Tryptamine, N,N-diethyl · Indole, 3-[2-(diethylamino)ethyl] · N,N-Diethyltryptamine · 3-[2-(Diethylamino)ethyl]indole · T-9
#3 DET SYNTHESIS: (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. This intermediate was removed by filtration and used directly in the following step. This was added to 20 mL anhydrous diethylamine. There was then added an excess of 2 N HCl, the mixture cooled, and the resulting solids removed by filtration. These were recrystallized from MeOH to give, after air drying, 19.4 g indol-3-yl N,N-diethylglyoxylamide with a mp of 175–177 °C.
A solution of 19 g indol-3-yl N,N-diethylglyoxylamide in 350 mL anhydrous dioxane was added, slowly, to 19 g LAH in 350 mL dioxane 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 dioxane, the filtrate and washings combined, dried over anhydrous MgSO4, and the solvent removed under vacuum. The residue was dissolved in anhydrous Et2O and saturated with anhydrous hydrogen chloride. There were formed crystals which were recrystallized from benzene/methanol to give a yield of 14.7 g (75%) of N,N-diethyltryptamine hydrochloride (DET) with mp of 170–171 °C.
(from tryptamine) To a solution of 1.6 g tryptamine base in 20 mL isopropanol, there was added 5.5 mL diisopropylethylamine and 2.3 mL ethyl bromide. After stirring at room temperature for 36 h the volatiles were removed under vacuum on the rotary evaporator and the light brown residue (5.17 g) was treated with 5 mL of acetic anhydride and heated in the steam bath for 5 min. After coming to room temperature, 3.5 mL ammonium hydroxide was added, and the exothermic reaction was allowed to return to room temperature. The reaction mixture was suspended in 150 mL 0.5 N H2SO4, and washed with 3×40 mL CH2Cl2. The pooled washes were again extracted with 150 mL 0.5 N H2SO4 and the aqueous phases again washed with CH2Cl2. The aqueous phases were combined, made basic with 6 N NaOH, and then extracted with 3×40 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue (1.49 g of a dark oil with a sharp smell) was distilled at the KugelRohr. The product, N,N-diethyltryptamine, distilled at 175–185 °C at 0.05 mm/Hg to yield a white oil weighing 1.02 g, which spontaneously crystallized. This product was dissolved in 20 mL boiling hexane, cooled to room temperature, and seeded. There was thus obtained 0.72 g of a white waxy crystalline material melting at 84–87 °C. IR (in cm-1): 741, 804, 970, 1018, 1067, 1090 and 1120. MS (in m/z): C5H12N+ 86 (100%); indolemethylene+ 130 (6%); parent ion 206 (1%). The hydrochloride salt (crystallizing spontaneously from an IPA solution of the base treated with a few drops of concentrated HCl) had a mp 169–171 °C, and the following fingerprint: IR (in cm-1): 717 (br.), 759, 847, 968, 1017, 1110. This salt appears to be unstable, darkening with time.
DOSAGE: 50–100 mg, orally
DURATION: 2–4 hrs h
QUALITATIVE COMMENTS: (with 44 mg, orally) “I was in a public place, and might have had to interact with someone at any moment, which probably accounted for a grim paranoia and wish to retreat. I had my full effect in just over an hour, with almost no visual or physical properties, but a crashing fear of interacting. I had to retreat to a private place to read and appear deeply involved, but in another hour I found it an increasingly easy task to pretend to be normal. I carried it off, OK. Good sleep, no residues.”
(with 75 mg, orally) “Onset seemed to be at 40 minutes, which were mostly physical symptoms, which seemed to fade away at 1.25 hours. All in all, an absolutely profound, enriching experience with both Brahms (G-minor piano quartet) and Verdi (requiem) contributing mightily. All over in 3.5–4.5 hours and a delightful afterglow.”
(with 150 mg, orally) “There was a slow onset. It was more than an hour before something started, which I didn’t believe at first but which became completely undeniable. I was heading toward an appointment, and walked right past the meeting place. I was unable to concentrate on just where I was and where I was hoping to go. With enormous effort I located my appointment coordinates but the sidewalk was doing funny things and I again managed to miss my target. I sat down to try to manage things, but I couldn’t.”
(with 150 mg, orally) “The effects were manifestly notable in 50–60 minutes, quite intense from hour one to hour three. Then there is an hour when trailing is still perceptible. By hour five it is all over. There appeared to be ‘vegetative effects’ as they used to say. I definitely noted sweating of hands and feet. There was a hollowness in the chest. There was an insignificant presser response, but pronounced tachycardia, with my normal resting pulse in the 60’s going up above 100 for a while. I think that 150 milligrams is a little too much.”
