SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL 95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under 2C-D for its preparation). This was followed with 23.5 g ethyl iodide, and the mixture was held at reflux overnight. The solvent was removed under vacuum and the residue suspended in 250 mL H2O. This was made strongly basic with NaOH and extracted with 3×50 mL CH2Cl2. Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an amber oil, which was used in the following step without further purification. Acidification of the aqueous phase followed by CH2Cl2 extraction gave, after removal of the solvent, crude recovered starting phenol as a dark brown crystalline solid. The reasonably pure phenol was best isolated by sequential extractions with portions of 80 °C H2O which, on cooling, deposited the phenol as white crystals.
A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to incubate for 1 h and then there was added to it 15.7 g 2-ethoxy-5-methoxytoluene. This was heated in the steam bath for 2 h, then poured into 1 L H2O and allowed to stir overnight. The solids that formed were removed by filtration and H2O washed, giving 20.7 g of a crude, amber product. This was extracted with 2×150 mL boiling hexane which gave crystals on cooling. These were filtered and hexane washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as pale cream-colored solids with a mp of 75–76 °C. Recrystallization of an analytical sample from EtOH two times gave a product with a white color, and a mp of 81–82 °C.
To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48 mL glacial acetic acid containing 4 g anhydrous ammonium acetate there was added 10 mL nitroethane, and the mixture heated on the steam bath for 2 h. Standing at room temperature overnight allowed a heavy crop of brilliant crystals to deposit. These were removed by filtration, washed cautiously with acetic acid, and air dried to give 8.6 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of 118–120 °C. Recrystallization of all from 200 mL boiling MeOH gave 8.3 g of lustrous crystals with a mp of 121–122 °C.
To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O under a He atmosphere, there was added 8.1 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise. Refluxing was maintained overnight, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 400 mL H2O containing 40 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 160 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3×50 mL CH2Cl2. Evaporation of the solvent under vacuum produced an oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride (IRIS) as fine white crystals. These weighed, after filtration, Et2O washing, and air drying to constant weight, 5.3 g and had a mp of 192–193 °C. Recrystallization of an analytical sample from boiling CH3CN gave lustrous crystals with a mp of 196–197 °C with decomposition.
DOSAGE: greater than 9 mg.
QUALITATIVE COMMENTS: (with 7.5 mg) “At about three hours I felt that I was at threshold, but an hour later there was nothing.”
(with 9 mg) “Maybe a little light headed? Maybe not. Little effect if any.”
EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the ten possible homologues of DOM, which I had discussed under ARIADNE (the first of the Ladies). The active level is unknown, but it is higher than 9 milligrams (the highest dose tried) and since DOM itself would have been smashingly active at this level, it is obvious that IRIS is a homologue with decreased potency.
This lack of activity brings up a fascinating point. I have referred to a drug’s action on the mind, quite frequently in these notes, with the phrase “reasonably complex.” By that, I do not mean that a drug’s action simply shows many facets, and if these were to be tallied, the drug-mind interaction would become clear. There is quite a bit of importance intrinsically implied by the term, complex. Simple things, as we have come to appreciate and depend upon them in our day-to-day living, can have simple explanations. By this, I mean explanations that are both completely satisfactory and satisfactorily complete. Answers that have all the earmarks of being correct. What is the sum of two plus three, you ask? Let’s try five. And for most of our needs, five is both factual and complete.
But some years ago, a mathematician named Gödel devised a proof for a theorem that anything that is reasonably complex cannot enjoy this luxury (I believe he used the word “interesting” rather than reasonably complex). If your collection of information is factual, it cannot be entirely complete. And if it is complete, it cannot be entirely factual. In short, we will never know, we cannot ever know, every fact that constitutes an explanation of something. A complete book of knowledge must contain errors, and an error-free book of knowledge must be incomplete.
