MDMA.pdf

MDMA; MDM; ADAM; ECSTASY;

3,4-METHYLENEDIOXY-N-METHAMPHETAMINE

(from MDA):

A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base

and 2.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap

until no further H2O was generated (about 20 h was sufficient, and 1.4 mL H2O was

collected). Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in

100 mL CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally once

again with dilute acid. The solvent was removed under vacuum giving 7.7 g of an amber

oil that, on standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine. An

alternate process for the of this amide involved holding at reflux for 16 h a solution of

10 g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles

yielded an oil that set up to white crystals, weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL

anhydrous THF was added dropwise to a well stirred and refluxing solution of 7.4 g

LAH in 600 mL anhydrous THF under an inert atmosphere. The reaction mixture was

held at reflux for 4 days. After being brought to room temperature, the excess hydride

was destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4 mL of 15%

NaOH and then another 22 mL H2O. The solids were 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 200 mL CH2Cl2. This solution was

extracted with 3ċ100 mL dilute HCl, and these extracts pooled and made basic with 25%

NaOH. Extraction with 3ċ75 mL CH2Cl2 removed the product, and the pooled extracts

were stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white

residue which was distilled at 100-110 C at 0.4 mm/Hg to give 5.0 g of a colorless oil.

This was dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the

addition of sufficient anhydrous Et2O to produce a lasting turbidity. On continued

stirring, there was the deposition of fine white crystals of 3,4-methylenedioxy-Nmethylamphetamine

hydrochloride (MDMA) which were removed by filtration, washed

with Et2O, and air dried, giving a final weight of 4.8 g.

(from 3,4-methylenedioxyphenylacetone):

3,4-Methylenedioxyphenylacetone is the key intermediate to all of the MD-series

can be made from either isosafrole, or from piperonal via 1-(3,4-

methylenedioxyphenyl)-2-nitropropene.

To a well stirred solution of 34 g of 30% hydrogen peroxide in 150 g 80% formic

acid there was added, dropwise, a solution of 32.4 g isosafrole in 120 mL acetone at a

rate that kept the reaction mixture from exceeding 40 C. This required a bit over 1 h,

and external cooling was used as necessary. Stirring was continued for 16 h, and care

was taken that the slow exothermic reaction did not cause excess heating. An external

bath with running water worked well. During this time the solution progressed from an

orange color to a deep red. All volatile components were removed under vacuum which

yielded some 60 g of a very deep red residue. This was dissolved in 60 mL of MeOH,

treated with 360 mL of 15% H2SO4, and heated for 3 h on the steam bath. After cooling,

the reaction mixture was extracted with 3ċ75 mL Et2O, the pooled extracts washed first

with H2O and then with dilute NaOH, and the solvent removed under vacuum The

residue was distilled (at 2.0 mm/108-112 C, or at about 160 C at the water pump) to

provide 20.6 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil. The oxime

(from hydroxylamine) had a mp of 85-88 C. The semicarbazone had a mp of 162-163

A suspension of 32 g electrolytic iron in 140 mL glacial acetic acid was gradually

warmed on the steam bath. When quite hot but not yet with any white salts apparent,

there was added, a bit at a time, a solution of 10.0 g of 1-(3,4-methylenedioxyphenyl)-2-

nitropropene in 75 mL acetic acid (see the of MDA for the preparation of this

nitrostyrene intermediate from piperonal and nitroethane). This addition was conducted

at a rate that permitted a vigorous reaction free from excessive frothing. The orange

color of the reaction mixture became very reddish with the formation of white salts and a

dark crust. After the addition was complete, the heating was continued for an additional

1.5 h during which time the body of the reaction mixture became quite white with the

product appeared as a black oil climbing the sides of the beaker. This mixture was added

to 2 L H2O, extracted with 3ċ100 mL CH2Cl2, and the pooled extracts washed with

several portions of dilute NaOH. After the removal of the solvent under vacuum, the

residue was distilled at reduced pressure (see above) to provide 8.0 g of 3,4-

methylenedioxyphenylacetone as a pale yellow oil.

