#50 4-D SYNTHESIS: To a solution of 34.0 g homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under 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 3×100 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 3×75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3×75 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).
QUALITATIVE COMMENTS: (with 275 mg) “The onset was smooth and gradual. Within the hour, the slight queasiness I experienced (not as much as with ) 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 .”
(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 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 . 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 are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from . 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 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 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-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 all have properties indistinguishable from one-another, at least in healthy subjects.
11 Aug 2018 · ·

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 history page has further details.

Cautionary note

“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.
“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
Alexander T. Shulgin

Copyright notice

The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.

Ordering information

PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.
Transform Press,
Box 13675
Berkeley, CA 94701

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