4-TM · 4-Thiomescaline · 3,5-Dimethoxy-4-methylthiophenethylamine
#156 TM SYNTHESIS: A solution of 24.2 g N,N,N′,N′-tetramethylethylenediamine and 27.6 g of 1,3-dimethoxybenzene was dissolved in 400 mL anhydrous hexane. This was stirred vigorously under a N2 atmosphere and cooled to 0 °C with an external ice bath. There was added 125 mL of 2.0 M butyllithium in hexane. The stirred reaction mixture became yellow and sludgy, and was briefly warmed back to room temperature to allow easy stirring. After cooling again to 0 °C, there was added 18.8 g of dimethyl disulfide which converted the viscous yellow phase to a loose white solid. Stirring was continued while the reaction mixture was brought up to room temperature, and then all was added to 2 L of dilute H2SO4. There was the immediate formation of a white cystalline solid which was removed by filtration, sucked relatively free of water, and recrystallized from 50 mL of boiling MeOH. There was thus obtained 18.9 g of 2,6-dimethoxythioanisole as white crystals with a mp of 81–82 °C. Extraction of the aqueous filtrate with 2×50 mL CH2Cl2 and removal of the solvent under vacuum gave a residue which, when combined with the mother liquors from the MeOH crystallization, afforded an additional 3.3 g product with a mp 77–79 °C.
To a stirred solution of 18.9 g of 2,6-dimethoxythioanisole in 200 mL CH2Cl2 there was added 16 g elemental bromine dissolved in 75 mL CH2Cl2. The initial dark red color gradually faded to a pale yellow color and there was a copious evolution of HBr. The solvent was removed under vacuum leaving 27.5 g of a pale yellow residual oil. This was distilled at 118–121 °C at 0.25 mm/Hg to yield 3-bromo-2,6-dimethoxythioanisole as a white oil weighing 25.3 g. Crystallization from hexane provided white crystals with a mp of 30–30.5 °C. Anal. (C9H11BrO2S) C,H.
To a solution of 19.3 g diisopropylamine in 150 mL anhydrous THF that was stirred under a N2 atmosphere and cooled to -10 °C with an external ice/MeOH bath, there was added in sequence 83 mL of 1.6 M butyllithium in hexane, 4.4 mL of dry CH3CN, and 11.6 g of 3-bromo-2,6-dimethoxythioanisole (which had been dissolved in a little anhydrous THF). The turbid reaction mixture gradually developed color, initially yellow and progressively becoming orange and finally a deep red brown. Stirring was maintained for a total of 20 min, and then the reaction mixture was poured into 1 L H2O that containing 10 mL concentrated H2SO4. This was extracted with 3×75 mL CH2Cl2, these extracts pooled, washed with dilute H2SO4 followed by saturated brine, and the solvent was removed under vacuum yielding 8.7 g of a viscous oil as a residue. This was distilled at 0.11 mm/Hg yielded two fractions. The first boiled at 115–125 °C and weighed 3.8 g. This material set to an oily crystalline mass which was filtered, washed with cold MeOH and then recrystallized from MeOH. The white solids had a mp of 60–63 °C and were not the desired product. This material has not yet been identified. The second fraction came over at 150–180 °C, weighed 1.8 g and spontaneously crystallized. It was triturated under cold MeOH and filtered yielding, after air drying, 1.1 g 3,5-dimethoxy-4- methylthiophenylacetonitrile, which had a mp of 95–96.5 °C. Anal. (C11H13NO2S) C,H.
A suspension of 1.0 g LAH in 40 mL anhydrous THF under N2 was cooled to 0 °C and vigorously stirred. There was added, dropwise, 0.7 mL 100% H2SO4, followed by 1.2 g 3,5-dimethoxy-4-methylthiophenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was stirred at 0 °C for a few min, then brought to room temperature for 1 h, and finally to a reflux for 30 min on the steam bath. After cooling to room temperature, there was added 1 mL H2O in 5 mL THF to destroy the excess hydride, followed by 3 mL of 15% NaOH to bring the reaction to a basic pH, and finally 2 mL H2O which converted the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed with THF. The filtrate and washes were stripped of solvent under vacuum, the residue was dissolved in 200 mL CH2Cl2, and this was extracted with 3×100 mL diute H2SO4. These extracts were pooled, washed with CH2Cl2, made basic with 25% NaOH, and extracted with 3×100 mL CH2Cl2. After combining, the solvent was removed under vacuum providing 1.2 g of a colorless oil as a residue. This was distilled at 122–132 °C at 0.05 mm/Hg to give a colorless oil. This was dissolved in 8 mL of IPA, neutralized with concentrated HCl and, with continuous stirring, diluted with 100 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 0.95 g. 3,5-dimethoxy-4-methylthiophenethylamine hydrochloride (4-TM) as spectacular white crystals with a mp of 193–194 °C. Anal. (C11H18ClNO2S) C,H.
DOSAGE: 20–40 mg.
DURATION: 10–15 h.
QUALITATIVE COMMENTS: (with 25 mg) I was first aware of any effects as I was sitting in back of the house on a big fluffy pillow. The sun was warm and the grass tall and green, but I felt strange inside. There was distinct uterine cramping, and I could not find a comfortable position for sitting. The others had gone out to the garden leaving me here. It seemed that walking might relieve the physical discomfort, so I went to find them. Walking was easy, but I was a little light-headed and I had to watch my steps with care. They were not there (we had passed on opposite sides of the house) and I returned in some haste to my warm nest behind the house to find my pillow gone. A strange detail, but it perhaps gave me the flavor for my day. The pillow was for me. It was gone. My place was gone. Therefore I am gone. I am dead and yet I can see and think. The small touch of panic at finding myself dead dispelled any internal concerns and I ran inside to find the others; they had brought my pillow in. I was alive again, but the entire day balanced between the alive unreality and the illusion that I was something removed and merely watching the surrounding alive unreality. Everything that happened was completely unlikely.
