SYNTHESIS: (from piperonal) To a solution of 15.0 g piperonal in 80 mL
glacial acetic acid there was added 15 mL nitroethane followed by 10 g
cyclohexylamine. The mixture was held at steam-bath temperature for 6
h, diluted with 10 mL H2O, seeded with a crystal of product, and
cooled overnight at 10 °C. The bright yellow crystals were removed by
filtration, and air dried to yield 10.7 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene with a mp of 93-94 °C.
This was raised to 97-98 °C by recrystallization from acetic acid.
The more conventional efforts of nitrostyrene synthesis using an
excess of nitroethane as a solvent and anhydrous ammonium acetate as
the base, gives impure product in very poor yields. The nitrostyrene
has been successfully made from the components in cold MeOH, with
aqueous NaOH as the base.
A suspension of 20 g LAH in 250 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically. There was added, dropwise,
18 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in solution in THF
and the reaction mixture was maintained at reflux for 36 h. After
being brought back to room temperature, the excess hydride was
destroyed with 15 mL IPA, followed by 15 mL of 15% NaOH. An
additional 50 mL H2O was added to complete the conversion of the
aluminum salts to a loose, white, easily filtered solid. This was
removed by filtration, and the filter cake washed with additional THF.
The combined filtrate and washes were stripped of solvent under
vacuum, and the residue dissolved in dilute H2SO4. Washing with 3x75
mL CH2Cl2 removed much of the color, and the aqueous phase was made
basic and reextracted with 3x100 mL CH2Cl2. Removal of the solvent
yielded 13.0 g of a yellow-colored oil that was distilled. The
fraction boiling at 80-90 °C at 0.2 mm weighed 10.2 g and was
water-white. It was dissolved in 60 mL of IPA, neutralization with
concentrated HCl, and diluted with 120 mL of anhydrous Et2O which
produced a lasting turbidity. Crystals formed spontaneously which
were removed by filtration, washed with Et2O, and air dried to provide
10.4 g of 3,4-methylenedioxyamphetamine hydrochloride (MDA) with a mp
of 187-188 °C.
(from 3,4-methylenedioxyphenylacetone) To a solution of 32.5 g
anhydrous ammonium acetate in 120 mL MeOH, there was added 7.12 g
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 2.0 g sodium cyanoborohydride. The resulting yellow
solution was vigorously stirred, and concentrated HCl was added
periodically to keep the pH of the reaction mixture between 6 and 7 as
determined by external damp universal pH paper. After several days,
undissolved solids remained in the reaction mixture and no more acid
was required. The reaction mixture was added to 600 mL of dilute HCl,
and this was washed with 3x100 mL CH2Cl2. The combined washes were
back-extracted with a small amount of dilute HCl, the aqueous phases
combined, and made basic with 25% NaOH. This was then extracted with
3x100 mL CH2Cl2, these extracts combined, and the solvent removed
under vacuum to provide 3.8 g of a red-colored residue. This was
distilled at 80-90 °C at 0.2 mm/Hg to provide 2.2 g of an absolutely
water-white oil. There was no obvious formation of a carbonate salt
when exposed to air. This was dissolved in 15 mL IPA, neutralized
with 25 drops of concentrated HCl, and diluted with 30 mL anhydrous
Et2O. Slowly there was the deposition of white crystals of
3,4-methylenedioxyamphetamine hydrochloride (MDA) which weighed 2.2 g
and had a mp of 187-188 °C. The preparation of the formamide (a
precursor to MDMA) and the acetamide (a precursor to MDE) are
described under those entries.
DOSAGE: 80 - 160 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 100 mg) The coming on was gradual and
pleasant, taking from an hour to an hour and one half to do so. The
trip was euphoric and intense despite my having been naturally
depleted from a working day and having started so late. One thing
that impressed itself upon me was the feeling I got of seeing the play
of events, of what I thought to be the significance of certain people
coming into my life, and why my `dance', like everyone else's, is
unique. I saw that every encounter or event is a potential for
growth, and an opportunity for me to realize my completeness at where
I am, here and now, not at some future where I must lug the pieces of
the past for a final assemblage `there.' I was reminded of living the
moment to its fullest and I felt that seeing this was indicative that
I was on the right track.
(with 128 mg) Forty-five minutes after the second dosage, when I was
seated in a room by myself, not smoking, and where there was no
possible source of smoke rings, an abundance of curling gray smoke
rings was readily observed in the environment whenever a relaxed
approach to subjective observation was used. Visually these had
complete reality and it seemed quite unneccessary to test their
properties because it was surely known and fully appreciated that the
source of the visual phenomena could not be external to the body.
