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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