Sasha Shulgin on 4-HO-DMT and how Mushrooms can make 4-HO-DET when fed DET
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.
