#6. DMT

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The demethylation of the iodide salt: Under an inert atmosphere, a solution of 0.40 g N,N,N-trimethyltryptammonium iodide in 5 mL THF was treated with 1.5 mL of 1M LiEt3BH in THF and held at reflux temperature for 9 h. After cooling, the mixture was acidified with dilute HCl and the THF removed under vacuum. The residue was suspended in dilute NaOH and extracted with Et2O. The extracts were pooled, and the solvent removed under vacuum to provide a residue of 0.12 g N,N-dimethyltryptamine (DMT) as a crystalline solid, with a mp of 57-59 °C. IR (in cm-1): 732, 740, 811, 859, 1011, 1037, 1110, 1171. The MS is discussed below.

The demethylation of the chloride salt: A hot aqueous solution of N,N,N-trimethyltryptammonium iodide was treated with an excess of freshly precipitated AgCl, and all was boiled gently for 15 min. The mixed silver halides were removed by filtration, and the filtrate stripped of H2O as rapidly as possible. To the residue there was added a small amount of MeOH follow by acetone until the crystallization of N,N,N-trimethyltryptammonium chloride was complete. It had a mp of 193 °C (80%), and it is considerably more water soluble than the starting iodide. This salt was pyrolysed under hard vacuum and the residue distilled. This distillate was dissolved in a small amount of methanol and acidified with dilute nitric acid. A small amount of insoluble material was removed by filtration, the aqueous phase washed with CHCl3, made basic with aqueous NaOH, and extracted with CHCl3. The solvent was removed under vacuum, and the residue treated with a hot solution of picric acid. This was decanted from a little insoluble material, and slowly cooled to provide the picrate of DMT as yellow needles with a mp of 167 °C. An aqueous suspension of this picrate was made basic with an excess of aqueous NaOH, extracted with Et2O, and the solvent removed under vacuum to provide a pale yellow residue that crystallized. This was pressed on a porous plate and washed with petroleum ether to give N,N-dimethyltryptamine (DMT) as an off-white solid with a mp of 47 °C.

The demethylation of the thiophenolate salt: A suspension of 2.5 g N,N,N-trimethyltryptammonium iodide in 25 mL MeOH was brought into solution by heating, and treated with 1.0 g Ag2O. The mixture was heated for 10 min on the steam bath, the solids removed by filtration and washed with an additional 20 mL MeOH. The methanol solutions were treated with 1.0 g thiophenol and the solvent was removed under vacuum. The resulting viscous oil (2.12 g) was heated with a flame to the reflux point and there was extensive bubbling. After 5 min, the light colored reaction mixture was cooled to room temperature, dissolved in 50 mL CH2Cl2, and extracted with two 25 mL portions of dilute HCl. These were pooled (pale yellow color), made basic with 5% aqueous NaOH and extracted with 3x25 mL CH2Cl2. After removal of the solvent from the pooled extracts, the residue (an amber oil, 1.04 g) was distilled at the KugelRohr. A white oil distilled over at 130-140 °C at 0.1 mm/Hg, and crystallized spontaneously. This distillate weighed 0.77 g, and was recrystallized from boiling hexane after decanting the solution from a small amount of insolubles. There was thus obtained 0.40 g of dimethyltryptamine (DMT) with a mp 67-68 °C. The distillate contained about 3% of 2-Methyl-1,2,3,4-tetrahydro-b-carboline (parent peak mass 186, major peak mass 186) as an impurity which was lost upon recrystallization.

(from tryptamine and ethyl formate) A suspension of 1.0 g tryptamine in 50 mL ethyl formate was held at reflux for 15 h during which time the mixture became homogeneous. The volatiles were removed under vacuum, yielding an oily residue of the formamide. This may be purified by distillation but this unpurified product can serve satisfactorily in the following reaction. This residue was dissolved in 50 mL anhydrous THF and added, dropwise, to a solution of 1.0 M LAH in THF (40 mL, 40 mmole) which had been diluted with another 50 mL THF. After the addition was complete the reaction mixture was heated under reflux for 15 hours. Reflux was continued as a solution of 40 mL 1.0 M freshly distilled ethyl formate in THF was added dropwise over the course of 2 h. Heating was discontinued and the reaction mixture was quenched by the addition of excess solid sodium sulfate decahydrate at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum to yield 1.15 g pure N,N-dimethyltryptamine as an oil which solidified upon storage in the freezer. The material can be recrystallized from hexane to give white crystals with a mp 67 °C.

