groups the 0 -phenethylammes, to which mescaline belongs, and a larger assortment of tetrahydroisoquinolines. Both kinds differ from LSD and most other compounds regarded as psychedelics in that they don t have a full indole structure. 

Hofmann, as it turned out, was probably the scientist best equipped to analyze the psychedelic agents, in that there is considerable chemical similarity between these substances and LSD (both contain the same kind of nucleus with a substitution at the fourth position in the indole ring). "Probably in no other laboratory in the world, wrote Hofmann later, "would there have been 4-hydroxy indole for comparison purposes. He and his colleagues... 

They also contain ethylamine side chains of various lengths. Taken together, the indole and side chain constitute tryptamines. Nearly all psychedelic tryptamines exhibit a rare substitution at the position marked by an asterisk in the drawing above. 

The major psychedelic agent in psilocybian mushrooms is psilocybin— the first indole derivative discovered to contain phosphorus. When ingested, the phosphorus radical is immediately "dephosphorylated by an intestinal enzyme, alkaline phosphatase, into psilocin and phosphoric acid Animal experiments suggest that psilocybin and psilocin appear at similar chemical concentrations at about the same time in various organs. Thus, the phosphorus radical is generally considered "dead weight in terms of psychoactivity. 

This compound cluster exhibits a two-ring, "open-chained, indolic chemical structure, and in contrast to other psychedelics it is all but inactive when taken orally unless accompanied by certain other compounds. Shortacting tryptamines are closely related to neurotransmitters (such as bufotenine), to MDA (a major botanical source of the snuffs belongs to the nutmeg family), to tryptophan (an essential amino acid produced in human digestion of proteins) and to psilocybin and psilocin (which are tryptamines of longer duration). DMT, the simplest member, occurs normally in the blood, brain and (in higher concentrations) in the cerebrospinal fluid. 

Ibogaine, the most studied of the alkaloids present in the roots of Tabemanthe iboga, is representative of another cluster of indolic molecules that have been included among psychedelics. Ibogaine is a naturally occurring compound of special interest because it comes from an entirely different botanical family than anything discussed above—a contribution to the mystery of psychedelics from equatorial Africa. 

Ibogaine was isolated in 1901 from Tabemanthe iboga roots by Dybowski and Landrin and by Haller and Heckel. The most abundant alkaloid in the shrub s root bark, ibogaine exhibts the indole nucleus structure common to most psychedelics. Its stereochemistry (the dotted lines are at angles to the rest of the molecule) was established in the late 1960s ... 

Mushrooms are the most important natural psychedelics of southern Mexico, used in ceremonies so sacred that Indians carefully concealed them from Europeans until the present century. It wasn t until the 1950s that descriptions of Mexican mushrooms came to the attention of the world. Soon after, botanists began to identify the mushrooms in use, and chemists found that their psychoactive properties came from psilocybin, an indole hallucinogen similar to LSD but with a shorter duration of action four to six hours. 

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