from PiKHAL [ Phenethylamines i Have Known and Loved ] by Alexander Shulgin

#100 MDA; 3,4-METHYLENEDIOXYAMPHETAMINE

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 produced 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.

HOME

Refs
MDMA
MBDB/Eden
MDMA advert
Claudio Naranjo
Ecstasy in the USA
Accidental Ecstasy?
Ecstasy and Honesty
MDMA/ecstasy: review
Post-E Prozac protection?
Alexander and Ann Shulgin
MDA-assisted psychotherapy
Buying Research Chemicals Online
Alexander Shulgin: "The Godfather of Ecstasy"

"The perception of things and people is not altered or even enhanced, usually, but negative reactions that permeate our everyday lives beyond our conscious knowledge are held in abeyance and replaced by unconditional acceptance. This is much like Nietzsche's amor fati, love of fate, love of one's particular circumstances. The immediate reality seems to be welcomed in such MMDA-induced states without pain or attachment; joy does not seem to depend on the given situation, but on existence itself, and in such a state of mind everything is equally loveable..."
Claudio Naranjo
The Healing Journey