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Donald A. Cooper
Drug Enforcement Administration
McLean, Virginia

Excerpt of one paragraph from the Indole, and the entire Indolealkylamine section:

Only nine compounds containing the indole nucleus are controlled substances under the United States Federal Statutes. Three of these compounds are classified as ergot alkaloids, five are simple 3-(2-ethylamino)indoles, and one is the pentacyclic alkaloid, ibogaine. The ergot alkaloids are lysergic acid, lysergic acid amide, and lysergic acid diethylamide (LSD). The five controlled indolealkylamines are:

N,N-dimethyltryptamine (DMT),
N,N-diethyltryp-tamine (DET),
N,N-dimethyl-5-hydroxytryptamine (bufotenine),
N,N-dimethyl-4-hydroxytryptamine (psilocin), and
the phosphate ester of N,N-dimethyl-4-hydroxytryptamine (psilocybin).


All of the hallucinogenic indolealkylamines can be classified as belonging to the family of compounds known as tryptamines and are substituted 3-(2-ethylamino)indoles (compound 2, Figure 2).

The tryptamines are a most interesting and bio logically useful class of compounds. In the human body, serotonin (5-hydroxytryptamine) functions as a vasoconstrictor, inhibits gastric secretion, stimulates smooth muscle, and is naturally present in the central nervous system where it is involved in neurotransmission (Goodman and Gilman 1970). The 5-methoxy homolog of serotonin is considered to be hallucinogenic in humans as is the 5-methoxy homolog of gramine (3-(N,N-dimethylaminomethyl)indole) (Gessner et al. 1961). Melatonin (N-acetyl-5-methoxytryptamine), formed by the mammalian pineal gland, appears to depress gonadal function and is known to cause contractions of melanophores. Bufotenine, the N,N-dimethyl homolog of serotonin, is classified as a very weakly active hallucinogen and is noted to have extremely unpleasant cardiovascular depressive side effects (Holmstedt et al. 1967). The O-methyl homolog of bufotenine, N,N-dimethyl-5-methoxytryptamine (5-methoxy-DMT), is reported to be an extremely potent hallucinogen, but it, like all other C-5 substituted indolealkylamines, is not active if taken by mouth (Brown 1972). Both DMT and DET are well known for their hallucinogenic activity, just as both of these compounds are also inactive if taken by mouth. The N,N-dipropyl and dialkyl derivatives are also hallucinogenic only if used either parenterally or by inhalation at approximately the same level as DET, whereas higher homologs abruptly become inactive (Szara and Hearst 1962). The compound 6-hydroxy-DET has been determined to be a major metabolite of DET in man (Szara et al. 1966), and it does not possess hallucinogenic activity (Szara 1970). Conversely, the 4-hydroxy-N,N-dimethyltryptamines (psilocin and psilocybin), are very active hallucinogens when taken orally. The activity of psilocybin (O-phosphoryl-4-hydroxy-DMT) when taken by mouth is not related lo the phosphoric acid radical since the pharmacological effects of psilocin (4-hydroxy-DMT) are identical (Horita and Weber 1961). Pharmacological information for baeocystin (4-hydroxy-N-methyltryptamine) was not found; however, one would expect hallucinogenic activity to parallel that of the N-alkyl-tryptamines and thereby would expect the drug to be weakly hallucinogenic.

It is thought that in the past most clandestine syntheses of indolealkylamines used indole as the starting material (Speeter and Anthony 1954). A modest literature search will convince a clandestine chemist that the use of the Fischer indole synthesis affords access to a greater variety of indole derivatives (Huisgen and Lux 1960; Robinson 1983) as it will also reduce the chance that law enforcement will be alerted by his purchases of essential chemicals. Hence, in the production of indolealkylamine derivatives, the covert chemist need not be limited by the commercial availability of appropriate indole precursors.