(from indole) To a well stirred solution of 10 g indole in 150 mL anhydrous Et2O there was added, dropwise over the course of 30 min, a solution of 11 g oxalyl chloride in 150 mL anhydrous Et2O. Stirring was continued for an additional 15 min during which time there was the separation of indol-3-ylglyoxyl chloride as a yellow crystalline solid. This intermediate was removed by filtration and washed with Et2O. It deteriorates at a significant rate at room temperature, and should be used as soon as possible after preparation. The diethylether in this synthesis can be replaced advantageously with t-butylmethylether (TBME) which works well as a solvent in this reaction, but which avoids the potential danger associated with peroxide formation. The above indol-3-ylglyoxyl chloride was added to 20 g anhydrous dimethylamine in 150 mL cold, stirred anhydrous Et2O. When the color had largely been discharged, there was added an excess of 2N HCl, the mixture was cooled, and the resulting solids were removed by filtration. These were recrystallized from EtOAc to give, after air drying, 14.6 g (79%) indol-3-yl N,N-dimethylglyoxylamide with a mp of 159-161 °C.

A solution of 14 g indol-3-yl-N,N-dimethylglyoxylamide in 350 mL anhydrous THF was added, slowly, to 19 g LAH in 350 mL THF which was well stirred and held at reflux temperature under an inert atmosphere. After the addition was complete, reflux was maintained for an additional 16 h, the reaction mixture cooled, and the excess hydride destroyed by the cautious addition of wet dioxane. The formed solids were removed by filtration, washed with hot THF, the filtrate and washings combined, dried over anhydrous MgSO4, and the solvent removed under vacuum. The residue was dissolved in hot petroleum ether. On cooling, crystals of N,N-dimethyltryptamine (DMT) were formed, filtered free of solvent, and air dried, weighing 11.1 g (91%). There have been reports of byproducts from this LAH procedure when performed in Et2O that can compromise the purity of the final product. To obtain the HCl salt of DMT, the residue was dissolved in anhydrous Et2O and saturated with anhydrous hydrogen chloride. The resulting crystals were recrystallized from benzene/methanol to give N,N-dimethyltryptamine hydrochloride with a mp of 165-167 °C. The yield from 14 g of the amide was 13.3 g of the salt.

There are several comments to be made as to salts, melting points, and spectra.

As to salts, this last recipe above, taken from the literature, is the only claim of a valid hydrochloride salt of DMT. In the original synthesis, by Manske, the following description appears. "The hydrochloride could be obtained only as a pale yellow resin which, when dried in a vacuum desiccator over potassium hydroxide, became porous and brittle." I have found no attempts at its synthesis in the literature, and I have personally had no success at all. The picrate salt is well defined, used mostly for isolation and purification. The oxalate is used occasionally in animal studies. Early human studies involving the injection of solutions of the hydrochloride apparently made by dissolving DMT base in dilute aqueous HCl, and neutralizing this with base to achieve an end pH of appropriate 6. The fumarate is the salt specifically approved by the FDA for human studies, and this was the form used for human intravenous injection employed in the recent New Mexico studies.

As to melting points, some in the literature are of plant isolates and other are of synthetic samples. A brief and incomplete survey has revealed the following numbers, all in °C: 44, 44.6-46.8, 46, 47, 48-49, 49-50, 56-57, 57-59, 58-60, 64-67, 67 and 67-68. The 58-60 and 64-67 values are from the Aldrich Chemical Company, for samples bearing the purity claims of "puriss" and 99+% "Gold Label" resp. The Merck Index gives the very early, very low values of 46 °C and 44.6-46.8 °C and claimes that the bp is 60-80 °C with atmospheric pressure being implied. It is clearly in error on both matters. No evidence has been published suggesting polymorphism. The published mp values for the trimethyl quaternary iodide span the range from 188 °C to 233 °C, including in-between values of 197 °C and 216-217 °C. This physical property is of limited value.