(with 400 mg, orally) “Too much.”
(with 40 mg, smoking) “I have found that ten milligrams of DET is the size of a match head, so I smoked four of them. The taste of the stuff is terrible—it smells like burning plastic—but I don’t care. The onset was gentle, in about five minutes, euphoric and empathogenic, and there was an immediate camaraderie with the group I was with (they were using between twenty and forty milligrams apiece). I found myself stroking a calico cat, and asked a friend, ‘Do people purr?’ and was told, ‘Sure, if you know how to listen.’ We began scratching one anothers backs, and made vaguely purring noises.”
(with 90 mg, smoking) “This was with 3×30 milligrams, at ten minute intervals. It took almost too much concentration for the last toke. Too stoned. Some emotional insights, but I can’t remember them to write them. Fine muscular tremor. Some hangover the next day, lassitude, fine edge of thought was blunted.”
(with 40 mg, subcutaneously) “There was a slight burning and a numbness of both the hands and feet some twenty minutes. A few minutes later I felt an alcohol-like intoxication and a slight drifting of thoughts. Music was slightly enhanced and eyes-closed patterning was noted, with a predominance of greens and oranges. No music, no patterns. The effects peaked at 30 minutes, but the numbness I felt lasted up to three hours. Overall, this was somewhat disappointing.”
(with 60 mg, intramuscularly) “The yellow walls with many windows in them, massing over one another, appeared in increased intensity, had an air of medieval mood about them. The ornaments, painted white, on the roof and eaves had a particularly strong decorative effect. A test subject, without a painter’s fantasy, must certainly be greatly impressed by this depth and colorfulness. I felt as I did when I began to learn painting, when I tried to look at things consciously with a painter’s eye. I felt that the drug acted on fantasy, in the first place, increasing its dynamism. On a subject with normal mind, this experience will certainly have an astonishing and marvelous effect. An artist with creative mind and fantasy will be less impressed.”
(with 60 mg, intramuscularly) “About 15 minutes after the injection came the same vegetative symptoms seen with . The illusions and hallucinations were the same. But the alteration of the surrounding world and the emotional reaction to them were strong and impressive. The mask-like faces of the persons, the dream-like mysteriousness of the objects in the room gave me the feeling that I had arrived in another world, entirely different and queer and full of secrecy and mystery. The wonderful but strange world attracted me at one moment, but the next moment I did not want to accept it. I became perplexed; I did not know what I ought to do. I began to walk anxiously up and down, and said, ‘I ought to do something, I must!’ There was a peculiar double orientation in space and time: I knew where I was, but I was inclined to accept this strange world as a reality, too. The dusk of the room was lightened for some minutes, and again the light was switched off, and that seemed to me as if this period might be an entire epoch, filled with events and happenings, but at the same time I knew that only several minutes had passed.”
(with 60 mg, intramuscularly) “The vertigo is gone—now comes the attraction. I have the honor of seeing the elements of the universe in this moment. As if I saw algae, flagellates under the microscope, in black and white. Now I see some colours, too. As if I saw a shell, the rainbow colours are disintegrating rapidly. One’s consciousness becomes air-like. From the neck upward I am feeling a shapeless lightness. If we could inoculate this into all men, human inter-relations would undoubtedly improve greatly.”
(with 60 mg, intravenously) “I was looking out of the window. I was seeing the leaves of a tree, the color of the grass, people walking to and fro utterly without thinking, like a small child staring at things. I felt as if I were discovering the world anew.”
(with 60 mg, intravenously) “The objects opened up their essence to me, I was feeling as if I knew them as they really are, I live in them and was in direct contact with them. I felt an enormous drive to write, to put down the marvelous feelings. The associations came spontaneously, but I was unable to concentrate in a way required for working. Anyway, I did not want to miss one moment of the visions.”
EXTENSIONS AND COMMENTARY: I have to bear the responsibility for much of the mythology that maintains that DET is only active by some parenteral route. All of the published human studies that explicitly mentioned dose and dosage, involved intramuscular administrations. Most of the people with whom I had private conversations about this material had evaluated it through the smoking route. It was only recently that I began to hear of oral trials. I had assumed that it was inactive orally, and ha said so in a number of reviews that I had published over the years. As they say in Latin, mea culpa. There was one mention of oral activity that had been made, in one table written by Steve Szara, in 1969, presented at a meeting that we both participated in, at Irvine, California. I gave the opening overview, and deferred tryptamine questions to Steve, later, in his talk. And in this talk, he presented a Table that referred to DET as being active at a dose of 60 mg, i.m. or p.o. This is the Latin for per os, and means that it was orally active, but he had never mentioned it explicitly to me, and I had never asked. Some 25 years later, we met again and rehashed old times, and at this meeting I gave yet another review paper with the parenteral restriction on DET activity, and he never mentioned anything. And yet, the damned thing is indeed orally active, and since I have said otherwise in publications, I accept the responsibility for the error. Apparently the MAO systems do not chomp up the dialkylamines higher than methyl. Certainly the dipropyl and the diisopropyl are active by mouth, and so is the diethyl.
