SYNTHESIS: To a solution of 5.0 g 4-hydroxyindole in 20 mL pyridine there was added 10 mL acetic anhydride and the reaction heated on the steam bath for 10 min. The reaction was quenched by pouring over chipped ice to which was added an excess of NaHCO3. After being stirred for 0.5 h the product was extracted with ethyl acetate and the extracts washed with brine and the solvent removed under vacuum. The residue weighed 6.3 g (95%) which, after crystallization from cyclohexane, had a melting point of 98–100 °C. IR (in cm-1): 1750 for the carbonyl absorbtion.
To a solution of 0.50 g 4-acetoxyindole in 4 mL Et2O, that was stirred and cooled with an external ice bath, there was added, dropwise, a solution of 0.5 mL oxalyl chloride in 3 mL anhydrous Et2O. Stirring was continued for 0.5 h and the intermediate indoleglyoxylchloride separated as a yellow crystalline solid but it was not isolated. There was then added, dropwise, a 40% solution of diethylamine in Et2O until the pH was raised to 8–9. The reaction was then quenched by the addition of 100 mL CHCl3, and the organic phase was washed with 30 mL of 5% NaHSO4 solution, with 30 mL of saturated NaHCO3, and finally with 30 mL of saturated brine. After drying with anhydrous MgSO4, the solvent was removed under vacuum. The residue set up as crystals and, after recrystallization from Et2O, provided 0.62 g (72%) 4-acetoxyindol-3-yl-N,N-diethylglyoxylamide with a mp of 150–151 °C.
A suspension of 0.5 g LAH in 10 mL anhydrous THF was held in an inert atmosphere and vigorously stirred. To this there was added, dropwise, a solution of 0.6 g of 4-acetoxyindol-3-yl-N,N-diethylglyoxylamide in 10 mL anhydrous THF at a rate that maintained a gentle reflux. After the addition was complete, the refluxing was maintained for an additional 15 min, cooled to 40 °C, and the excess hydride killed by the addition of 1.0 mL EtOAc, followed by 2.3 mL H2O. The reaction mixture was filtered free of solids under a N2 atmosphere, washed with THF, and the filtrate and washings combined and stripped of solvent under vacuum. The residue was distilled in a KugelRohr apparatus and the solid distillate recrystallized from EtOAc/hexane to give 0.24 g (52%) 3-[2-(diethylamino)ethyl]-4-indolol (4-HO-DET) as white crystals with a mp of 103–104 °C. The product discolored quickly in the presence of air, and was best stored under an inert atmosphere at -30 °C. Conversion to the phosphate ester was achieved by reaction of the sodium salt of 3-[2-(diethylamino)ethyl]-4-indolol with dibenzylchlorophosphonate, followed by the reductive removal of the benzyl groups with catalytic hydrogenation, as described for psilocybin.
DOSAGE: 10–25 mg, orally (as the indolol, the acetate or the phosphate)
DURATION: 4–6 hrs h
QUALITATIVE COMMENTS: (with 15 mg indolol, orally) “This was in a gelatin capsule and it came on from a half hour to the three-quarter hour point like gang-busters. Time really slowed down, with sparkly-ness, interesting, and yet there was a touch of sadness. The intense visuals held the scene, and there was the compulsion to talk and to interact and to share stuff, but the erotic was not to be found. I slept OK but there was something uncomfortable at a deep level. Am OK.”
(with 15 mg phosphate ester, orally) “It is meaningful to say that I ceased to exist, becoming immersed in the ground of Being, in Brahman, in God, in ‘nothingness,’ in Ultimate Reality, or in some similar religious symbol for oneness. The feelings I experienced could best be described as cosmic tenderness, infinite love, penetrating peace, eternal blessing and unconditional acceptance on one hand and, on the other, as unspeakable awe, overflowing joy, primeval humility, inexpressible gratitude and boundless devotion. Yet, all of these words are hopelessly inadequate and can do little more than meekly point toward the genuine, inexpressible feelings actually experienced. It is misleading even to use the words, ‘I experienced,’ as during the peak of the experience (which must have lasted at least an hour) there was no duality between myself and what I experienced. Rather, I was these feelings, or ceased to be in them and felt no loss at the cessation. Four days after the experience itself, I continue to feel a deep sense of awe and reverence, and am simultaneously intoxicated with an ecstatic joy. This euphoric feeling is in no sense analogous to hebephrenic giddiness; it includes elements of profound peace and steadfastness, surging like a spring from a depth of my being which has rarely, if ever, been tapped prior to the drug experience.”
