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#168 TMPEA

2,4,5-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 39.2 g 2,4,5-trimethoxybenzaldehyde in 160 mL nitromethane there was added 7.0 g anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excesssolvent/reagent was removed under vacuum, leaving a deeply colored residue that spontaneously crystallized. This was mechanically removed and triturated under 60 mL cold MeOH. Filtration, washing with cold MeOH and air drying, gave 49.3 g of bright orange crystals. Trial recrystallizations from EtOAc gave a mp of 132-133 °C; from CH3CN, 130.5-131.5 °C. The entire product was recrystallized from 1.1 L boiling IPA to provide, after filtration, IPA washing, and air drying, 34.5 g of beta-nitro-2,4,5-trimethoxystyrene as yum-yum orange crystals with a mp of 132-133 °C. Literature values are usual one-degree ranges, anywhere in the area of 127-130 °C.

To a suspension of 30 g powdered LAH in 800 mL of well stirred and refluxing anhydrous THF there was added a solution of 34.9 g beta-nitro-2,4,5-trimethoxystyrene in 200 mL anhydrous THF. The mixture was maintained at reflux for an additional 36 h, cooled, and the excess hydride activity destroyed by the addition of 30 mL H2O followed by 30 mL 15% NaOH, and finally with another 90 mL H2O. The solids were removed by filtration, washed with THF, and the pooled mother liquor and washings stripped of solvent under vacuum. The residue was dissolved in CH2Cl2, washed with both 5% NaOH and then H2O, removing much of the color. It was then extracted with 3x75 mL N HCl. The pooled red-colored acid extracts were washed with CH2Cl2, made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. Removal of the solvent gave some 25 g of residue which was dissolved in 100 mL IPA and neutralized with concentrated HCl. The crystalline mass that formed was diluted with an equal volume of Et2O, and the solids removed by filtration. Washing with cold IPA, followed by Et2O and air drying, gave 17.7 g of 2,4,5-trimethoxyphenethylamine hydrochloride (TMPEA) as a white product. The reported melting point was 187-188 °C.

DOSAGE: greater than 300 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with less than 300 mg) Since it was not easy, however, to judge the extent of a 'Rausch'-action from experiments on animals, some injections of beta-2,4,5-trimethoxyphenethylamine were administered to the author, and finally a control test was carried out with an equal quantity of mescaline. The action of both these substances in these experiments agreed only to a limited extent with the effects described for mescaline by, for example, Beringer. It must be remembered, however, in this connection, that the quantities used by Beringer were larger than the doses administered in these experiments. Nevertheless, it may be concluded that the pharmacological action of beta-2,4,5-trimethoxyphenethylamine agrees to a large extent with that of mescaline. However, the new compound had more unpleasant secondary effects (nausea) and did not bring about the euphoristic state caused by mescaline.

(with 300 mg) Under double blind conditions, I was unable to distinguish this from a placebo. Both were without any of the changes described after the ingestion of psychotomimetic drugs.

(with 200 mg, followed after 45 minutes, with 100 mg mescaline) RThe normally modest effects known to be due to mescaline alone at this level, were strongly potentiated with the earlier taking of 2,4,5-TMPEA. The effects were stronger as well as longer lived.

EXTENSIONS AND COMMENTARY: The code letters used for this drug are not as ambiguous as they might seem at first glance. A large number of the 2-carbon homologues are given names based on the code for the 3-carbon compound. On that basis, this should be 2C-TMA-2, since it is the 2-carbon counterpart of TMA-2. But since the first of the trimethoxyphenethylamines already had a trivial name, mescaline, the code TMPEA was unassigned. So, here is the logical place to use it.

There have been just two reports published of self-experimentation with TMPEA, and these comments are taken from them.

The first is presented here, word for word, as it was originally published (this was in 1931). It leaves much to be desired. The administration was by injection (intramuscular injection?). The dose was not given, but it was less than those reported by Beringer in his studies with mescaline, and this latter experimenter's published levels were all between 300 and 500 milligrams. What can one conclude from all this? Only that TMPEA apparently did not measure up to mescaline in his comparisons.

The second, reported some 40 years later, is not really contradictory. Here the TMPEA was administered orally, and the subject surrounded himself with a battery of psychological tests. This might allow statistics to provide an aura of validity to the observations. But the comments are pretty self-explanatory. The drug was not active in its own right, but when employed preliminary to mescaline, greatly enhanced the effects of the latter.

This is an area of research that deserves more attention. The simple compound that results from the stripping of all three of the O-methyl groups from TMPEA is the extremely potent neurotoxin, 6-hydroxydopamine. When it is ad-ministered to an otherwise intact experimental animal, it produces sympathectomy, effectively destroying the sympathetic nervous system. And some of the methyl groups of TMPEA are known to be stripped off through the normal metabolic processes that occur in the liver. There are many fascinating psychedelics that have a signature of methoxyl groups para to one-another. It is known that they, too, can lose a methyl group or two. It would be intriguing to see if there was some biochemical overlap between the metabolism of some of these centrally active drugs and the metabolic fate of 6-hydroxydopamine. But in a test animal, of course, rather than in man.

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