5-MeO-α-MT · Tryptamine, 5-methoxy-α-methyl · Indole, 3-(2-aminopropyl)-5-methoxy · Serotonin, α,O-dimethyl · 5-Methoxy-α-methyltryptamine · 3-(2-Aminopropyl)-5-methoxyindole · α,O-Dimethylserotonin · Alpha-O
#5 α,O-DMS SYNTHESIS: To a solution of 2.0 g 5-methoxyindole-3-carboxaldehyde in 25 g nitroethane there was added 0.5 g anhydrous ammonium acetate, and the mixture held at reflux for 1.5 h on the steam bath. The excess nitroethane was removed under vacuum yielding a wet, orange solid. This was dissolved in 20 mL boiling isopropanol which, after cooling, deposited bright orange crystals. These were removed by filtration, washed with cold isopropanol, and air dried to provide 1.56 g 1-(5-methoxyindol-3-yl)-2-nitropropene mp 179–180 °C (lit. 182–184 °C). Evaporation of the filtrates gave 0.81 g crude product which was recrystallized from 10 mL ethanol giving a second crop as dull gold crystals. This weighed, after EtOH washing and air drying, 0.57 g (80% total yield), with a mp of 178–179 °C.
A solution of 1.54 g 1-(5-methoxyindol-3-yl)-2-nitropropene in 60 mL anhydrous THF was added dropwise to 50 mL 1 M LAH in THF, well stirred, in an argon atmosphere. Each drop generated a red color which immediately discolored. The addition took 0.5 h and the reaction mixture was held at reflux for 18 h, then allowed to stir at room temperature for 7 days. There was added, in sequence, 1.6 mL H2O in 10 mL THF (much gas evolution), 1.6 mL 15% aqueous NaOH (no more gas) and finally 5 mL H2O. The Al2O3 was removed by filtration, washed with THF, and the combined filtrate and washing stripped of solvent under vacuum. The residue (1.83 g of a clear oil) was dissolved in 300 mL dilute HCl, washed with 3×50 mL CH2Cl2, made basic with 25% NaOH, and extracted with 3×50 mL of CH2Cl2. The extracts were stripped of solvent under vacuum, and the 1.13 g residue distilled at the KugelRohr. A clear oil distilled at 145–155 °C at 0.2 mm/Hg as a white oil that spontaneously crystallized, mp 95–96 °C. MS (in m/z): C2H6N+ 44 (100%); methoxyindolemethylene+ at 161/160 (88%, 43%, again, as with the secondary amines, this primary amine has the 161 greater than the 160, nonmethoxylated tryptamines, the 131 greater than the 130); 146 (22%); parent ion 204 (4%). These solids (0.51 g) were dissolved in 5 mL boiling isopropanol, neutralized with several drops of concentrated HCl, and diluted with Et2O. The solution became turbid and scratching produced a fine white crystalline product. After 20 min standing this was removed by filtration, washed with Et2O, and air dried. There was obtained 0.44 g 3-(2-aminopropyl)-5-methoxyindole (α,O-DMS) as white crystals, with a mp of 216–218 °C. A sample prepared some 20 years earlier (brown as the salt, not distilled as the base, mp 220–222) now melted at 215–217 °C. The residue from the aqueous acid wash above, contained no additional α,O-DMS as assayed by TLC (19:1; CH3CN/NH4OH). The infra-red spectra are different for these two material materials, indicating polymorphism. The new white crystals; IR (in cm-1): 805, 816, 872, 1023, 1055, 1102, 1169, NH at 3300. The old brown crystals; IR (in cm-1): 809, 839, 1021, 1041, 1080, 1112, 1170, NH at 3250. The brown morph, upon recrystallization from IPA/Et2O had an IR identical to the new white material.
DOSAGE: 2.5–4.5 mg, orally
DURATION: 12–18 hrs h
QUALITATIVE COMMENTS: (with 2.0 mg, orally) “Initial anxiety about getting nauseated or having diarrhea was almost immediately dissolved after ingestion. It took a little while before I felt the energy. By the way, before I took the medicine, I had read some lurid details about other people’s experiences, and was rather anxious about it, because there was a lot of diarrhea and vomiting mentioned. But it didn’t happen. Matter of fact, I felt really good afterwards. The dosage level seemed just right. I had a very enjoyable day. Communication was easy and fun. Sleep was easy to reach and it was great. Next morning, feel wonderful. Would I repeat? Yes. At about the same level.”