(with 20 mg orally indolol) “I felt this faster than psilocin, but being twenty mg this is probably less potent.”
(with 20 mg acetate ester, orally) “A mild stomach discomfort for twenty minutes, followed by intoxication to the 40 minute point. A strange mixture of things at an hour, sedation, jaw-tightening, and a generalized body tremor. The light from the fireplace gave me bursts of color. Music allowed me to drift with my thoughts. Anorexia was intense, in fact there was some gut disturbance throughout the day, plus a lot of diuretic effect. Four hours into it I was fine on the telephone to a friend who knew nothing about the day.”
(with 25 mg acetate ester, orally) “There was nausea and motor incoordination going into this. And my blood pressure went up a bit. The mental part of it all peaked at 90 minutes and all closed-eye effects had stopped after three hours. Another couple of hours and the body seemed to be OK again. Sleep OK, too. I am not impressed with this stuff.”
EXTENSIONS AND COMMENTARY: On the topic of psilocybin and psilocin, one of the most frequent questions I am asked is, “Isn’t it true that psilocybin is immediately converted to psilocin in the blood stream, and so the two chemicals are in essence identical, molecule for molecule?” At this moment I always suppress a brief sense of mental fragmentation, with the automatic reply, “Where is the evidence that psilocybin is converted to psilocin in man?” If it exists, I certainly do not know of it. This clears my conscience. I really do not know the answer. But I have a tremendously strong suspicion that it really does. Any such ester, be it the phosphate, the sulfate, or the acetate, would all be easily split to the archetypal indolol by the ubiquitous esterases in the body. I do indeed believe, in my inner heart, that they all act upon the brain as the same end product, psilocin. And here, with the N,N-diethyl homologue, the same arguments probably hold as well.
The ratios of molecular weights for these ethyl homologues, 314 for the phosphate (CEY-19), the same for the sulfate (by the way, it’s not yet explored in man, to my knowledge), 276 for the acetate and 234 for the free phenol (CZ-74), all fall into a pretty narrow range, from about 4 to 3. So, the weight of the ester component in the actual molecule being considered is a relatively minor factor in the dose calculation. I am at peace with the hypothesis that all four compounds are interchangeable in potency.
Some fascinating studies have been done in Germany where the metabolically active mycelium of some Psilocybe species have been administered diethyltryptamine as a potential diet component. Normally, this mushroom species dutifully converts N,N-dimethyltryptamine (DMT) to psilocin, by introducing a 4-hydroxyl group into the molecule by something that is probably called an indole 4-hydroxylase by the biochemists. You put DMT in, and you get 4-hydroxy-DMT out, and this is psilocin. Maybe if you put Mickey Mouse in, you would get 4-hydroxy-Mickey Mouse out. It is as if the mushroom psyche didn’t really care what it was working with, it was simply compelled to do its sacred duty to 4-hydroxylate any tryptamine it came across. It was observed that if you put N,N-diethyltryptamine (DET, not a material found in nature) into the growing process, the dutiful and ignorant enzymes would hydroxylate it to 4-hydroxy-N,N-diethyltryptamine (4-HO-DET) a potent drug also not known in nature. This is the title drug of this commentary. What a beautiful burr to thrust into the natural versus synthetic controversy. If a plant (a mushroom mycelium in this case) is given a man-made chemical, and this plant converts it, using its natural capabilities, into a product that had never before been known in nature, is that product natural? What is natural? This is the stuff of many long and pointless essays.
A valuable concept was championed by one of the most respected psychotherapists and academicians in recent years, Hanscarl Leuner, the Chairman of the Psychotherapeutic Department of the University of Göttingen. Leuner was convinced that the value of the psychedelic drug was in the opening of the psyche with repeated modest exposures, with therapy carried forth over a period of time. This is the “psycholytic” approach to therapy. An opposite approach is called “psychedelic.” Here there is what might well be a one-time interaction, in which the patient is blasted into orbit with the hopes of his confronting his problem and also finding its solution. When LSD is used in the former approach, in psycholytic dosages, one would expect levels of between 50 and 150 micrograms to be used; in the latter (psychedelic) approach, the dosage would be in the 500 to 1500 microgram range. The first calls upon the activation and development of a process of understanding; the second can be seen as a religious crisis, or a conversion event. In Europe, the first was favored, but there were strong advocates (Unger, Pahnke, Grof) in the United States favoring the latter process. Here, CZ-74 was thought to be suitable only in the psycholytic role, in that it was too short lived and, at high doses, there was a restlessness and body disturbance that was not usually seen with LSD.