There is a small warning light deep inside me that starts flashing any time I hear someone begin to advance an explanation of some reasonably complex phenomenon with an air of confidence that implies, “Here is how it works.” What the speaker usually has is an intense familiarity with one particular discipline or specialty and the phenomenon is viewed through those eyes, often with the assurance that looking at it that way, intently enough and long enough, will reveal the complete explanation. And be attentive to the phrase, “We are not yet completely sure of exactly how it works.” What is really meant is, “We haven’t the slightest idea of how it really works.”
I must admit to some guilt in this matter, certainly as much as the next person. I am a chemist and I suspect that the way that the psychedelic drugs do their thing can eventually be understood through a comparison of the structures of the molecules that are active and those that are inactive. I put those that have methoxyl groups in pigeon hole #1, and those that are bicyclic into pigeon hole #2. And then, if pigeon hole #2 becomes more and more cluttered, I will subdivide the contents into pigeon hole #2A for bicyclics with heteroatoms and pigeon hole #2B for bicyclics without heteroatoms. The more information I can accumulate, the more pigeon holes I need.
But in the adjoining lab, there is a molecular biologist who feels that the eventual explanation for the action of the psychedelic drug will come from the analysis and understanding of the intimate geometry of the places in the brain where they act. These classification pigeon holes are called receptor sites. But they, too, can become more and more subdivided as they become cluttered. One reads of a new sub-sub type quite regularly in the literature. The favorite neurotransmitter of the moment, as far as the current thinking of how these marvelous drugs work, is serotonin, or 5-HT (for 5-hydroxytryptamine). There are 5-HT1 and 5-HT2A and 5-HT2B and (for all I know right now) 5-HT2C and 5-HT2D receptors, and I don’t really think that either he or I have come much closer to understanding the mechanism of action.
And, since the mind is a reasonably complex system, Gödel has already informed us both that neither of us will be completely successful. Sometimes I feel that the pigeon hole approach to the classification of knowledge might actually limit our views of the problem. A Harvard Professor of Medicine recently noted: “We must recognize for what it is, man’s predilection for dividing things into tidy categories, irrespective of whether clarity is gained or lost thereby.”
No. No one will ever have it all together. It is like sitting down in front of a jigsaw with a zillion zillion pieces spread all over the kitchen table. With diligent searching you will occasionally find a piece that matches another, but it rarely provides any insight into the final picture. That will remain a mystery, unless you had the chance to see the cover of the box in some other incarnation. But Oh my, what fun it is, whenever you do happen to find a new piece that fits!
This harangue is really a lengthy prelude to the story of putting an ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of these psychedelic families. The making of IRIS was the first move in this direction, done back in 1976. One can have a pigeon hole that is named “Ethoxy In Place of Methoxy” and toss in there the names of perhaps twenty pairs of compounds, which differ from one another by just this feature. Yet when they are looked at from the potency point of view, there are some which show a decrease in potency (which is the case with IRIS and most of the Tweetios) and there are some which seem to maintain their potency (such as the TMA-2/MEM pair) and there are some where there is a distinct potency increase (the mescaline/escaline pair, for example).
What does one do to clarify the contents of this particular pigeon hole? The current fad would be to subdivide it into three subdivisions, maybe something like “Ethoxy in Place of Methoxy if 2- or 5-located” and “Ethoxy in Place of Methoxy if 4-located and other things 2,5” and “Ethoxy in Place of Methoxy if 4-located, and other things 3,5.” The end point that soon becomes apparent, down the line, will be to have as many pigeon holes as compounds! And at the moment, this particular piece of the jigsaw puzzle doesn’t seem to fit anywhere at all.
Perhaps both my neighboring molecular biologist and I are asking the wrong questions. I am looking at the molecules and asking, “What are they?” And he is following them and asking, “Where do they go?” And neither of us is fully attentive to the question, “What do they do?” It is so easy to replace the word “mind,” in our inquiries, with the word “brain.”
Yup. The operation of the mind can certainly be classified as a “reasonably complex” phenomenon. I prefer Gödel’s term. The mind is without question an “interesting” phenomenon.
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Still others remain to be added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore most of the typographic niceties found in the printed edition. 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.
“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 Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. 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 PiHKAL 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.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,