To 40 g of thin aluminum foil cut in 1 inch squares (in a 2 L wide mouth

Erlenmeyer flask) there was added 1400 mL H2O containing 1 g mercuric chloride.

Amalgamation was allowed to proceed until there was the evolution of fine bubbles, the

formation of a light grey precipitate, and the appearance of occasional silvery spots on

the surface of the aluminum. This takes between 15 and 30 min depending on the

freshness of the surfaces, the temperature of the H2O, and the thickness of the aluminum

foil. (Aluminum foil thickness varies from country to country.) The H2O was removed

by decantation, and the aluminum was washed with 2ċ1400 mL of fresh H2O. The

residual H2O from the final washing was removed as thoroughly as possible by shaking,

and there was added, in succession and with swirling, 60 g methylamine hydrochloride

dissolved in 60 mL warm H2O, 180 mL IPA, 145 mL 25% NaOH, 53 g 3,4-

methylenedioxyphenylacetone, and finally 350 mL IPA. If the available form of

methylamine is the aqueous solution of the free base, the following sequence can be

substituted: add, in succession, 76 mL 40% aqueous methylamine, 180 mL IPA, a

suspension of 50 g NaCl in 140 mL H2O that contains 25 mL 25% NaOH, 53 g 3,4-

methylenedioxyphenylacetone, and finally 350 mL IPA. The exothermic reaction was

kept below 60 C with occasional immersion into cold water and, when it was thermally

stable, it was allowed to stand until it had returned to room temperature with all the

insolubles settled to the bottom as a grey sludge. The clear yellow overhead was

decanted and the sludge removed by filtration and washed with MeOH. The combined

decantation, mother liquors and washes, were stripped of solvent under vacuum, the

residue suspended in 2400 ml of H2O, and sufficient HCl added to make the phase

distinctly acidic. This was then washed with 3ċ75 mL CH2Cl2, made basic with 25%

NaOH, and extracted with 3ċ100 mL of CH2Cl2. After removal of the solvent from the

combined extracts, there remained 55 g of an amber oil which was distilled at 100-110

C at 0.4 mm/Hg producing 41 g of an off-white liquid. This was dissolved in 200 mL

IPA, neutralized with about 17 mL of concentrated HCl, and then treated with 400 mL

anhydrous Et2O. After filtering off the white crystals, washing with an IPA/Et2O

mixture, (2:1), with Et2O, and final air drying, there was obtained 42.0 g of 3,4-

methylenedioxy-N-methylamphetamine (MDMA) as a fine white crystal. The actual

form that the final salt takes depends upon the temperature and concentration at the

moment of the initial crystallization. It can be anhydrous, or it can be any of several

hydrated forms. Only the anhydrous form has a sharp mp; the published reports describe

all possible one degree melting point values over the range from 148-153 C. The

variously hydrated polymorphs have distinct infrared spectra, but have broad mps that

depend on the rate of heating.

DOSAGE: 80 - 150 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS

(with 100 mg) MDMA intrigued me because everyone I asked, who had used it,

answered the question, "What's it like?" in the same way: "I don't know." "What

happened?" "Nothing." And now I understand those answers. I too think nothing

happened. But something seemed changed. Before the "window" opened completely, I

had some somatic effects, a tingling sensation in the fingers and temples a pleasant

sensation, not distracting. However, just after that there was a slight nausea and

dizziness similar to a little too much alcohol. All these details disappeared as I walked

outside. My mood was light, happy, but with an underlying conviction that something

significant was about to happen. There was a change in perspective both in the near

visual field and in the distance. My usually poor vision was sharpened. I saw details in

the distance that I could not normally see. After the peak experience had passed, my

major state was one of deep relaxation. I felt that I could talk about deep or personal

subjects with special clarity, and I experienced some of the feeling one has after the

second martini, that one is discoursing brilliantly and with particularly acute analytical

powers.

