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#39. 4-MEO-MIPT


[3D .mol structure]
SYNTHESIS : A solution of 4.0 g of 4-methoxytryptamine in 50 mL toluene was combined with another containing 5.52 g K2CO3 in 50 mL H2O and vigorously stirred at room temperature. To this there was added, dropwise, a solution of 3.0 mL benzyl chloroformate in 20 mL toluene. Stirring was continued for 15 h, then the reaction was treated with 200 mL EtOAc, the organic layer separated, and dried with anhydrous MgSO4. After filtration, the solvent was removed under vacuum, and the solid residue recrystallized from Et2O / hexane to give 3.9 g N-(benzyloxycarbonyl)-4-methoxytryptamine with a mp of 84 °C. Anal: C19H20N2O3. C,H,N.

A suspension of 0.76 g LAH in 50 mL THF was stirred under an inert atmosphere, and treated with the dropwise addition of a solution of 2.5 g N-(benzyloxycarbonyl)-4-methoxytryptamine in 30 anhydrous THF. The reaction mixture was held at reflux for 30 min, then cooled to 40 °C and the excess hydride destroyed with the addition of 50% aqueous THF. The solids were removed by filtration, washed with THF, the filtrate and washings combined, and the solvent removed under vacuum. The residue, impure 4-methoxy-N-methyltryptamine, was dissolved in 50 mL ethanol, treated with 1.0 mL acetone, then with 0.5 g 10% Pd / C, and the reaction mixture shaken under a hydrogen atmosphere at 50 psi for 15 h. The catalyst was removed by filtration through a bed of Celite, the filtrate stripped of solvent under vacuum, and the solid residue recrystallized from Et2O / hexane to give 0.51 g 4-methoxy-N-methyl-N-isopropyltryptamine (4-MeO-MIPT) which had a mp 80-81 °C. Anal: C15H22N2O. C,H,N. MS (in m/z): C5H12N+ 86 (100%); indolemethylene+ 160 (4%); parent ion 246 (6 %).

DOSAGE : 20 - 30 mg, orally

DURATION : 4 - 6 hrs

QUALITATIVE COMMENTS : (with 10 mg, orally) "In 30-40 minutes, I found I could get some distortions of objects around me, if I really tried hard. There are no color changes. It is unexpectedly mild, and I have no anxiety, no tachycardia. At the two hour point, the peak must be past, and I feel somehow disappointed. I am not sure, in retrospect, if there was ever anything there at all."

(with 17 mg, orally) "I am aware of this at 40 minutes, and was in a very light but not very well defined place for about two hours. It was neither good nor bad. It kind of drifted away and I was not sure when I regained baseline."

(with 26 mg, orally) "I took this orally, in dilute hydrochloric acid so that it would be in solution going down. I was aware in 20 minutes, and went right up to a +3 within the hour. That was quite a bit of change in a half hour. Extremely erotic, but absolutely no visuals to music, either with eyes open or with them closed. I know I am at +3 since there is no way I could drive a car, not for anything in the world, but why not? Don't know, but no way. Cold gespatcho tastes superb, but one cup is enough, and the croissant seems dry and hard. By seven hours I am back where I started from again. Pity."

(with 26 mg, orally) "This is my first try with this drug, ever. First indications of effects in twenty minutes. Quiet onset, no remarkable visuals, in fact no particular visuals at all. To a plus two within about ten or fifteen minutes more. Body is comfortable, mind-set pretty much unchanged from baseline. No euphoria, no insights. But also, no discomfort. Erotic was extremely successful, and orgasm seemed easier than with other materials. Still no visuals but seemed to be a soft plus three. Music fine. Hard to define exactly how we knew we were in an altered state, because of the lack of visual clues. Body aware more than mind. Would like to explore this further. Perhaps for writing? Nice material. Maybe higher next time?"

EXTENSIONS AND COMMENTARY : It would be nice if this compound were not so very difficult to make. It seems to me to be somehow a pivotal compound, in that it carries the pattern of nitrogen substituents that appears to be the most effective orally (the methyl group and the isopropyl group) and it is oxygenated in the aromatic ring. Both the 4-hydroxy analogue (4-HO-MIPT) and the 5-methoxy analogue (5-MeO-MIPT) are very active at these levels. Perhaps if the oxygen is in the 4-position, it must be exposed as in psilocin, to reveal an active zwitterion. And if the oxygen is in the 5-position, it must be masked as a methyl ether to hide its intrinsic polarity. But these are observations, not explanations. Why is this compound 4-MeO-MIPT, so seductive and appealing a hybrid, not as potent as one might expect? The remaining two, the 6-isomer and the 7-isomer, are described in the recipe for 5-MeO-MIPT.

A similar discussion could be made about the corresponding compounds that possess the N,N-dimethyl pattern of DMT. Again, there are a total of four possible ring-methoxylated isomers. The 5-substituted compound is 5-MeO-DMT and, as it is remarkably potent, it is given its own entry. However, the other three monomethoxy analogues, 4-methoxy-, 6-methoxy- and 7-methoxy-N,N-dimethyltryptamine, remain relatively unknown.

The 4-methyl ether of psilocin, 4-MeO-DMT, is especially appealing, in that it is a simple homologue of psilocin and it is quite stable. But the methyl group as an ether link lacks the lability of the phosphate or acetate esters, and it cannot be easily hydrolyzed off to form psilocin. The immediate homologue is 4-MeO-DET which is completely without action either orally or by smoking at dosages up to 30 mgs. The two remaining DMT isomers are with the methoxy at the 6-position (to give 6-MeO-DMT originally thought to be a minor alkaloid in B. caapi) and at the 7-position (to give 7-MeO-DMT which was observed as a minor impurity in the preparation of 7-MeO-MIPT). Some rat studies were performed in the mid 60's on all three of these compounds. A couple of years later the 4-isomer was studied in the squirrel monkey and found to have weak central activity (size discrimination studies with rewards of grapes, underwater maze running with rewards of simply being allowed to survive). These studies suggested that it was not very potent, certainly much less potent than 5-MeO-DMT, but no trial has as yet been reported in man for any of these three isomers. If this lower potency were to hold up in human trials, it would give additional support to the positional parallels between the "4-position" of the phenethylamines, and the "5-position" of the tryptamines. That is where, indeed, the action is to be found. All of these methoxylated DMT analogues will probably be pretty easily destroyed metabolically, so some parenteral route might have to be used in exploring them. Right here, in the above preparation, 4-methoxy-N-methyltryptamine (4-MeO-NMT) has been made as a chemical intermediate, but it was not characterized, and no spotlight was put on it as a potential drug in its own rights. It is the ether that corresponds to the natural ester baeocystine, and it probably wouldn't come off gracefully, either chemically or metabolically. There is yet another mushroom analogue here. The starting material is the bare tryptamine itself, 4-MeO-T, which is the ether counterpart to norbaeocystine.

The bottom line is, that all of these intriguing compounds are largely strangers to us.

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