Several clinical studies were conducted in the late 1950’s and early 1960’s. They employed the oppresive oppressive research environment that was considered scientific at that time, and there were variable results. One study involved ten physically normal subjects, who were unemployed men from a depressed mining area. The DET was administered in i.m. injections and trials were conducted in a partially soundproofed experimental clinic equipped with a one-way mirror and microphones. The subjects were subjected to a battery of psychological tests and body function measurements at frequent intervals. The consensus expressed was one of dysphoria. Neurological signs varied from slight generalized tremors to gross athetoid movements. Among the bizarre somatic complaints were such as: “Air is rushing through my body,” “My chest is empty and there is a jelly ball in my spine,” “My hands aren’t there, my whole body feels funny.” All subjects experienced dizziness and increased sweating. Six of the subjects stated that the experience was an unpleasant one, three of them markedly so. There was no enthusiasm in the group for a repetition of the experience, and several stated that they would leave the clinical center before submitting to it again. A similar study with ten chronic paranoid schizophrenic patients (in the same setting and with the same dosage) produced similar effects. Most became pale, shaky, and either complained of feeling sick or actually vomiting. Several also developed tremors. In general, these were pretty negative experiences, and contribute to the negative medical and scientific opinions that are held concerning these drugs.
Another study was carried out in an entirely different setting, with professional colleagues, with other professionals and with artists. These were with personal friends of the research scientists, rather than strangers to them. The observed mood changes (produced, in this study, by the i.m. administration of 0.70 to 0.80 mg/kg of DET) were described as being in the direction of euphoria; the subjects generally enjoyed the experience and wished to repeat it. The volunteered comments under the drug tended towards the mystical and philosophical, and several of these experimental subjects responded to music and art in ways that were new to them.
In the earliest research with DET and the related dialkyltryptamines, the chemistry of metabolism was studied for any clues that could explain the activity of these materials. It must be remembered that this was in the heyday of the concept of psychotomimesis, the search for drugs that would imitate the psychotic state. What an appealing concept, that there might be a drug that could produce the syndrome of mental illness and thus be an accepted model for designing some treatment for it. There was a delicious search made at that time (the 1950’s) for names that could be given to these remarkable substances that would obscure any spiritual or positive aspects, so that one could present one’s findings into the orthodox medical literature. At that time, I chose to use the name psychotomimetic in the titles of my publications, because I knew it might deflect criticism from the medical community for the findings that I described. But such a variety of names were used as keywords to these studies. In my notes I find: “delirients,” “delusionogenics,” “dysleptics,” “misperceptinogens,” “mysticomimetics,” “phanerothymes,” “phantasticants,” “pharmakons,” “psychosomimetics” (an “s” for the “t”? why?), “psychotaraxics,” “psychoticants,” “psychotogens,” “psychogens,” “psychotoxins” and “schizogens.” Not a very appealing collection from which to choose a week-end trip.
In 1956, Humphry Osmond suggested, at a New York Academy of Science meeting that it might be less pejorative to soften the prefix that was used to relate to the mind from psychoto- or psycho-(used in medical diagnoses that are largely negative) to a misspelled but softer alternative, psyche- (which had not yet been tarred by the image of medical pathology). His suggestion was “psychedelic,” it was aped in many trials with such creations as “psychephoric” (mind-moving), “psychehormic” (mind-rousing), “psycheplastic” (mind-molding), “psychezymic” (mind-fermenting), “psycherhexic” (mind-bursting-forth) and “psychelytic” (mind-releasing). But, psychedelic (mind-manifesting) has weathered all storms, and is now a fixed component of our vocabulary. There are several recent contributions for possible class names for some of these compounds, such as entheogen (God-created-within), entactogen (touching-within) or empathogen (the discovery of empathy), are creations that try to address the integrity and warmth that can be part of the psychedelic experience. Each uses the suffix, “-gen,” that suggests genesis, or creation. Each has its use, and each has its limitations. One must remember that none of these terms describe what occurs within an experience. Their value is limited to the search for a label for the drugs that allow these experiences to happen.