(with 100 mg) Beforehand, I was aware of a dull, uncaring tiredness that might

have reflected too little sleep, and I took a modest level of MDMA to see if it might

serve me as a stimulant. I napped for a half hour or so, and woke up definitely not

improved. The feeling of insufficient energy and lack of spark that I`d felt before had

become something quite strong, and might be characterized as a firm feeling of

negativity about everything that had to be done and everything I had been looking

forward to. So I set about my several tasks with no pleasure or enjoyment and I hummed

a little tune to myself during these activities which had words that went: "I shouldn`t

have done that, oh yes, I shouldn`t have done that, oh no, I shouldn't have done that; it

was a mistake." Then I would start over again from the beginning. I was stuck in a gray

space for quite a while, and there was nothing to do but keep doing what I had to do.

After about 6 hours, I could see the whole mental state disintegrating and my pleasant

feelings were coming back. But so was my plain, ornery tiredness. MDMA does not

work like Dexedrine.

(with 120 mg) I feel absolutely clean inside, and there is nothing but pure

euphoria. I have never felt so great, or believed this to be possible. The cleanliness,

clarity, and marvelous feeling of solid inner strength continued throughout the rest of the

day, and evening, and through the next day. I am overcome by the profundity of the

experience, and how much more powerful it was than previous experiences, for no

apparent reason, other than a continually improving state of being. All the next day I felt

like "a citizen of the universe" rather than a citizen of the planet, completely

disconnecting time and flowing easily from one activity to the next.

(with 120 mg) As the material came on I felt that I was being enveloped, and my

attention had to be directed to it. I became quite fearful, and my face felt cold and ashen.

I felt that I wanted to go back, but I knew there was no turning back. Then the fear

started to leave me, and I could try taking little baby steps, like taking first steps after

being reborn. The woodpile is so beautiful, about all the joy and beauty that I can stand.

I am afraid to turn around and face the mountains, for fear they will overpower me. But I

did look, and I am astounded. Everyone must get to experience a profound state like this.

I feel totally peaceful. I have lived all my life to get here, and I feel I have come home. I

am complete.

(with 100 mg of the "R" isomer) There were the slightest of effects noted at about

an hour (a couple of paresthetic twinges) and then nothing at all.

(with 160 mg of the "R" isomer) A disturbance of baseline at about forty minutes

and this lasts for about another hour. Everything is clear by the third hour.

(with 200 mg of the "R" isomer) A progression from an alert at thirty minutes to a

soft and light intoxication that did not persist. This was a modest +, and I was at baseline

in another hour.

(with 60 mg of the "S" isomer) The effects began developing in a smooth, friendly

way at about a half-hour. My handwriting is OK but I am writing faster than usual. At

the one hour point, I am quite certain that I could not drive, time is slowing down a bit,

but I am mentally very active. My pupils are considerably dilated. The dropping is

evident at two hours, and complete by the third hour. All afternoon I am peaceful and

relaxed, but clear and alert, with no trace of physical residue at all. A very successful ++.

(with 100 mg of the "S" isomer) I feel the onset is slower than with the racemate.

Physically, I am excited, and my pulse and blood pressure are quite elevated. This does

not have the 'fire' of the racemate, nor the rush of the development in getting to the

plateau.

(with 120 mg of the "S" isomer) A rapid development, and both writing and

typing are impossible before the end of the first hour. Lying down with eyes closed

eliminates all effects; the visual process is needed for any awareness of the drug's

effects. Some teeth clenching, but no nystagmus. Excellent sleep in the evening.

EXTENSIONS AND COMMENTARY

In clinical use, largely in psychotherapeutic sessions of which there were many in

the early years of MDMA study, it became a common procedure to provide a

supplemental dosage of the drug at about the one and a half hour point of the session.