Like the soup scene. We decided that some hot soup would be welcome, and so R. brought out three cans of Campbell soup for the three of us. But one was cream mushroom, one asparagus, and one tomato. The discussion as to how to use two cans only, which two, without mixing, and even how to decide to decide was totally beyond any of us. The situation was hopelessly unresolvable, hilariously funny, and distinctly schizophrenic.
Or like the kite scene. We were returning from a short walk to the back of the property, and I spotted a red thing in the parking area. It had not been there before. None of us could identify it from this distance, and we speculated wildly as to what it was, as we came closer. And at the last approach, we found that there was loose string everywhere about the driveway, all part of a downed kite. The red object had apparently fallen from the sky, right here in front of the garage. There had been no sounds of voices of kite-flyers, and there was no one to be seen in any direction. And then one of us spotted a sheet of paper, torn to the center where there was a small hole, and it was flattened up against the kite. There was a message. Apparently whoever had been flying it had put a message on the string, and let the wind take it up to the kite itself. I reached for the sheet of paper, and removed it. Nothing on either side. The message was that there was no message. Exactly out of Marshall McLuhan. Completely appropriate for this particular day.
That evening we were to be picked up by my friends for dinner. Choosing what to wear, how to dress myself, how to adjust my persona to fit other people, all this was chaotic. Somehow the dinner succeeded, but I was able to flip in and out of the immediate company easily, but not completely voluntarily. Sleep was comfortable that night, and I feel that the entire day had been very intense, not too much fun, but somehow quite rewarding.
(with 30 mg) At the one and a half hour point, I was reminded more than anything of , with a distinct feeling of standing just a few feet to the right of ordinary reality. There has been a mild tremor ever since the first effects were evident, but it doesn’t bother me except to make my handwriting uncertain. I would not want to double this level. Suddenly the concept of my 5:30’s swept over me. I had a penetrating view of myself as a person who had become invested in a pattern of behavior that I had succumbed to, to come home and complete my day with a transition from the work-world to the home-world, by changing the inside clock at 5:30. My wife had been my 5:30 for nearly 30 years and this had been my tacit agreement with her. Never questioned, never challenged, and certainly never violated. And with her death, I have found myself imposing this same 5:30-ness on myself, as some form of an emasculating pattern that is comfortable and stable. No, it is not comfortable, it is simply the course of the least thought and the least disruption. If I were to meet someone else, would I have such a negative image of myself that I would expect her to become my 5:30 so as not to have to disrupt these tired and comfortable patterns? That would be completely unfair to this other person. And I can see where it is completely destructive to me. No new person should ever have to play my wife’s old role. I need never again play my old role. And I won’t.
(with 30 mg) At 2:20 p.m. I ingested 30 mg of TM. It had a mildly alkaloid taste. Since the afternoon was warm, I took a two mile walk with the dog, and with my two companions K.T. and T.T., both also with 30 mg. We talked without any difficulty even after the onset of the first signs of effect. The major emotional and physical effects came on very gradually and quite pleasantly as we sat in the patio. But soon we all grew chilled, and put on more clothing. Nothing really helped the inward chill, and we were to discover that it stayed with us throughout the experience. At 3:30 we went inside where the room temperature was set at 70 degrees, and we all lay down. I launched into an engrossing, somewhat chaotic and erotic reverie, that followed no linear progression, but which lasted perhaps an hour. The ease of talking surprised me; the content was cogent and I felt myself to be articulate. It dawned on me after about two hours had gone by, that the height of the experiment had already passed without any real exhilaration on my part. But my companions suggested that my expectations from the past had been misleading me and, as time went on, they proved to be correct. The clarity and the continued ability to talk, especially with K.T. on a personally difficult topic, were for me the particular genius of this material. When I went inward, which I could do without effort, the sensations were neutral in affect but restful in some way. But coming out was entirely lucid and pleasant. I soon found that I preferred this. I enjoyed a light supper at 8:30 and found the dropoff gentle, and the conversation most amiable until we separated at 1:00 a.m. Sleep did not come until 3:00 a.m. and then only after 10 mg Librium to quell the active mental processes. The next day I awoke around 8:30 a.m. feeling languid but cheerful.