As to spectra, the EI-MS of DMT presents no surprises. MS (in m/z): C3H8N+ 58 (100%), indolemethylene+ 130 (10%); parent ion 188 (4%). A remarkably consistent feature has been mentioned earlier. With tertiary amines such as DMT, the 130+ mass ion is usually the second or third most intense in the spectrum. A companion 131+ mass ion is very small. However, when isomers are observed that may have the same atomic composition, but which are secondary amines, there is a prominent 131+ peak, always exceeding the 130+ peak in size. As an example, NET, with the same molecular weight, had the same major amine ion fragment at the mass of 58, but at about a half this height is a 130/131 ion pair with the 131+ being the major one. DMT had a CI-MS (with NH3) with the expected M+1 at mass 189 and a fragment at mass 166.

DOSAGE : >350 mg (orally)
60 - 100 mg (intramuscularly)
60 - 100 mg (subcutaneously)
60 - 100 mg (smoking)
4 - 30 mg (intravenously)

DURATION : Up to 1h

QUALITATIVE COMMENTS : (with 150 mg, orally) "No observable psychic or vegetative effects."

(with 250 mg, orally) "It was inactive."

(with 350 mg, orally) "Completely without effect either physiological or psychological."

(with 100 mg, via the buccal mucosa) "Numbness at the site, but no central effects."

(with 20 mg, intramuscularly) "I began to see patterns on the wall that were continuously moving. They were transparent, and were not colored. After a short period these patterns became the heads of animals, a fox, a snake, a dragon. Then kaleidoscopic images appeared to me in my inner eye, fantastically beautiful and colored."

(with 30 mg, intramuscularly) "There was eye dilation and, subjectively, some perception disturbances."

(with 50 mg, intramuscularly) "I feel strange, everything is blurry. I want my mother, I am afraid of fainting, I can't breathe."

(with 60 mg, intramuscularly) "I don't like this feeling -- I am not myself. I saw such strange dreams a while ago. Strange creatures, dwarfs or something; they were black and moved about. Now I feel as if I am not alive. My left hand is numb. As if my heart would not beat, as if I had no body, no nothing. All I feel are my left hand and stomach. I don't like to be without thoughts."

(with 75 mg, intramuscularly) "The third or fourth minute after the injection vegetative symptoms appeared, such as tingling sensation, trembling, slight nausea, mydriasis, elevation of the blood pressure and increase of the pulse rate. At the same time, eidetic phenomena, optical illusions, pseudohallucinations, and later real hallucinations, appeared. The hallucinations consisted of moving, brilliantly colored oriental motifs, and later I saw wonderful scenes altering very rapidly. The faces of people seemed to be masks. My emotional state was elevated sometimes up to euphoria. At the highest point I had compulsive athetoid movements in my left hand. My consciousness was completely filled by hallucinations, and my attention was firmly bound to them; therefore I could not give an account of the events happening to me. After 3/4 to 1 hour the symptoms disappeared, and I was able to describe what had happened.

(with 80 mg, intramuscularly) "My perceptual distortions were visual in nature and with my eyes closed I could see colored patterns, primarily geometrical patterns moving very fast, having sometimes very deep emotional content and connotation. My blood pressure went up and my pupils were dilated."

(with 30 mg smoked) "I spread it evenly on a joint of Tanacetum vulgare and melted it with a heat lamp. In about 30 seconds a strong light-headedness starts, with a feeling of temporal pressure. Some yellowing of the visual field. There was nothing for me to do because I had to turn complete control over to the drug. Off the plateau in 3-4 minutes and the fact that the radio was on became apparent. I was out in a few more minutes."

(with 60 mg smoked) "We did it together. Swift entry -- head overwhelmed -- elaborate and exotic. Slightly threatening patterns -- no insight -- slight sense of cruelty and sharpness between us, but enjoying. His face, as before with MDA, demonic but pleasantly so. He said he saw my face as a mask. He asked me to let him see my teeth. I laughed -- aware that laughter slightly not-funny. Heavy, massive intoxication. Time extension extraordinary. What seemed like 2 hrs was about 30 minutes."