(with 2.3 mg, orally) “It has been an hour and a half, but now I am really turning on. Physically, I have had some pretty thorough diarrhea, but mentally I am still waiting for some sensory or perceptual, or conceptual event to occur. At the sixth hour I think I am clearing, and I don’t know what it was all about. It was as if I was in a state of preparedness like a plate of sterile agar waiting to provide nutrition to whatever was to be introduced into it. But there was no inoculation. I didn’t contribute my share. A good argument for threshold being a better measure of drug potency than a full dose. Had a slight fragile headache the next a.m.—gone by noon.”
(with 2.5 mg, orally) “Came on fairly nicely, but at about 40 minutes, began to feel slightly nauseous. This stuck with me for a couple of hours. I could get out of it by concentrating, so it wasn’t debilitating. But then, as I began to come out of that, felt a nice warm glow, and a nice centered feeling, and felt really good the rest of the day. Evening was very tired, and had a difficult time going to sleep because there was still a powerful push from the substance. In fact, I think it’s the most tenacious stuff I’ve taken, and I never could detect much let-up during the afternoon. Then, I don’t think I got into good sleep until about 2 a.m. No problem after that. Good sleep. Next morning, felt good. Still a bit languid. Today feels good. Everything looks and feels fine, but I’m not a ball of energy. At the moment, haven’t fully integrated it all. No great enthusiasm about taking it again.”
(with 3.0 mg, orally) "Just over an hour into it, some mild vomiting relieved my nausea and I began building into a wild ASC. With my eyes closed the cloud are rolling and I have strange imagery. I am going into a zombie place, my walk is a bit Frankensteinish, the piano keys are unreal, the typewriter keys are unreal—music and text that comes out has little bearing on my intentions. The most fun was writing with the power off; no inhibitions, no record. Tried a bit with the power on, and this is an exact copy of what came out: what an alien keyboard—what will it produce? anilan alina anein alein alean ailean alain alein wow wowowowowow. The face on the lion’s chair is many things, cheeks become boxing gloves, mouth talks but no words are evident, entertaining but not profound. Such mileage from just three milligrams of C, H, N & O. Obviously it is my own energy pool that has been tapped. Fourth hour, diarrhea again—modest—just symbolic. All through the last two hours—in addition to the interpretive changes, there were wild visual distortions. Things tended to flow—not bothersome—but I know I couldn’t drive a car. Here was a marvelous chemical gestalt. Reasoning from the o-hydroxybenzyl alcohol Rx c CN- Æ benzyl cyanide, why not dehydrate HOPhCH=CHCH2OH, then reduce 1,6 Æ p-OH allylbenzene and 1,8 Æ p-OH propenylbenzene—then—if reduction goes from methoxy group, a compound such as normetanephrine would Æ two-carbon (b-OH reduced off at expense of guaiacol becoming a methylenedioxy). Phoned friend. He was amused. By the fifth hour, I was mending; the physical zombie is not there anymore. I can ignore the crawling. At the ten hour point I am still dilated, and teeth rubby, and hypoxic. Something is still poisonous. Sleep not satisfactory. Restless, with strange mental interpretations. The next day, I am clear and totally without residues. This α,O-DMS is probably the most potent indolic psychedelic yet uncovered, at least via the oral route. Any higher dose would require a baby-sitter, and I must remember that there is a big toxic component that is part of this trip."
(with 3.5 mg, orally) “I started with 2.5 milligrams followed in two hours by 1 more. Never got above 1.75 plus. Not much insight. Pleasant generally, but essentially non-productive. Slept easily at post-lunch nap time. Had trouble sleeping near midnight. Had to take a Restoril. Sleep okay, but like , dreams slightly annoying and repetitive.”
(with 4.0 mg, orally) “Slight nausea with no problem at an hour, and then developed to a plateau for about a ++ for the three to seven hour slot. I slept but was still not baseline at the 16 hour point. A wonderful drug for interacting with others and formulating ideas. It bestows a remarkable ability to multi-task mental activities. No hang-over the next day, in fact quite the reverse. Can’t wait to try 5 milligrams.”
