I like to call 4-HO-DET "The Living Rainbow Crystal". I had the fortunate experience of aquiring 1.5 grams of this material before it was swept off the face of the earth by the DEA's Operation Web Tryp. I experimented a lot with it. Some of my experiences included: out of body experiences, merging of conciousness, connectedness to everything, multidimensional awareness, and pretty colors.

4-HO-DET is a synthetic analouge of psilocin (4-HO-DMT). It was first synthesized by Albert Hoffman, the discoverer of LSD. After inventing LSD Hoffman extracted psilocin, psilocybin, and baeocystine from psilocybe cubensis and started tweaking the psilocin molecule to see what he could come up with. The 4 position on the benzene ring of DET (diethyltryptamine) is hydroxylated. This is some magical stuff. The fact that it has an amino diethyl group is interesting because at the "top" of the LSD molecule there is also a diethyl group comming off of a nitrogen atom (albeit, an amide group). This is somewhat more difficult to synthesize than DET, its non-4-hydroxylated cousin. The use of diethyl ether, LAH, and THF makes it kind of dangerous for an ameture chemist to be messing with and 4-hydroxyindole is getting expensive. DET starts from tryptamine, which is inexpensive and pretty easy to find in sizeable quantities.

The indolol 4-HO-DET does not need to be salted out of solution as a HCl salt, it sets up as fine white crystals all by itself. This is because it is something of an internal salt. The lone pair of electrons on the amine are on one side of the molecule, the slightly positively-charged hydroxyl group is on the other side.

From Tihkal:

TRYPTAMINE, N,N-DIETHYL-4-HYDROXY; 4-INDOLOL, 3-[2-(DIETHYLAMINO)ETHYL]; N,N-DIETHYL-4-HYDROXYTRYPTAMINE; 3-[2-(DIETHYLAMINO)ETHYL]-4-INDOLOL; CZ-74; 4-HO-DET PHOSPHATE ESTER; TRYPTAMINE, N,N-DIETHYL-4-PHOSPHORYLOXY; 4-INDOLOL, 3-[2-(DIETHYLAMINO)ETHYL], PHOSPHATE ESTER; N,N-DIETHYL-4-PHOSPHORYLOXYTRYPTAMINE; 3-[2-(DIETHYLAMINO)ETHYL]-4-INDOLOL, PHOSPHATE ESTER; CEY-19


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

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 spacial 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.

The first half of the book is kept under strict copyright, however part 2 has been officially released for non-commercial use by the authors under the conditions described below. Each compound from part two will be separately hardlinked and noded. Unlike the hardlinks in the PiHKAL node, I have chosen to hardlink the common abbreviation or common name rather than the long chemical name. I believe this is friendlier to E2 noders and the search box. I mean, honestly, who is going to look for melatonin under n-acetyl-5-methoxy-tryptamine?

Copyright Notice
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-commercial reproduction provided that this notice, the cautionary notice and the ordering information are retained.

Cautionary Note - Please read before proceeding
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.

Ordering Information
If you are seriously interested in the chemistry contained in these files, you can order the books TIHKAL: The Continuation, and PIHKAL: A Chemical Love Story by Ann and Alexander Shulgin. These books are available from:

Transform Press
P.O. Box 13675
Berkeley, CA 94712
PHONE: 925-934-2675
FAX: 925-934-5999
Call or write to get ordering information.

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