(with 60 mg smoked) "Rapid onset, and in a completely stoned isolation in about a minute for about three minutes. Slow return but continued afterglow (pleasant) for thirty minutes. Repeated three times, with no apparent tolerance or change in chronology. Easily handled. The intoxication is of limited usefulness but the residues are completely relaxing,"

(with 100 mg, smoked) "As I exhaled I became terribly afraid, my heart very rapid and strong, palms sweating. A terrible sense of dread and doom filled me -- I knew what was happening, I knew I couldn't stop it, but it was so devastating; I was being destroyed -- all that was familiar, all reference points, all identity -- all viciously shattered in a few seconds. I couldn't even mourn the loss -- there was no one left to do the mourning. Up, up, out, out, eyes closed, I am at the speed of light, expanding, expanding, expanding, faster and faster until I have become so large that I no longer exist -- my speed is so great that everything has come to a stop -- here I gaze upon the entire universe."

(with 15 mg, intravenously) "An almost instantaneous rush began in the head and I was quickly scattered. Rapidly moving and intensely colored visuals were there, and I got into some complex scenes. There were few sounds, and those that were there were not of anyone talking. I was able to continue to think clearly."

(with 30 mg, intravenously) "I was hit harder that I had ever been when smoking the stuff. The onset was similar, but the euphoria was less."

EXTENSIONS AND COMMENTARY : There is a staggering body of information on the subject of intoxicating snuffs and their use throughout the area of the Caribbean, the Amazon, and on to the west, past the Andes, in Colombia and Peru. The literature that has accumulated over the last forty or so years is fascinating, but extremely difficult to organize. The problem lies in deciding on which discipline shall dictate the hierarchy of classification. Does one organize by snuff name? But each different tribe will have a different name. Does one classify by the plants employed? This requires actual observation in the field, but a given plant may have several native names. And one snuff may use any of several different plants or plant combinations, depending on cultural tradition. To add uncertainty to this complexity, these traditions are being rapidly lost, with the eradication of folklore. So perhaps one should turn to the snuff itself, and classify according to the chemical composition. This is appealing in that there are many museum samples available, as well as a host of anthropological artifacts such as snuff trays and botanical residues that can be identified. But that is a luxury that requires the sophistication of the laboratory, and precludes any botanic assignment.

No matter which system might eventually prove to be the best, the use of a chemical assignment of drug structure to the active components allows some form of clinical challenge to the native use in the field. DMT and 5-MeO-DMT are the mainstay chemicals in most snuffs, and can be introduced into the product from any of several plants.

A major plant source for one of the best studied of the snuffs, cohoba, are the ground beans of the Piptadenia peregrina. There are two alternative generic names, Anadenanthera and Mimosa, which may represent the same, or similar, plants, but this is the stuff for battles between botanical taxonomists. There are several species in this classification, and the alkaloid content amongst them is most variable. With P. peregrina and P. macrocarpa, the major contents of the beans and their pods appears to be bufotenine, its N-oxide and the oxide of DMT. It may be only the pods of the seeds that contain the DMT. And the bark seems to be the major source of N-methyltryptamine, of 5-MeO-NMT (its 5-methoxy analogue) and of 5-MeO-DMT itself. The species P. columbrina has been reported to have bufotenine in its seeds as the only active component. This plant, in Argentina, occurs in only two major species P. macrocarpa and P. excelsa, and the composition seems to parallel that of the Amazonian counterparts. Other forms, (P. rigida, P. paraguayensis, and P. varidiflora), are without any alkaloid content.