(with 4.5 mg, orally) “I started with 3.0 milligrams and with the complete absence of physical malaise I supplemented with 1.5 milligrams at two hours. There were some shakes appearing, but there was a super window-state that developed, not intellectual, not psychotic, but things are crawling. At five hours fully +++ but some beginning to drop, but drop very slowly. The mental memory was there still at nine hours and the mental memory at twelve hours. There was teeth clench.”
(with 0.8 mg of the R-isomer) “I feel excellent, but I felt excellent before the experiment. No drug effect.”
(with 1.5 mg of the R-isomer, orally) “There is a faint light-head-light body feel about two hours into it. And light diarrhea at the fourth hour. Certainly nothing at 6 hours.”
(with 3.0 mg of the R-isomer, orally) “I am aware at one hour, and to a real plus one at three hours. Still real at four hours, vaguely pleasant, and the diarrhea is right on schedule. Pretty much out of whatever this was, by eight hours.”
(with 0.8 mg of the S-isomer, orally) “There is an honest threshold, a real tingle at one hour. This clearly is the active isomer. At 2 1/2 hours, this is pushed up to a plus one, , not just in the body but there is something active in the head. At the third hour, everything seems stable, there is complete diarrhea, the body knows that it has been affected, but there is some mental still. Six hours dropping, eight hours clear, but there are body memories.”
(with 2.4 mg of the S-isomer, orally) “I took 1.5 milligrams initially, and was aware in a half hour. No nausea, but diarrhea. Stuck at a mental plus two at three hours, so I augmented this with another 0.9 milligrams. The supplement became apparent in another half hour, and I was at a +++ in short order. Not too much in the way of eyes-open visual effects, but there was a thorough intoxication that lasted for another three hours. Attempted sleeping at fifteen hours failed—I am far too guarded to sleep. Finally OK, but I don’t remember my dreams. Next morning, the body still not completely baseline. Is this ever the active isomer!”
EXTENSIONS AND COMMENTARY: From the point of view of the neuropharmacologist, this has to be one of the most appealing and seductive of compounds. (5-HT) is the “in” neurotransmitter, and the first receptor system that is looked at in any research lab working with psychedelic drugs. An association with serotonin is a strong justification for grant writing and funds solicitation from the mother of most medical research funding, the branches of the National Institutes of Health in Washington. Although this specific neurotransmitter is a big item in the brain, if you feed it to a person, or put it into him via the blood or tissue, it can’t get there. It has no way of moving this specific molecule from the outside of the brain (the periphery) into the brain itself (the central Kingdom).
Two obstacles effectively prohibit this availability. has a free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a big polar water-loving pimple which denies it any passage across the brain’s defensive Maginot Line, the blood-brain barrier. And there is the second problem. There is a exposed amino group, the amine of T of 5-HT, the tryptamine, which is immediately removed by the body’s monoamine oxidase enzyme. In short, it is blocked from entry into the brain because it is both too polar and too metabolically fragile.
The structure of alpha-O is designed to overcome these two restrictions. A methyl group on the oxygen (the O-methyl) removes the polarity restriction. A methyl group next to the amine function (the alpha-methyl) protects the molecule from enzymatic attack. With the two obstacles removed, this compound apparently has easy access directly to the brain. Hence, alpha,O-dimethylserotonin (α,O-DMS) goes directly into the central nervous system and has proved to be one of the most potent tryptamines yet described. And it is active following oral administration, where it is exposed to all of the body’s protective machinery.
I have been sent one report from an anonymous source, that told me that the compound did not have any increased potency when it was smoked. His report was with 5 milligrams, and said: “Not too intense a smell, but it has quite a bite. Slow onset, unlike . After a few minutes there was some dizziness, light giddiness, dysphoria, stretching of the limbs, some gastrointestinal disturbances, a sense of the body floating, and pupil dilation. Even with the eyes closed, and concentration, there were only indistinct visual hallucinations. With the eyes open, a strong intensification of colors, and a harmonization of visual impressions just like everything was ‘velvet coated and has its own mystical movement.’ Sleep was restless and on the next day there were some remaining effects with tiredness and mental exhaustion.” If the oral and a parenteral route indeed both produce the same effects and show the same potency, the argument against metabolic catabolism may be valid. This would be an interesting experiment to repeat.