Relative to those which lack an aryl ring substitution, there is no doubt that the activity of psilocybin/psilocin upon ingestion is due to an enhancement of gastrointestinal absorption which, in turn, must be structurally related to the presence of the C-4 hydroxyl substitution. Therefore, if the CsA amendment were not a consideration, derivatives derived from psilocin would be the obvious first choice. These derivatives are the 4-hydroxy-N,N-alkyl homologs starting with N,N-dimethyl, N,N-methyl-ethyl, and on to N,N-diallyl to give a total of 10 possible derivatives. As is also the case for hallucinogenic phenylalkylamines, alkyl substitution, not to exceed a C-3 moiety, at the position alpha to the side chain nitrogen generally will maintain hallucinogenic activity. This brings the total possible number of hallucinogenic CsA's of psilocin to 40. A somewhat removed second choice would be the same series of derivatives in conjunction with either acetylation or methylation of the indole nitrogen. This would then bring the total number of the possible 4-hydroxy substituted tryptamine CsA's (less one for psilocin) to 119.

The 5-methoxy derivatives of gramine and serotonin are first choices for future CsA's when considering the new U. S. amendment. Substitution at the alpha carbon on the side chain will probably maintain psychotropic activity only for serotonin derivatives. Hence, allowing only a methoxy substituent at the aryl C-5 position, and a substitution at the carbon alpha to the nitrogen (the nitrogen being any combination of hydrogen, methyl, ethyl, n-propyl, and allyl) 75 CsA's can be obtained. Then substitution of the indole nitrogen with either methyl or acetyl brings the total number of possible CsA's that can be argumentatively related to serotonin to 225.

An additional series of compounds that could serve as future CsA's under U. S. law are those which are substituted with alkyl groups at the carbon alpha to the side chain nitrogen. Recently, a commercially available tryptamine which has an ethyl moiety substituted at the alpha carbon has become the newest U.S. tryptamine CsA. Known as ET in the illicit CsA drug market is 3-(2-amino-butyl)indole (etryptamine, monase by Upjohn (Kalamazoo, MI); compound 3, Figure 3). Because ET does not appear in either Schedule I or II of the CFR and is a legally marketed product, ET and derivatives thereof are exempted from control under the CsA amendment. Pharmacokenitic data on ET indicates that it is a monoamine oxidase inhibitor (Govier et al. 1953; Klein and Davis 1969) and psycho-energizer (Robie 1961; deHaen 1964). Hence, ET could produce some degree of hallucinogenic activity in man. In 1986 ET was reported as the she causative agent in a fatal overdose in Duesseldorf, Germany (Daldrup et al. 1986). This may be one of the few times that a CsA has originated outside of the U. S. The sample of ET which was submitted to our laboratory appears to have been obtained from the Aldrich Chemical Company ($48.05/100 gm; Milwaukee, WI). Unfortunately, it is not yet clear if ET is actually the substance which is producing the biological response being sought by the illicit user. It is the case that the sample of ET we examined and the batch of ET which the Aldrich Chemical Company is presently selling contains a major quantity (about 30%) of the agent shown in Figure 4 which could also be a hallucinogen (Turner 1963; Naranjo 1967).

Nomenclature for this possible hallucinogen can either be 1-methyl-3-ethyl-1,2,3,4-tetrahydro-harmane, or 2,2-dimethyl-4-ethyl-2,3,4,5-tetrahydro-[beta]-carboline. The creation of this substance most probably occurred after synthesis and during the purification of ET. Under anhydrous conditions, the reaction of acetone and ET would give the corresponding enamine which could then undergo a Mannich condensation to yield the hallucinogen (Whaley and Govindachari 1951; Shoemaker et al. 1979). The compound 2-methyl-8-methoxy-4,5-dihydro-[beta]-carboline (harmaline) is considered to be a hallucinogen (Hochstein and Paradies 1957) as well as a monoamine oxidase inhibitor (Burger and Nara 1965). On the other hand, the compound 2-methyl-8-methoxy-2,3 4,5-tetrahydro-[beta]-carboline is classified as a tranquilizer (Usdin and Efron 1972). We were not able to attain any literature whatsoever on the hallucinogen shown in compound 4 (Figure 3), much less any pharmacokenetic data. Hence, due to the apparently unpredictable pharmacological behavior of structurally similar [beta]-carboline derivatives, I will not speculate as to the pharmacological properties of said substance.