The native intoxicant search becomes even cloudier as one goes from snuff to decoction. There are several drinks, sometimes described as "narcotic" and sometimes as hallucinogenic or dream-inducing, that come from closely related plants. The roots of the acacia-like tree, Mimosa hostilis, are reputed to be the source of the drink jumera, or vihno de jurema. But the only alkaloid present, originally called nigerine, has proved to be DMT, and this is not orally active. There are pasture grasses, such as reed canarygrass, that can produce a central nervous system disruption in grazing sheep. Chemical analyses of these plants (such as Phalaris tuberosa, P. arundinacea, and P. aquatica ) have revealed the presence of alkaloids like DMT and 5-MeO-DMT, but these compounds require intravenous administration to duplicate the toxicity symptoms. The observation of 5-MeO-NMT being present does not help explain the toxicity. How can something that is not orally active be orally active? A possible explanation is the presence of another indole with a one-carbon shorter chain. This is gramine, or 3-(N,N-dimethylaminomethyl)indole which is synthesized in the plant with an entirely different set of enzymes. Its human pharmacology is not known. A related homologue, one carbon longer, is the three-carbon chain compound 3-[3-(dimethylamino)propyl]indole, produced by the Upjohn Company. It has been studied clinically under the code name U-6056, at levels of up to 70 milligrams in 10 subjects, by i.m. injection. There were no reports of visual, auditory or tactile disturbances. Physically, there was a slight increase in blood pressure anad pulse rate. Certainly there were no psychological effects.

The drink ayahuasca is also a DMT-containing decoction, but the presence of some harmaline-containing plant is required to make it active by mouth. This area is discussed under harmaline, although there is some information to be found in the 5-MeO-DMT commentary section. And, there are several species of Acacia found in both Africa and Australia that contain DMT, but there is no native medical use that suggests psychotropic action. Most of this is part and parcel of the chapter, "DMT is Everywhere." Let's not repeat it here.

In the early clinical studies of DMT and DET, frequent use was made of schizophrenic patients, in the belief that if these drugs imitate the mental disorder in normal subjects, the use of schizophrenic population might be especially informative, either through some enhanced response or a loss of effect. One clinical study with a group of female patients (with 1.0 or 1.5 mg/Kg DMT being administered, presumably by intramuscular injection) showed a delayed onset (doubling of time), a relative freedom from autonomic effects, and an absence of hallucinations. I truly admire the logic patterns that allow the construction of a research study that will have it either way. Positive effects, our hypothesis is supported. Negative effects, out hypothesis is supported. Do schitzys get better or do they get worse? See? We were right.

A study conducted on 40 normals, this in Hungary some 30 years ago, found that the administration of 40 mg quantities to be symptom free. With several of the experimental subjects in this study, the DMT was preceded by the administration of 1-methyl-d-lysergic acid butanolamide (UML-491), a potent serotonin antagonist. This was given either orally (1-2 mg 30 to 40 minutes before) or intramuscularly (0.5 mg 10 minutes before). This served to greatly intensify the effects of the DMT, with intense and agitated hallucinations, highly intensified colors, and a more extreme loss of time and space perception. It was assumed that UML-491 was inactive, but recent trials indicate that there can be central effects produced. It is discussed in the entry for LSD.

DMT is the only psychedelic tryptamine that has recently been taken through the Kafkaesque processes for approval for human studies (via the FDA, the DEA, and the other Health agencies of the Government) and is one of the few Schedule I drug that is being looked at clinically in this country today. It has been studied in New Mexico, in Albuquerque. The first published results of this study show a smooth grading of subjective effects as a function of injected dose. The lowest dose (i.v.) was 0.05 mg/Kg, about 4 milligrams, and it could not be distinguished from placebo. At 8 milligrams, there were the physical effects without the mental. At 15 milligrams (the threshold psychedelic dose) nearly all subjects had visual hallucinations, but the auditory changes were rare. At 30 milligrams, the effects were overwhelming both in speed and in intensity. The rush, the freight-train as several subjects call it, was well underway well before the 45 second infusion was complete. A study of repeated administrations of dosages of 16 mg i.v., at half-hour intervals, were made to explore the possible development of tolerance, showed that there was none observed.

Thanks to the existence of ever-increasingly sensitive scientific instruments, the search of body fluids for possible psychedelics has brought forth a number that appear to be natural components of the human animal. DMT has been reported to be in the urine of schizophrenic patients, and so have 5-MeO-DMT, bufotenine, and its demethylated homologue N-methylserotonin. The levels are increased with the administration of monoamineoxidase inhibitors. A methylating enzyme has been found in blood, capable of forming DMT in plasma, and it is present in both normal subjects and schizophrenics. It is not surprising that studies comparing DMT blood levels between patients (psychotic depression, acute and chronic schizophrenia) and normal subjects have shown no differences.

