SYNTHESIS: To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for its preparation) in 215 g glacial acetic acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g nitroethane. This mixture was heated for 3 h on the steam bath, the reaction mixture was cooled in a wet ice bath, allowing the spontaneous formation of yellow crystals. As much H2O as possible was added (just short of a persistant cloudy oily character) and after a few additional h standing, the crystalline 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by filtration and recrystallized from boiling acetic acid. The yield, after drying to constant weight, was 28.3 g and the mp was 87–88 °C. Anal. (C12H15NO4) C,H,N.
A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 9.5 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 4 h, then cooled to room temperature and allowed to continue stirring overnight. The excess hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously, until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 225 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3×150 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 9.6 g of a clear oil which spontaneously formed crystals with a mp of 60.5–61 °C from hexane. These solids were dissolved in 150 mL anhydrous Et2O, and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 8.25 g of glistening white crystals that had a mp of 190.5–191.5 °C. The sulfate had a mp of 131 °C. Anal. (C12H20ClNO2) C,H,N.
The above nitrostyrene may also be converted to the final amine product through the intermediary of the corresponding phenylacetone. To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial acetic acid held at reflux temperature, there was added 4.9 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid. Refluxing was continued for 2 h and then all was filtered through wet Celite. After washing with 300 mL H2O followed by 300 mL Et2O, the combined filtrate and washes were separated, and the aqueous phase extracted with 2×100 mL Et2O. The organic phase and extracts were combined and washed with 2×100 mL saturated K2CO3 and the solvent was removed under vacuum yielding a reddish oil weighing 3.3 g. This was distilled at 111–115 °C at 0.5 mm/Hg to give a pale green solid. After recrystallization from benzene, there was obtained 2.8 g 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a mp of 57–59 °C. This ketone has also been described as a pale-yellow oil with a bp of 115–118 °C at 0.4 mm/Hg. A solution of 0.7 g 1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g Linde 3 A molecular sieves. The mixture was stirred overnight, the solids removed by filtration, and the filtrate dissolved in 100 mL H2O. The solution was acidified with dilute H2SO4, and washed with 2×25 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2×25 mL CH2Cl2. The solvent was removed under vacuum, and the residue distilled (at 160 °C at 0.2 mm/Hg) to give colorless product which was dissolved in 3 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O. There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) as a white solid with a mp of 187–188 °C.
The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or “S” isomer of DOM preferentially. Also, the above-mentioned 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alphα-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The mp of either of the optical isomers, as the hydrochloride salts, was 204–205 °C.
DOSAGE: 3–10 mg.
DURATION: 14–20 h.
QUALITATIVE COMMENTS: (with 1.0 mg) “There is almost certainly an effect. Physically there is a slight dryness in the mouth, and my eyes are noticeably dilated. There is an eerie feeling overall.”
(with 2.3 mg) “Mood elevation at 2–3 hrs. After 3 hours, emotional effects become more pronounced, enhancement of color also. Very little distortion of perception, no disorientation, no creeping or flowing, but color enhancement considerable. The emotional content and empathy for others was closer to mescaline than to amphetamine, a welcome change. No suggestion of nausea at any time. Unable to sleep at ten hours, so I took 3/4 grain Seconal. Headache and listlessness next morning, probably due to the Seconal.”
(with 3 mg) “In the middle of the experience I found that I was able to separate components of complex things so as to evaluate them separately. There is no need to respect their normal purpose. The sharpness of observation is enhanced, but one can focus at every different depth of a thing or a concept. Colors are not just brighter; there are more of them. There is a profoundness of meaning inherent in anything that moves. A line of thought or a bit of personal history ties the thinker to the objects that had been thought of, or once experienced. It is this relationship that will prove productive. Not like in a movie which is circular in its totalness, but as in true life where the future is the result of your own involvement with everything about you.”
(with 4 mg) “The first four hours were largely directed to the body. There was a shuddering, and a tight jaw, and I am not particularly motivated to talk to anyone. It is more arousing (like amphetamine) than depressing (like phenobarb). I am feeling just a little sick at the three hour point, but a bit of regurgitation clears this up. Then at the fourth hour, it went totally outside of me. I saw the clouds towards the west. The clouds!!! No visual experience has ever been like this. The meaning of color has just changed completely, there are pulsations, and pastels are extremely pastel. And now the oranges are coming into play. It is a beautiful experience. Of all past joys, LSD, mescaline, cannabis, peyote, this ranks number one. Normally I have no color effects with mescaline. A dynamic experience. Feels good, too.”