When I concentrated my attention on the details of the curling gray
forms by trying to note how they would be affected by passing a finger
through their apparent field, they melted away. Then, when I relaxed
again, the smoke rings were there. I was as certain that they were
really there as I am now sure that my head is on top of my body.
(with 140 mg) I vomited quite abruptly, and then everything was OK.
I had been drinking probably excessively the last two days, and maybe
the body needed to unpoison itself. The tactile sense is beautiful,
but there seems to be some numbness as well, and I feel that nothing
erotic would be do-able. Intimacy, yes, but no performance I'm pretty
sure. I saw the experience start drifting away only four hours into
it, and I was sad to see it go. It was an all around delightful day.
(with 200 mg, 2x100 mg spaced 1 h) The first portion was apparent at
one-half hour. There was microscopic nausea shortly after the second
portion was taken, and in an hour there was a complete +++ developed.
The relaxation was extreme. And there seemed to be time distortion,
in that time seemed to pass slowly. There was a occasional LSD-like
moment of profoundness, but by and large it was a simple intoxication
with most things seeming quite hilarious. The intoxication was also
quite extreme. Some food was tried later in the experiment, and it
tasted good, but there was absolutely no appetite. None at all.
(with 60 mg of the "R" isomer) There was a light and not too gentle
development of a somewhat brittle wound-up state, a + or even a ++.
Chills, and I had to get under an electric blanket to be comfortable.
The effects smoothed out at the fourth hour, when things started to
return to baseline. Not too entertaining.
(with 100 mg of the "R" isomer) Rapid development from the 40 minute
point to an hour and a quarter; largely a pleasant intoxication, but
there is something serious there too. No great insights, and not too
much interference with the day's goings-on. Completely clear at the 8
hour point.
(with 120 mg of the "R" isomer) This is a stoning intoxicant. I
would not choose to drive, because of possible judgement problems, but
my handwriting seems to be clear and normal. The mental excitement
dropped rapidly but I was aware of physical residues for several
additional hours.
(with 80 mg of the "S" isomer) A very thin, light threshold, which is
quite delightful. I am quite willing to push this a bit higher.
(with 120 mg of the "S" isomer) Perhaps to a one +. Very light, and
very much like MDMA, but perhaps shorter lived. I am pretty much
baseline in three hours.
(with 160 mg of the "S" isomer) The development is very rapid, and
there is both muscular tremor and some nausea. The physicals are
quite bothersome. With eyes closed, there are no effects noticeable,
but with eyes open, things are quite bright and sparkling. The
muscular spasms persist, and there is considerable teeth clenching. I
feel that the mental is not worth the physical.
EXTENSIONS AND COMMENTARY: There are about twenty different synthetic
routes in the literature for the preparation of MDA. Many start with
piperonal, and employ it to make methylenedioxyphenylacetone or a
methylenedioxydihydro-cinnamic acid amide instead of the nitrostyrene.
The phenylacetone can be reduced in several ways other than the
cyanoborohydride method mentioned here, and the amide can be
rearranged directly to MDA. And there are additional methods for the
reduction of the nitrostyrene that use no lithium aluminum hydride.
Also there are procedures that have safrole or isosafrole as starting
points. There is even one in the underground literature that starts
with sassafras root bark. In fact, it is because safrole is one of
the ten essential oils that MDA can humorously be referred to as one
of the Ten Essential Amphetamines. See the comments under TMA.
There is a broad and checkered history concerning the use and abuse of
MDA, and it is not the case that all the use was medical and all the
abuse was social. One of the compulsive drives of both the military
and the intelligence groups, just after World War II, was to discover
and develop chemical agents which might serve as "truth serums" or as
incapacitating agents. These government agencies considered the area
of the psychedelics to be a fertile field for searching. The giving
of relatively unexplored drugs in a cavalier manner to knowing and
unknowing subjects was commonplace. There was one case in 1953,
involving MDA and a psychiatric patient named Howard Blauer that
proved fatal. The army had contracted with several physicians at the
New York State Psychiatric Institute to explore new chemicals from the
Edgewood Arsenal and one of these, with a chemical warfare code number
of EA-1298, was MDA. The last and lethal injection into Blauer was an
intravenous dose of 500 milligrams.
There have been a number of medical explorations. Under the code
SKF-5 (and trade name of Amphedoxamine) it was explored as an anorexic
agent. It has been found promising in the treatment of psychoneurotic
depression. There are several medical reports, and one book (Claudio
Naranjo's The Healing Journey), that describe its values in
psychotherapy.
