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#50 4-D

3,5-DIMETHOXY-4-TRIDEUTEROMETHOXY-PHENETHYLAMINE


SYNTHESIS: To a solution of 34.0 g homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under ESCALINE for its preparation) in 350 mL acetone containing 0.5 g decyltriethylammonium iodide, there was added 25 g trideuteromethyl iodide followed by 50 g of finely powdered anhydrous K2CO3. This mixture was held at reflux on a steam bath for 12 h, added to 2 L of dilute HCl, and extracted with 3x100 mL of CH2Cl2. The extracts were washed with 5% NaOH, and the solvent removed under vacuum, yielding 28.0 g yellow solids. These were distilled at 135-150 °C at 0.5 mm/Hg providing 19.4 g 3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile which melted at 76.5-77.5 °C after crystallization from toluene, or 77-78 °C from methylcyclohexane/CHCl3 3:1. The mp of the proteo-reference compound, from toluene, was 77-78.5 °C. The OCD3 stretch in the infra-red occured at 2072 cm-1.

A solution of 275 mL of 1.0 M LAH in THF was cooled under He to 0 °C and treated with 7.25 mL 100% H2SO4 added very slowly with vigorous stirring. A solution of 19.3 g 3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile in 200 mL anhydrous THF was added slowly, and following the addition stirring was continued for 20 min. The reaction mixture was brought to a reflux for 30 min on a steam bath, cooled again to 0 °C, and the excess hydride destroyed with 25 mL IPA. About 15 mL of 15% NaOH was required to convert the solids to a filterable white consistency. These were removed by filtration, the cake washed with IPA, the filtrates and washes were combined, and the solvent removed under vacuum leaving a white oil as residue. This was dissolved in 1.5 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 18.5 g of a colorless oil which was distilled at 120-150 °C at 0.5 mm/Hg to provide 13.5 g of a white oil. This was dissolved in 70 ml IPA and neutralized with concentrated HCl, producing spontaneous crystals. These were removed by filtration, washed first with IPA then with anhydrous Et2O. After air drying, the final yield of 3,5-dimethoxy-4-trideuteromethoxyphenethylamine hydrochloride (4-D) was 13.50 g.

DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the hydrochloride salt).

DURATION: 12 h.

QUALITATIVE COMMENTS: (with 275 mg) The onset was smooth and gradual. Within the hour, the slight queasiness I experienced (not as much as with mescaline) completely disappeared. Some visual enhancement, good energy, good communication. It was a very special day for me as I was in a good place pretty much the whole day, and able to communicate clearly without deeper feelings getting in the way. While most enjoyable, and at times remarkable fun, I did not experience the intensity I am familiar with, with mescaline.

(with 300 mg) The taste was bitter to a moderate degree but faded fast. About 40 minutes later the first stirrings of pleasurable experience came on. It was very mild. Twenty minutes after that an unease of the stomach was apparent, and it stayed with me until I ate some crackers an hour or so later. I got no sharpened visual reactions and no physical instability at any time. I did feel a quickening of thought and verbal flow; again, this was mild and unlike my earlier mescaline patter.

(with 350 mg) A rapid onset--alert in 20 minutes. Climbed to a plus two in about one hour and stayed there. During the first two hours had a slight queasiness or pre-nausea, and cold hands and feet, but this all disappeared completely and I became very hungry during the whole latter half of the experience. I did not eat much at any one time, but did a lot of snacking and everything tasted good. Very pleasant after the plateau was reached. Pretty good visuals with eyes closed, but not as bright as 2C-B. Very little visuals with eyes open --some movement and flow of objects--pupils dilated. Spent most of the day lying down--had no aversion to conversation but it felt good just to be still. I was in a funny place I can't quite describe--I was in an 'alert lassitude,' a state of 'interested detachment,' or a place of 'vibrating equanimity' or whatever. While trying to recapture the day, it seemed to me that it was a good day, but that nothing much had really transpired. However, upon reflection, I am startled to find that several important shifts took place. It was a day that allowed some peaceful gear-shifting in the mind.

(with 400 mg) Not a great taste. Some type of awareness at approx. 20 minutes. Considerable nausea peaking at about 1 hr. Some nausea continued through the experience but became quite low. I enjoyed the color show considerably. Trees outside would change color in a wave-like manner. The book-covers upstairs would also change colors and become distorted. Brightly lighted items would undergo the same thing. Believed I could suppress the vision, but concentrating on something would cause it to easily undergo the color and visual changes. Evidently I had little problem following the conversation downstairs, but I remained somewhat quiet. Had an element of confusion that seemed to last for some 4 or 5 hours. Had no problems dropping off to sleep that evening.

EXTENSIONS AND COMMENTARY: The effects of 4-D and beta-D are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although no metabolic studies have ever been published.

A similar deuterium substitution pattern is of course completely feasible with TMA and related 3,4,5-trimethoxy-substituted analogues. Some studies have supported the idea that the ability to remove methyl groups from such aromatic ethers might be correlated to endogenous schizophrenia. It is possible to imagine that, in such individuals, the effects of substituting trideuteromethyl groups for normal methyl groups might result in psychopharmacological differences of action. Two reports exist that describe metabolic products of mescaline that have lost this methyl group on the 4-position oxygen. It is possible that these might be produced in abnormal quantities in mentally ill subjects. There are also similar reports of the 3-methoxyl group being demethylated in man. Here, studies with 3,5-D (3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some differences in quantitative responses in man. These are extremely minor metabolites, however. I suspect that more extensive studies will establish that 4-D, 3,5-D and beta-D all have properties indistinguishable from one-another, at least in healthy subjects.


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