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 3x60 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 3x75 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
mescaline, missing only the intense color enhancement. The world is
filled with distorted. moving things. Then my little fingers on both
hands got periodically numb. And there was an occasional
light-headedness that hinted at fainting. The two phenomena
alternated, and never got in each other's ways. Both passed, once I
realized that I would recover from this experience. Then the humor
and joy of the world returned. The drop-off was quite rapid from the
fifth to eighth hour, and no effects remained at all by the twelfth
hour.
(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 TMA from the
classic 3,4,5-positions to this new, 2,4,5-orientation, would
dramatically increase potency like this. Mescaline,
3,4,5-trimethoxyphenethylamine, is an extraordinary compound, but it
is not particularly potent, requiring hundreds of milligrams for a
trip. And going from its 3,4,5-pattern to the 2,4,5-pattern of TMPEA
makes the compound even less potent. There was essentially nothing
reported in the scientific literature about central activity of
2,4,5-substituted stuff, so there could not have been any logical
preparation for the activity of TMA-2. My very first trials were with
a rather liberal 400 micrograms, and the levels being explored leaped
up in fairly large steps, mostly on separate days. On November 26,
1962, at 6:00 AM, when 12 milligrams proved to be inactive, another 12
milligrams went in and down an hour later. This was the 24 milligram
discovery experiment, a fragment of which is given above. The anxiety
of being thrust into the unknown certainly played a role in what can
now be seen as obvious psychosomatic difficulties.
The unexpected ten-fold increase of effectiveness uncovered by the
simple relocation of a single methoxy group of TMA gave the further
juggling of methoxy groups a very high priority. There are a total of
six arrangements possible for the three groups, namely, 3,4,5- (the
original TMA), 2,4,5- (the present TMA-2), and then and in systematic
sequence, 2,3,4-, 2,3,5-, 2,3,6-, and 2,4,6. These compounds were
totally unknown at that time, and they could and would be assigned the
sequential names TMA-3, TMA-4, TMA-5 and TMA-6, respectively. I made
them all, and they are all included in this book.
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 TMA. The
natural skeleton is found in asarone, with alpha-asarone being
trans-propenyl, beta-asarone the cis-propenyl and gamma-asarone (also
called euasarone) being the allyl-isomer. I had mentioned, in the
spice cabinet discussion under TMA, the tasting of asarone at up to 70
milligrams without any effects.
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 2,beta-dihydroxy-4,5-dimethoxyphenethylamine. It had
everything. The 6-hydroxydopamine hydroxy group and the rest of the
dopamine molecule intact as represented by the two methoxyl groups.
And the beta-hydroxy group gave it the final "norepinephrine" touch.
And, with due modesty, we proposed that it might be "an endogenous
psychotogen." Why not "the endogenous psychotogen?" And then, to
compound the picture, what should arrive in the mail a month or two
later, and from a most respected scientist, but a sample of just this
stuff, synthesized for our investigations. I must have bought a
little of my own promotion, as I noted that even after my first four
graded dosages with the compound, I was still only up to a 250
microgram dose. And then, as the sample became increasingly brown and
was clearly decomposing, the project was finally abandoned.
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.
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