MDA was also one of the major drugs that was being popularly used in
the late 1960's when the psychedelic concept exploded on the public
scene. MDA was called the "hug-drug" and was said to stand for Mellow
Drug of America. There was no difficulty in obtaining unending
quantities of it, as it was available as a research chemical from
several scientific supply houses (as were mescaline and LSD) and was
sold inexpensively under its chemical name.
A few experimental trials with the pure optical isomers show a
consistency with all the other psychedelic compounds that have been
studied in their separated forms, the higher potency with the "R"
isomer. The less potent "S" isomer seemed to be more peaceful and
MDMA-like at lower doses, but there were worrisome toxic signs at
higher levels.
The structure of MDA can be viewed as an aromatic ring (the
3,4-methylenedioxyphenyl ring) with a three carbon chain sticking out
from it. The amine group is on the second of the three carbon atoms.
The isomers, with the amine function moved to the first of these
carbons atoms (a benzylamine) and with the amine function moved to the
third (furthest out atom) of these carbon atoms (a (n)-propylamine),
are known and both have been assayed.
The benzylamine counterpart (as if one were to move the amine function
from the beta-carbon to the alpha-carbon of the three carbon chain of
the amphetamine molecule) is alpha-ethyl-3,4-methylenedioxybenzylamine
or 1-amino-1-(3,4-methylenedioxyphenyl)propane, ALPHA. The
hydrochloride salt has a mp of 199-201 °C. At low threshold levels
(10 milligram area) there were eyes-closed "dreams" with some body
tingling. The compound was not anorexic at any dose (up to 140
milligrams) and was reported to produce a pleasant, positive feeling.
It is very short-lived (about 3 hours). The N-methyl homologue is
alpha-ethyl-N-methyl-3,4-methylenedioxybenzylamine or
1-methylamino-1-(3,4-methylenedioxy-phenyl)propane, M-ALPHA. It is
similar in action, but is perhaps twice as potent (a plus one or plus
two dose is 60 milligrams) and of twice the duration.
The (n)-propylamine counterpart (as if one were to move the amine
function the other direction, from the beta-carbon to the gamma-carbon
of the three carbon chain of the amphetamine molecule) is
gamma-3,4-methylenedioxyphenylpropylamine or
1-amino-3-(3,4-methylenedioxyphenyl)propane, GAMMA. The hydrochloride
salt has a mp of 204-205 °C. At oral levels of 200 milligrams there
was some physical ill-at-ease, possible time distortion, and a feeling
of being keenly aware of one's surroundings. The duration of effects
was 4 hrs.
The phenethylamine that corresponds to MDA (removing the alpha-methyl
group) is 3,4-methylenedioxyphenethylamine, or homopiperonylamine, or
MDPEA, or simply H in the vocabulary of the Muni-Metro world. This
compound is an entry in its own rights. The adding of another carbon
atom to the alpha-methyl group of MDA gives compound J, and leads to
the rest of the Muni-Metro series (K, L etc). All of this is
explained under METHYL-J. The bending of this alpha-methyl group back
to the aromatic ring gives an aminoindane, and with J one gets an
aminotetralin. Both compounds react in animal discrimination studies
identically to MDMA, and they appear to be free of neurochemical
toxicity.
The two possible homologues, with either one or two methyl groups on
the methylene carbon of the methylenedioxy group of MDA, are also
known. The ethylidene compound (the acetaldehyde addition to the
catechol group) has been encoded as EDA, and the acetone
(isopropylidine addition to the catechol group) is called IDA. In
animal discrimination studies, and in in vitro neurotransmitter
studies, they both seem to be of decreased potency. EDA is down two
to three-fold from MDA, and IDA is down by a factor of two to
three-fold again. Human trials of up to 150 milligrams of the
hydrochloride salt of EDA producd at best a threshold
light-headedness. IDA remains untested as of the present time. The
homologue of MDA (actually of MDMA) with the added carbon atom in,
rather than on, the methylenedioxy ring, is a separate entry; see
MDMC.
A final isomer to be mentioned is a positional isomer. The
3,4-methylene-dioxy group could be at the 2,3-position of the
amphetamine skeleton, giving 2,3-methylenedioxyamphetamine, or
ORTHO-MDA. It appears to be a stimulant rather than another MDA. At
50 milligrams, one person was awake and alert all night, but reported
no MDA-like effects.
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