An additional complication and opportunity is provided by the fact that the placement of the methyl group on the alpha-position introduces a chiral carbon. The R- and S-isomers have been compared (see in the Qualitative Comments section) and the S-isomer is clearly three or four times more potent that the R-isomer. These were assayed completely blind, with the code having been broken only after the completion of the study. The dramatic differences in potency let the assignment of the more active isomer be made without hesitation. This S-isomer is the d- or dextrorotary one, and has the absolute configuration of the active member of the isomer pairs of , of and of . All the psychedelic derivatives (all that have been assayed, that is) have the R-isomer as the more potent one.
Some half of the subjects I specifically queried as to their sleeping patterns confirmed my own observation that the dreams were generally negative. A few actually had memories of catastrophes or high danger. This, coupled with the extremely high potency of this compound and many options for structural variation, allows a treasure trove of speculation. The 5-methoxy group is in every way the positional analogue of the 4-substituent in the world. Would the 5-ethoxy, the 5-isopropoxy, the 5-something-else-oxy provide psychedelic compounds? Would alpha-ethyl or higher provide anti-depressants, as had been seen with and related phenethylamines? Would N-substitution (N-methyl, N-isopropyl, N,N-dimethyl, N-methyl-N-isopropyl) lead to orally active things with increased potency or increased drama? Would any of these changes improve the ratio of mental effects over the body toxicity? Are the occasional nightmares reported with sleep following alpha-O unique to this compound, or might a specific dream-modifying agent be uncovered with structural modifications?
I am aware of one of these modifications, specifically on that magical 5-methoxy-position. This is the sterically similar, but metabolically totally dissimilar fluorine analogue, 5-fluoro-alpha-methyltryptamine, or 5-F-. The fluorine atom is the darling of the manipulators of molecular structure in that it is a form of fake hydrogen. True, as an atomic lump on an aromatic ring it is a lot larger and a lot heavier, but it is a lump that doesn’t like to associate with anything else. It’s bonding with a ring carbon is the same sort of two-electron bond that the hydrogen atom makes, but it cannot be oxidized off in the same way. So, when a drug has a position of sensitivity to oxidation, and that oxidation is thought to be responsible for some particular pharmacological property, put a fluorine there and you will deny the drug that property. This was discussed in the section on where the metabolism attacks a 6-position hydrogen.
And it may play such a role here. When one balances the sort-of stimulant nature of with the potent psychedelic properties of α,O-DMS, one can ask if the oxidation of the tryptamine system at this 5-position can be of some significance. Tryptamine becomes by this action. becomes by this action. If there is some extension of this to the α-MT world, then the placement of a fluoro group at that position of attack would be interesting. has been made, and it appears to be of reduced activity in man. But it has proven to be an extremely potent monoamineoxidase inhibitor, and strongly influences the brain serotonin levels. The 6-fluoro isomer, , is also effective.
This kind of molecular manipulation is the ultimate treasure of the research pharmacologist. The taking off of one atom and the replacement of it with another. This is the simplest single maneuver that can be done to a drug, and any change in the observed pharmacology must be the result of that change. Some of the explorations have been described in this book are of exactly this nature. Some have been tried. Most have not and are completely unknown. All must eventually be explored if we ever hope to learn what is going on up there in the human mind.
[Erowid online version editor’s note: The initial online version of this page was missing several experience reports. Added with the help of AH, July 2005.]
13 May 2016 · Creative Commons BY-NC-SA ·

About TiHKAL · info

This version of Book II of TiHKAL is based on the Erowid online version created by Bo Lawler with the help of Erowid, from content generously provided in electronic format by the Authors.
The Erowid online version does not always align precisely with the printed version. Text appears to have been inserted, deleted, or changed at various points. Where the two are seen to diverge both the Erowid and print versions are given. Sharp-eyed readers are encouraged to report novel discrepancies.
As with PiHKAL, I’ve again attempted to reproduce the typographic style of the printed edition. I’ve again 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

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The copyright for Book I of TiHKAL has been reserved in all forms and it may not be distributed. Book II of TiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.

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TiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of tryptamines. 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 TiHKAL 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.
TiHKAL (ISBN 0-9630096-9-9) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.
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