(with 40 mg) For quite a while there was some physical concern. Not actual nausea but a generalized uneasiness, with a distinct body tremor. There was little urine produced (500 mL in 18 hours), and I felt the need to search out fluids. There was mild intestinal cramping. I found that my thoughts were able to go in several directions at once, but since they stayed nowhere long enough to structure anything, this was more annoying than constructive. I saw this as a reality shell about me like a Möbius strip, continuous, yet with no consistent side being presented. I was reminded of a similar place with , some few years ago. While lying down with eyes closed, I found the imagery to be very impressive, but my thought processes were quite convoluted and disjointed. Some were most interesting, and some were ugly. I cannot see this as a party drug.
EXTENSIONS AND COMMENTARY: The dosage range has been broadened to include the 20 milligram level, in that several subjects found that even with that small amount there was difficulty in walking and in keeping one’s equilibrium. Walking was described as a floating procedure, and one could tilt to one side or the other if care was not taken. Anorexia was occasionally noted, and most people commented on some degree of anesthesia to touch.
All in all, this drug evoked a mixed bag of responses. The most startling and unexpected property was the dramatic increase in potency over the parent prototype, . The substitution of a sulfur atom for an oxygen atom increased the power of the drug some ten-fold, without any apparent decrease in complexity of action. As there were many materials that were outgrowths of with the studies of ethyl this and diethyl that, each and all of these would be interesting candidates for synthesis with this or that oxygen atom replaced with sulfur. Most of these have been made, and many of them have proven to be interesting.
What is meaning of the phrase, “sulfur-for-oxygen replacement?” Let me try to explain it for non-chemists.
One of the most exciting bits of architecture in science is the Periodic Table. The principles of electrons and orbitals and different counts of protons in a nucleus gets to be a complex story to try to explain the grid-like structure of the arrangements of atoms. It is easier to simply give the music. And this melody goes: As you look across a row, elements are simple in their binding arrangements on the left, become more complex towards the center where they kind of change polarity, and then get progressively simple again but with the opposite charge as you approach the right-hand side.
And when you look at a column from top to bottom, the bonding complexity stays pretty much the same but the atom gets more and more massive as you go down the column.
The combinations of atoms from the Periodic Table, by and large, is the province of the inorganic chemist. Take one of this, and two of that, and the combination is called a salt, or a complex, or an adduct, and probably has interesting colors, and may even be found in nature as part of a rock somewhere, or coming out of the vent of a volcano.
But if one were to look at just four elements, three in the middle right of the first row, namely carbon, nitrogen and oxygen, and the one up there at the top and the lightest of all, hydrogen, you would find quite a different story. These can be combined in an infinity of ways since there can be dozens of atoms hooked to one-another; this is the territory of the organic chemist, and this is the chemistry of life. With a few exceptions, every molecule within the body, and the food that maintains the body, and the drugs that affect the body, are made up of a bunch of carbons, and an occasional oxygen or two, usually a nitrogen somewhere, and all the remaining loose ends satisfied with hydrogen atoms.
Almost every drug that is to be found in this book is nothing more than a different arrangement of atoms of these four elements.
This compound, thiomescaline, is a byway that takes advantage of one of those vertical columns. Directly below the element oxygen, there is found sulfur, which has much the same binding complexity, but is twice as massive. The prototype of all the phenethylamine drugs being discussed in this book is , a very simple compound containing these basic four elements of life and pharmacology; it contains eleven carbon atoms, three oxygen atoms, one nitrogen atom, and there are a total of seventeen hydrogen atoms required to balance the books. One of the oxygen atoms holds a central position, and the other two are reflections of one another and cannot be distinguished chemically. The structure of thiomescaline is generated by plucking out that central oxygen atom of , and putting a sulfur atom back in its place. The definition of the term “thio” is quite simple—it means a sulfur-in-place-of-an-oxygen, with everything else left alone. It is a little awe-inspiring to think that every oxy anything can have a thio something as a spatially similar analogue. And there are a lot of oxy things in the body and in the medicine cabinet. A number of them are discussed in this book.
13 May 2016 · Creative Commons BY-NC-SA ·

About PiHKAL · info

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. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.

Cautionary note

“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

Copyright notice

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.

Ordering information

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.
Though 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.
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