This supplement, characteristically 40 milligrams following an initial 120 milligrams,

would extend the expected effects for about an additional hour, with only a modest

exacerbation of the usual physical side-effects, namely, teeth clenching and eye

twitching. A second supplement (as, for instance, a second 40 milligrams at the two and

a half hour point) was rarely felt to be warranted. There are, more often than not, reports

of tiredness and lethargy on the day following the use of MDMA, and this factor should

be considered in the planning of clinical sessions.

With MDMA, the usual assignments of activity to optical isomers is reversed

from all of the known psychedelic drugs. The more potent isomer is the "S" isomer,

which is the more potent form of amphetamine and methamphetamine. This was one of

the first clear distinctions that was apparent between MDMA and the structurally related

psychedelics (where the "R" isomers are the more active). Tolerance studies also support

differences in mechanisms of action. In one study, MDMA was consumed at 9:00 AM

each day for almost a week (120 milligrams the first day and 160 milligrams each

subsequent day) and by the fifth day there were no effects from the drug except for some

mydriasis. And even this appeared to be lost on the sixth day. At this point of total

tolerance, there was consumed (on day #7, at 9:00 AM) 120 milligrams of MDA and the

response to it was substantially normal with proper chronology, teeth clench, and at most

only a slight decrease in mental change. A complete holiday from any drug for another 6

days led to the reversal of this tolerance, in that 120 milligrams of MDMA had

substantially the full expected effects. The fact that MDMA and MDA are not crosstolerant

strengthens the argument that they act in different ways, and at different sites in

the brain. A wide popularization of the social use of MDMA occurred in 1984-1985 and,

with the reported observation of serotonin nerve changes in animal models resulting

from the administration of the structurally similar drug MDA, an administrative move

was launched to place it under legal control. The placement of MDMA into the most

restrictive category of the Federal Controlled Substances Act has effectively removed it

from the area of clinical experimentation and human research. The medical potential of

this material will probably have to be developed through studies overseas.

A word of caution is in order concerning the intermediate 3,4-methylenedioxyphenylacetone,

which has also been called piperonylacetone. A devilish ambiguity

appeared in the commercial market for this compound, centered about its name. The

controversy focused on the meaning of the prefix, piperonyl, which has two separate

chemical definitions. Let me try to explain this fascinating chaos in non-chemical terms.

Piperonyl is a term that has been used for a two-ring system (the methylenedioxyphenyl

group) either without, or with, an extra carbon atom sticking off of the side of it. Thus,

piperonylacetone can be piperonyl (the two-ring thing without the extra carbon atom

attached) plus acetone (a three carbon chain thing); the total number of carbons sticking

out, three. Or, piperonylacetone can be piperonyl (the two-ring thing but with the extra

carbon atom attached) plus acetone (a three carbon chain thing); the total number of

carbons sticking out, four. Does this make sense? The three carbon sticking out job gives

rise to MDA and to MDMA and to many homologues that are interesting materials

discussed at length in these Book II comments. This is the usual item of commerce,

available from both domestic and foreign suppliers. But the four-carbon sticking out job

will produce totally weird stuff without any apparent relationship to psychedelics,

psychoactives or psychotropics whatsoever. I know of one chemical supply house which

supplied the weird compound, and they never did acknowledge their unusual use of the

term piperonyl. There is a simple difference of properties which might be of value. The

three carbon (correct) ketone is an oil with a sassafras smell that is always yellow

colored. The four carbon (incorrect) ketone has a weak terpene smell and is white and

crystalline. There should be no difficulties in distinguishing these two compounds. But

unprincipled charlatans can always add mineral oil and butter yellow to otherwise white

solids to make them into yellow oils. Caveat emptor.

MDA

3,4-METHYLENEDIOXYAMPHETAMINE

A) 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 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 3ċ75 mL

CH2Cl2 removed much of the color, and the aqueous phase was made basic and

reextracted with 3ċ100 mL CH2Cl2. Removal of the solvent yielded 13.0 g of a yellowcolored

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.

B) 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 3ċ100 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 3ċ100 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-

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