Back to the metabolism discussion. And to the search for the actual drug, the magic bullet, that actually precipitated a model schizophrenic state. If one were to find it, one could look skillfully for the counterpart in the human animal, the one that simply appeared on the scene from some mismanaged metabolic process, and thus could be blamed for mental illness. It had been observed that the longer the chains on the N,N-disubstituted tryptamine, the less the potency. And the longer the chains, the less of the drug was excreted as the 6-hydroxyl metabolite. This focused attention on the hydroxy metabolites of the two simplest and most potent of the dialkyltryptamines, and DET.
has been observed to be a minor human metabolite of DET, with the excretion of about 20% of the administered dose as the glucoronide conjugate. In a study with normal and schizophrenic patients, a positive correlation was observed between the amount of 6-HO-DET excreted and the intensity of the experience. Also, there was a suggestion that the schizophrenics produced greater amounts of this metabolite. This led to a hypothesis that perhaps it was an active factor in the generation of the intoxicated state. In principle, as with , that bare, exposed polar hydroxyl group should make its entry to the brain quite difficult. But, on the other hand, if it were generated there from DET after it had gotten into the brain, entry would not be a concern and the lipophilic barrier could serve to make its exit difficult. Then, if it were an effective compound, it might well be a long acting one. There is an early report of the self-administration intramuscularly, within a single subject, of 10 milligrasms milligrams 6-HO-DET with the description of what appeared to be DET-like effects from about the second to fourth hour. Although this report suggested that it was several times more potent than DET, it has never been replicated and it does not jibe too well with the report below.
As a challenge to the hypothesis that hydroxylation at the 6-position of the N,N-dialkyltryptamines might play some role in the expression of the activity, this position was metabolically blocked by the insertion of a fluorine atom there, giving . This compound, with DET as the control, was studied in some twelve hospitalized alcoholics at doses of about 60, 80 and 100 milligrams intramuscularly. It “does produce autonomic effects, pupillary changes, blood pressure changes; but it does not produce the drifting away into a dream world and other phenomena characteristic for the hallucinogenic activity.” The experimenters considered its possible experimental role as an “active placebo” but nothing more was done with it.
is a minor metabolite of in man, and it was studied for the same reasons. Could this compound play a role in explaining the activity of the parent dialkylamine? It was explored in a series of subjects who had responded spectacularly to DMT. The five volunteers in this study were former opium addicts who were serving sentences for violation of United States narcotics laws. They were administered 6-HO-DMT at either 0.75 mg/kg (one subject) or 1.0 mg/kg (four subjects) and reported no differences from the inactive placebo control. The objective measures (blood pressure, respiration and heart rate, pupillary dilation) confirmed this absence of activity at this level. The active control drug was DMT itself, and it showed the expected responses in all regards.
I have always been quite skeptical, and just a little embarrassed, that so many of these early studies used hospitalized patients, schizophrenics, alcoholics, and prisoners as subjects. These latter experiments were carried out at the Lexington, Kentucky Public Health Service Hospital. This has been for years a major site for human research in the area of addictive or psychotropic drugs. But it cannot be forgotten that it was first, and foremost, a prison and the people there were prisoners. A complete Complete objectivity of reporting, from a person who is in custody and who might wish to please his jailers, is unlikely. The whole scene started shortly after the Harrison Narcotics Act passed back near the time of World War I. The medical profession held that narcotics addiction was a medical problem, and the legal authorities held that it was a legal problem. In other words, was a heroin user sick, or was he a criminal? The law enforcement viewpoint prevailed, the physicians who objected went to jail, and the addicts went to what were called “narcotics farms.” They were indeed prisons, but the name carried the politically correct suggestion of rehabilitation. And it was at the last of these, at Lexington, that this hydroxylated study was done.
The results were negative, to the disappointment of the researchers. It is pretty generally accepted that is inactive. I am not too surprised. There are so few things with open and exposed hydroxyl groups that succeed in making it through the lipid barriers to that protect the brain.
13 May 2016 · Creative Commons BY-NC-SA ·

About TiHKAL · info

This version of Book II of TiHKAL is based on the Erowid online version created by Bo Lawler with the help of Erowid, from content generously provided in electronic format by the Authors.
The Erowid online version does not always align precisely with the printed version. Text appears to have been inserted, deleted, or changed at various points. Where the two are seen to diverge both the Erowid and print versions are given. Sharp-eyed readers are encouraged to report novel discrepancies.
As with PiHKAL, I’ve again attempted to reproduce the typographic style of the printed edition. I’ve again made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.

Cautionary note

“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.
“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
Alexander T. Shulgin

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TiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of tryptamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of TiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
TiHKAL (ISBN 0-9630096-9-9) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.
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