There is a second instructive point to be learned from Leuner. It was he who had made early observations of the psychological effects of CZ-74 in man (within two years of the reported synthesis in about 1959) and had carried out the most extensive clinical studies ever conducted, involving at least 160 trials in human volunteers. He presented two separate reports in 1965, to two very different audiences. To the psychotherapeutic audience there was a strong emphasis made of the psycholytic virtues to be found in CZ-74, including its very short duration and the positive nature of the experience. The sessions are called “overwhelming and ecstatic” with the “elimination of the hangover of LSD—or any pathological after-effects—even with dosages of up to 40 milligrams.” The plaudits continued: “Thus, this drug must be considered to be particularly safe and suited for ambulant psycholytic treatment and use by psychiatrists in their practices.” Almost everything was positive.
However, in addressing a neurosciences conference, also in 1965, and referring to the same studies and the same experimental population, he reported some pretty heavy duty neuropharmacological negatives. “In all sessions there were disturbance of body image, illusions, pseudo-hallucinations and hallucinations. In 50% of [the] cases, motor restlessness, aphasia, loss of concentration and temporal and special disorientation could be clearly observed. In 25% of the cases there was loss of impetus, derealization and acoustic hallucinations. More rarely and only with the highest doses did extreme psychotic symptoms occur, with increased volubility, depersonalization, cosmic-mystic experiences, delirium, schizophrenic behavior with catatonic fits and temporary paranoia.” Almost everything was negative.
At a banquet associated with an international conference on the study of consciousness, held in Göttingen a few years ago, Alice and I had the pleasure of sitting at the table with Hanscarl Leuner and his wife. He thanked me for inventing 2C-D which he and his students had been exploring as an adjunct to psychotherapy. They had renamed it, initially DMM-PEA and then LE-25, and had apparently explored it at dosages that reached into the hundreds of milligrams. In PiHKAL, I had offered an effective range for this drug of from 20 to 60 milligrams. It would seem that in his later years, Dr. Leuner chose to move from the psycholytic camp over to the psychedelic camp.
One final comment. When you read a paper or listen to a lecture offered by a researcher of impeccable qualifications, take a moment to look about you to see who is along side you in the audience that is being addressed. Who else is reading his paper? Who else is hearing his lecture? How might the presentation be tailored to fit the interests of the recipients? The identification and recognition of your neighbors should play a role in your evaluation and acceptance of the presentation.
Repke, DB; Ferguson, WJ; Bates, DK. Psilocin analogs. 1. Synthesis of 3-[2-(dialkylamino)ethyl]- and 3-[2-(cycloalkylamino)ethyl]indol-4-ols. J. Heterocycl. Chem., 1 Jan 1977, 14 (1), 71–74. 273 kB. doi:10.1002/jhet.5570140113
McKenna, DJ; Repke, DB; Lo, L; Peroutka, SJ. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes. Neuropharmacology, 1 Mar 1990, 29 (3), 191–198. 679 kB. doi:10.1016/0028-3908(90)90001-8
Meyers-Riggs, B. Biosynthesis of 4-substituted tryptamine derivatives. countyourculture: rational exploration of the underground, 17 Feb 2012.
Meyers-Riggs, B. 4-Hydroxy tryptamines. countyourculture: rational exploration of the underground, 7 Jul 2012.
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 match the printed version—I’ve found over 300 inconsistencies. Text has been inserted, deleted, or changed at various points. Perhaps the Erowid version was created from an earlier (or later) draft? In several places the Erowid version is plainly wrong; elsewhere it’s a tougher call. I don’t claim to have found every discrepancy; in those cases I have found, both the Erowid and print versions are given and marked as such. I would be grateful if any sharp-eyed readers would report any I have missed.
As with PiHKAL • info, I’ve again attempted to reproduce the typographic style of the printed edition. And again, I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.
“I would like to take a moment to reiterate that 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
The Copyright for Part 1 of TiHKAL has been reserved in all forms and it may not be distributed. Part 2 of TiHKAL may be distributed for non-commerical reproduction provided that the introductory material, copyright notice, cautionary notice and ordering information remain attached.
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.
Although 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.Transform Press,