In the definition of DMT either as an endogenous psychotogen or, equally appealing, as a natural neurotransmitter, it would be desirable to show that the body does not build up tolerance to it (otherwise the psychotic would spontaneously repair, and the brain would spontaneously shut down). To address this, four subjects were given some 50 mg of DMT intramuscularly, twice daily, for 5 days. The blood levels that were achieved, and the picture of autonomic effects (both in mydriasis and in cardiovascular function) were not changed. No tolerance was seen. The psychological conclusions were a little bit less convincing. Several said that the "high" was diminished, but others seemed to feel a maintenance of subjective responses. The jury is still out on this one.

The principal reason that DMT must be administer parenterally is its rapid and efficient metabolism. It can be oxidized to the N-oxide. It can be cyclized to b-carbolines, both with and without an N-methyl group. It can be N-dealkylated to form NMT and simple tryptamine itself. Best known is its oxidative destruction, by the monoamine oxidase system, to the inactive indoleacetic acid. There is a wild biochemical conversion process known for tryptophan that involves an enzymatic conversion to kynurenine by the removal of the indole-2-carbon. A similar product, N,N-dimethylkynuramine or DMK, has been seen with DMT, when it was added to whole human blood in vitro.

Several simple substitution derivatives of DMT are known. Those that are known to be psychedelic have their own recipes, of course, but the others will be summarized here. The 1-methyl homologue of DMT (1,N,N-trimethyltryptamine) can be prepared from DMT in KOH and DMSO, with CH3I. It forms a picrate salt which melts at 175-179 °C, and bioxalate, mp 174-176 °C. It is more toxic than DMT in rats, but has an identical serotonin binding capacity. The compound with a methoxy group substituent at the 1-position is called Lespedamine, 1-MeO-DMT. With an NO bond, this should be classified as a substituted hydroxylamine. I would love to know if anyone anywhere has ever tried smoking it. I suspect it might very well be active, but it is, to my knowledge, untried. I wonder why it deserves a trivial name, vis., Lespedamine? Two additional ring-substituted derivatives of DMT come from the marine world. 5-Bromo-DMT and 5,6-dibromo-DMT are found in the sponges Smenospongia auria and S. echina resp. I have no idea if they are active by smoking (the 5-Br-DMT just might be) but they are quantitatively reduced to DMT by stirring under hydrogen in methanol, in the presence of palladium on charcoal. A very closely related sponge, Polyfibrospongia maynardii, contains the very closely related 5,6-dibromotryptamine and the corresponding monomethyl NMT. I had the fantasy of trying to scotch the rumor I'm about to start, that all the hippies of the San Francisco Bay Area were heading to the Caribbean with packets of Zig-Zag papers, to hit the sponge trade with a psychedelic fervor. This is not true. I refuse to take credit for this myth.

The demethylated homologue is N-methyltryptamine (NMT) and it is also widely distributed in nature. It has a synthesis in an entry of its own.

Both the N-hydroxy and the 2-hydroxy analogues of NMT are found in another legume Desmanthus illinoensis, but have not been pharmacologically evaluated. Another provocative mono-alkyl analogue of DMT is N-cyclopropyltryptamine, made from indole-3-oxalylchloride and benzyl cyclopropylamine with eventual hydrogenolysis of the benzyl group; mp 180-182. This compound, as with the 5-methoxy and the 7-methoxy counterparts, is a potent monoamineoxidase inhibitor, and it has also been reported to have hypoglycemic activity. The 2-methyl-homologue of NMT was made from 2-methyl-3-(2-bromoethyl)tryptamine and methylamine. This is 2,Me-DMT (or 2,N,N-TMT). Both it and tryptamine itself (T) have their own entries.

Before this is closed, a couple of points need be made regarding nomenclature. Older literature uses alpha for the 2-position of the indole ring. Thus, alpha-methyltryptamine, in early literature, refers to the indole-2-methyl, not to a side-chain methyl derivative. Throughout TiHKAL, the numbers are devoted to the indole ring, and the alpha and beta terms to the side-chain. And the use of the letter N refers to the side-chain amino nitrogen atom. The pyrrole nitrogen is the indole position 1.