(with 5 mg) “There was the magnification of light, color and odors. It was all very pleasant and beautiful, except that I had an overwhelmingly negative feeling. This at times grew to considerable intensity, and I feel it was clearly due to anger. At times the negativity disappeared completely, and I broke into the most enjoyable, even hilarious experiences. I alternated about 50–50 between joy and discomfort. As the evening drew on, I became withdrawn and pensive. It seemed clear that I had made all the wrong decisions—choice of partner, place to live, isolation, no meaningful activity. The greatest shocker was that my practice of meditation, which is one of my central focuses, and which I thought had brought me much peace and understanding, seemed to be a delusional solution to my unhappiness and isolation. The experience continued unabated throughout the night with much tension and discomfort. I was unable to get any sleep. I hallucinated quite freely during the night, but could stop them at will. While I never felt threatened, I felt I knew what it was like to look across the brink to insanity.”
(with 8 mg) “The very quiet development picks up speed betweeen the first and second hour. There is a rich curly-imaged eyes-closed show that interlocks closely with music. It is occasionally an off-beat fantasy and not directly knit together, and even occasionally unenjoyable. But always intense and completely appropriate to the music. There is a continuous thirst, and little urine. Napping seems OK at 16 hours, but real sleep must wait until the 20 hour point. Overall a rolling +++, and I am looking forward to a repeat some day.”
(with 10 mg) “If on this page I shall have expressed it to you then it is true that DOM has the glory and the doom sealed up in it. All that’s needed to unseal it is to surround it with a warm living human for a few hours. For that human for those hours all the dark things are made clear.”
(with 12 mg) “The first awareness was at 30 minutes and it was in the tummy. The development was extremely rapid, something more like LSD than previously remembered. The body tremor feels like poisoning, there is no escaping the feeling of being disabilitated, but at least there is no nausea. This transition ended and the trauma cleared completely at about the second hour. The music was exceptional, the erotic was exceptional, the fantasy was exceptional. Listz’s “A Christmas Cantata #1,” part 1, with eyes closed was an experience without precedent. There were some residual effects still noted the next day. This may be a bit much for me.”
(with 0.3 mg of the “R” isomer) “Maybe slightly wiry? No effects.”
(with 0.5 mg of the “R” isomer) “There is a real effect, and it is significant that the first effects of the racemate were noted at 1.0 milligram. There is a trace of time slowing and in general a pretty full manic state. There is some mydriasis. Everything had pretty much cleared up by evening.”
(with 2.0 mg of the “S” isomer) “No effects. There was an unexpected slight tachycardia at the two hour point, but nothing suggesting psychotropic action.”
(with 2.6 mg of the “S” isomer) “There are signs of both pulse increase and blood pressure increase. There is some teeth-rubbiness, but still no psychological turn on at all.”
EXTENSIONS AND COMMENTARY: The rationale for the design and making of DOM has already been discussed. One could predict that it could have been, theoretically, a totally inactive compound and maybe an effective blocker for whatever receptor sites are being occupied by other psychoactive drugs and even for strange things that some unbalanced people might actually make within their bodies, using their own personal chemistry. On the other hand, it could have been a potent psychedelic in its own rights, and if so, probably long lived. The latter “could have been” proved to be so.
The very modest amount of study of the individual optical isomers clearly indicates that the “R” isomer is the more active. The sparse comments suggest that some of the heavier physical aspects of the racemate might be due to contributions from the “inactive” “S” isomer. It is, after all, the “S” isomer of amphetamine that carries the major punch of that stimulant. Maybe if that isomer were removed, and one were to explore the pure “R” isomer of DOM, the dramatic visual aspects of the larger dosages might not be complicated with a troublesome physical component.
