Book II of PiHKAL: A Chemical Love Story. Alexander & Ann Shulgin #158: TMA-2
SYNTHESIS: To a solution of 50 g 2,4,5-trimethoxybenzaldehyde in 175 mL nitroethane there was added 10 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 2 h. The excess nitroethane was removed under vacuum, and the deep orange oily residue was drained out into a beaker, and the flask washed with 3×60 mL boiling MeOH. On stirring the combined decantation and washings, there was a spontaneous formation of crystals. After cooling, these were removed by filtration, washed sparing with MeOH, and air dried to constant weight to yield 35.1 g of 2-nitro-1-(2,4,5-trimethoxyphenyl)propene as yellow crystals with a mp of 98–99 °C. Recrystallization from MeOH increased the mp to 101–102 °C.
A suspension of 31.6 g powdered LAH in 1 L anhydrous THF containing a little anhydrous Et2O was brought to a gentle reflux, and then there was added a solution of 40.0 g of 2-nitro-1-(2,4,5-trimethoxyphenyl)propene in 200 mL anhydrous THF over the course of 4 h. The mixture was held at reflux temperature for 24 h, cooled to 0 °C with external ice, and the excess hydride destroyed by the addition, in sequence, of 32 mL H2O (which had been diluted with a little THF), 32 mL 15% NaOH, and finally with 96 mL H2O. The white inorganic solids were removed by filtration, and the filter cake was washed with THF. The combined filtrate and washings were stripped of solvent under vacuum to give 48 g of an impure amber oil. This was dissolved in 180 mL IPA, neutralized with 30 mL concentrated HCl, and the mixture diluted with 1500 mL anhydrous Et2O. After a short induction period, an oily precipitate separated, which on stirring changed into a loose crystalline phase. This was removed by filtration, washed with Et2O, and air dried to yield 29.0 g of 2,4,5-trimethoxyamphetamine hydrochloride (TMA-2) as fine white crystals with a mp of 188.5–189.5 °C. Anal. (C12H20ClNO3) C,H,N. A 4.0 g sample of the free base was dissolved in 15 mL pyridine, treated with 2.5 mL acetic anhydride, heated on the steam bath for 20 min, added to 400 mL H2O, acidified with HCl, and extracted with 3×75 mL CH2Cl2. After washing with H2O the pooled extracts were stripped of solvent under vacuum to give 4.5 g of flakey, off-white solids which, on recrystallization from MeOH, were white, weighed 2.3 g, and had a mp of 132–133 °C. Recrystallization from this acetamide from MEK did not improve its quality. Anal. (C14H21NO4) C,H,N.
DOSAGE: 20–40 mg.
DURATION: 8–12 h.
QUALITATIVE COMMENTS: (with 20 mg) “I took it in two 10 milligram doses, spaced by two hours. There was a slight movement of surface textures, my hearing was deepened and spatially defined. The body was relaxed and stretching seemed necessary. The further I got into it the more I realized that I was totally lazy. Very lethargic, to the point of laughter. At the sixth hour, I was seeing more life in the woodwork, and the wooden angel hanging on the ceiling was flesh and feathers when I stared at it. Great vision. But by no means overwhelming. Sleep was fine.”
(with 20 mg) “The first two hours seemed like an eternity, with time passing slowly. Then it settled into a very calm and enjoyable event (not that it wasn’t already). The material seemed somewhat hypnotic. I suspect that I would believe suggestions, or at least not challenge them too much. I had a little confusion but it was not troublesome. On reflection, the material was quite good. It was benign in the sense that there appeared to be no dark spots. I would try it again, perhaps at 30 milligrams. Almost base-line after 12 hours, but not quite.”
(with 24 mg) “I took the dosage in two halves, an hour apart. Initially, I was a little nauseous, with light tremors and modest eye dilation. But after another hour, there was the entire package of
(with 40 mg) “Very slow coming on. Didn’t feel it for an hour, but then at a full +++ in another hour. Beautiful experience. Erotic excellent. Eyes-closed imagery and fantasy to music. No dark corners. Benign and peaceful and lovely. There were brief intestinal cramps early, and a little diarrhea, but no other problems. I was able to sleep after eight hours, but had guarded dreams.”
(with 40 mg) “Beautiful plus 3. Some visuals, but not intrusive. Moderate, good-mannered kaleidoscopic imagery against dark. Music superb. Clear thinking. Calmly cosmic. This is a seminal, or archetypal psychoactive material. A very good experience and good for repeats. About 10–12 hrs. Sleep difficult but OK.”
EXTENSIONS AND COMMENTARY: There was absolutely no reason to suspect that the simple rearrangement of the methoxy groups of
The unexpected ten-fold increase of effectiveness uncovered by the simple relocation of a single methoxy group of
Having found the treasure of 2,4,5-ness, it is instructive to look back at nature, to see what its plant equivalents might be. There are indeed a few essential oils that have their methoxy groups in this arrangement. TMA-2 is thus one of the essential amphetamines, and most of the botanical connections are discussed under
A couple of additional experiments involving TMA-2 had been set up and started, but somehow never had enough fire to get completed. Studies on the optical isomers had gotten up to assays of 6 milligrams on each of the separate isomers, but had never been taken higher. The “R” isomer is much the more potent in rabbit assays, but the human comparisons remain unknown at present. Also, a study of the 14C labeled racemate (5 microcuries in 40 milligrams) was conducted with a view to metabolite analysis, but again, the project was abandoned before any results were obtained. In the rat, the 4-methoxyl carbon appeared as expired carbon dioxide to the extent of about 20%. And this is some four times the amount seen from either of the other two methoxyl carbon atoms.
One final memory in the TMA-2 area. About twenty years ago I co-authored a rather thorough review article in the British journal Nature, that described the structure-activity relationships between the simpler one-ringed psychotomimetics. It also quietly served as a vehicle for mentioning a number of newly-discovered compounds and their human activities. But as a magnificent attestment to youth and brashness, we proposed a complex compound that embraced each and every clue and hint that might tie it to the neurological process. This hybrid monster was
A sad note on how things have changed since that time. I recently queried the editors of Nature, about their thoughts concerning a twenty year retrospective of this area, written by the three authors of the original review. We had each followed quite divergent paths, but each of us was still keenly the researcher. It would have been a marvelous paper to put together, and it would have delighted the reading audience of Nature, had it been the audience of twenty years ago. But not today. The journal is now dedicated to neutron stars and x-ray sources. The respected old English journal of interdisciplinary interests is not the grand and curious lady she used to be. The Editor’s reply was polite, but negative. “Such an article would be unsuitable for publication in Nature at present,” they said. And, I am sad to say, they’re right.
And I am afraid that the American counterpart journal, Science, has suffered a similar deterioration. It, too, has abandoned multidisciplinary interest, but in a different direction. They are now dedicated to chromosomes, and nucleotide identification, and are totally captivated by the attention paid to, and the apparent importance of, the human genome project. There is where you automatically go to publish, now, if you have unraveled some DNA sequence from the Latvian cockroach.
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 errata and changes page has further details.
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