This compound, unbeknownst to me, was scattered widely and plentifully in the heyday of the Haight-Ashbury in San Francisco, in mid-1967. It was distributed under the name STP, which was said to stand for Serenity, Tranquility, and Peace. It was also claimed to represent Super Terrific Psychedelic, or Stop The Police. The police called it: Too Stupid to Puke. Actually, the name was taken from the initials of a motor additive which was completely unrelated chemically. Incredibly, and sadly, one of the avowed experts in the area of the “sensuous drugs” actually stated that STP, the motor oil additive, was really one and the same as STP, the highly dangerous psychedelic. The motor oil additive, he wrote in a book of his, had properties somewhat related to those of LSD, mescaline, and the amphetamines. How fortunate that the love children of the time didn’t do much reading, for they might have gotten into yet deeper pharmacological troubles with drug raids on the local gasoline stations.
Two complications became apparent during this first appearance and they led to serious difficulties. One, there was no equation made between STP and DOM. No one knew what this drug was which had been distributed in a cavalier way throughout the city. There could be no educated guess as to the best treatment of overdose emergencies. And secondly, the initial tablets that had been distributed apparently contained 20 milligrams of DOM per tablet; later, it was dropped to 10 milligrams. Either of these, in retrospect, is now known to be a thoroughly whopping dose. The overdose situation was aggravated by the slow onset of DOM. The user may be aware of some initial effects at the half-hour point, there will be what might be called a + or ++ at the end of the first hour, and the full impact of the drug is not appreciated until some two hours have elapsed. But many of the recipients of the free handouts of DOM were familiar with LSD which can show its alert in 15 to 20 minutes, or even sooner with a large dose, and there is already a deep and compelling intoxication felt at the half-hour point. They, quite reasonably, expected this familiar activity pattern with STP and assumed, when there was little if any activity noted at the half-hour point, that the potency was less than expected. They took one or even two additional dosage units. Thus, some of the overdose victims of that period may well have taken as much as 30 mg of DOM. The slow onset of action, coupled with the remarkably long duration, caught many innocent users unprepared.
Clinical studies have documented the rapid tolerance development from repeated exposures to DOM. Five volunteers were given 6 milligrams daily for three days. Objectively, psychological tests showed a decrease in responses. Subjectively, all found extremely intense effects on the first day, and all but one found it unpleasant. By the third exposure on the third day, all had diminished responses, ranging from only “moderately strong” to “felt absolutely nothing.” One actually slept during the experience on the third day.
The hexadeutero-analogue (deuterium atoms on the two methoxyl groups) has been prepared as an internal standard for analytical work, but there are no reports of its human pharmacology. A study with this sort of derivative would be a fine companion to the studies already underway with the mescaline analogues that are similarly substituted. A difference exists, however. With mescaline, it is believed that the loss of a methoxyl group is a step towards the inactivation of the compound, whereas with DOM this loss may be associated with the formation of an active metabolite. The several fascinating questions raised by possible differences in both the rates and the degree of demethylation of these two compounds are well worth trying to answer.
A number of compounds related to DOM had been synthesized and studied at the University of California at San Francisco, at about this time. Two of these were simply the juggling of the two methoxyl groups and the methyl group on the ring, still maintaining the 2,4,5-ness relative to the amphetamine chain. These are 2,4-dimethoxy-5-methylamphetamine and 4,5-dimethoxy-2-methylamphetamine. Since the slang name for DOM in and about the medical center was STP, and since STP was the name of a motor oil additive, it is not unreasonable that the first of these to be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by the name of another motor oil additive popular at that time, F-310. The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp 117–118 °C) with a yellow malononitrile derivative from EtOH with a mp of 193–194 °C. The nitrostyrene from this and nitroethane formed yellow crystals from CH3CN, with a mp 138–139 °C. The amine formed easily with LAH in ether, and the product F-310 (or 5-DOM) gave white crystals from CH3CN with a mp of 182–183 °C.
And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became known familiarly as F-320, or sometimes simply 2-DOM. Its preparation followed an identical procedure, starting from 3,4-dimethoxytoluene. I have been told that F-310 is not active even at 20 milligrams in man, which would make it several times less potent than DOM (STP). I know of no trials with F-320. The use of the letter “F” does not imply any relationship between these two compounds and the series described elsewhere with the “F” code followed by other numbers, such as F-2 and F-22. These latter are F’s because they are furans, not motor oil additives. And yet another oil additive, well known at the time as Z-7, became associated with the synthesis of the DOM (STP) isomer with its groups in the 2,4,6-positions. This is entered separately under Ψ-DOM.
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,