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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #97: 4-MA
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#97 4-MA: PMA; 4-Methoxyamphetamine

#97 4-MA SYNTHESIS: A solution of 27.2 g anisaldehyde and 18.0 g nitroethane in 300 mL benzene was treated with 2.0 mL cyclohexane and refluxed using a Dean Stark trap until H2O ceased to accumulate. A total of 3.8 mL was generated over about 5 days. After the removal of the solvent under vacuum, the viscous red oily residue was cooled and it spontaneously crystallized. This was ground under an equal volume of MeOH, producing lemon-yellow crystals of 1-(4-methoxyphenyl)-2-nitropropene. The final yield was 27.4 g of product with a mp of 45–46 °C. Recrystallization from 4 volumes MeOH did not improve the mp. An excellent alternate synthesis with a comparable yield involved letting a solution of equimolar amounts of the aldehyde and nitroethane and a tenth mole of n-amylamine stand in the dark at room temperature for a couple of weeks. The product spontaneously crystallized, and could be recrystallized from MeOH. The more conventional synthesis involving acetic acid as a solvent and ammonium acetate as a catalyst, produced a poor yield of the nitrostyrene and it was difficult to separate from the white diacetate of the starting anisaldehyde, mp 59–60 °C.

A suspension of 32 g LAH in 1 L anhydrous Et2O was well stirred and 32.6 g 1-(4-methoxyphenyl)-2-nitropropene in Et2O was added at a rate that maintained a reflux. After the addition was complete, reflux was continued for 48 h. The reaction mixture was cooled, and the excess hydride was destroyed by the cautious addition of dilute H2SO4. The Et2O was separated, and extracted with additional aqueous H2SO4. A solution of 700 g potassium sodium tartrate in 600 mL H2O was added, and the pH brought to >9 with 25% NaOH. This aqueous phase was extracted with 3×200 mL CH2Cl2 which provided, after removal of the solvent, 32.5 g of a clear amber oil. This was dissolved in 100 mL IPA, neutralized with concentrated HCl, and then diluted with 300 mL anhydrous Et2O. There was obtained white crystals of 4-methoxyamphetamine hydrochloride (4-MA) that weighed, after filtering, Et2O washing and air drying, 22.2 g and had a mp of 208–209 °C. The amphetamine metabolite, 4-hydroxyamphetamine hydrochloride (4-HA), was prepared by heating 5.0 g 4-MA in 20 mL concentrated HCl at 15 lbs/in. After recrystallization from aqueous EtOH, the product weighed 3.8 g and had a mp of 171–172 °C.

DOSAGE: 50–80 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 60 mg) “At just over an hour, there was a sudden blood pressure rise, with the systolic going up 55 mm. This was maintained for another hour. I found the effects reminiscent of DET, distinct after-images, and some parasthesia. I was without any residue by early evening (after 5 hours).”

(with 70 mg) “It hit quite suddenly. I had a feeling of druggedness, almost an alcohol-like intoxication, and I never was really high in the psychedelic sense.”

EXTENSIONS AND COMMENTARY: This is another of the essential amphetamines, because of the appearance of the 4-methoxy group in two most important essential oils. These are the allylbenzene (estragole or esdragol) and the propenyl isomer (anethole). Their natural sources have been discussed under TMA.

Two comments are warranted concerning 4-MA, one of scientific interest, and the other about a social tragedy.

A major metabolites of amphetamine is 4-hydroxyamphetamine, from oxidation at the 4-position. It has been long known that with chronic amphetamine usage there is the generation of tolerance, which encourages ever-increasing doses to be used. When the daily load gets up around one or two hundred milligrams, the subject can become quite psychotic. The question was asked: might the chronic amphetamine user be methylating his endogenously produced 4-hydroxyamphetamine to produce 4-methoxyamphetamine (4-MA), and maybe this is the agent that promotes the psychosis? To address this question, several studies were done with normal subjects, about 20 years ago, to see if 4-MA might produce a psychotic state (it didn’t at the highest levels tried, 75 milligrams) and to see if it was excreted to some extent unchanged in the urines of these normal subjects (it was seen even at the lowest dosage tried, 10 milligrams). It produced excitation and other central effects, it produced adrenergic pressor effects, and it consistently produced measurable quantities of 4-MA in the urine, but it produced no amphetamine-like crazies. And since the administration of up to 600 milligrams of amphetamine produced no detectable 4-MA in the urine, this theory of psychotomimesis is not valid.

On the tragic side, a few years later, 4-MA became widely distributed in both the US (as the sulfate salt) and in Canada (as the hydrochloride), perhaps inspired by some studies in rats that had reported that it was second only to LSD in potency as a hallucinogen. The several deaths that occurred probably followed overdose, and it was clear that 4-MA was involved as it had been isolated from both urine and tissue during post mortems. It had been sold under the names of Chicken Power and Chicken Yellow, and was promoted as being MDA. I could find no record of a typical street dosage, but comments collected in association with the deaths implied that the ingested quantites were in the hundreds of milligrams. Recently, the ethoxy homologue, 4-EA, appeared on the streets of Canada. The dosage, again, was not reported. It was promptly illegalized there. Icon for an external reference Icon for an external reference

The two positional analogues of 4-MA are known; vis., 2-MA and 3-MA. Their synthesis is straightforward, in imitation of that for 4-MA above. The meta-compound, 3-MA, has been metabolically explored in man, but no central effects were noted at a 50 milligram dose (2×25 milligrams, separated by three hours). There appears to be no report of any human trial of 2-MA. The N-methyl homologue of 2-MA is a commercial adrenergic bronchodilator called Methoxyphenamine, or Orthoxine. It has been used in the prevention of acute asthma attacks in doses of up to 200 milligrams, with only slight central stimulation. The N-methyl homologues of 3-MA and 4-MA are known, and the latter compound is the stuff of a separate entry in this book.

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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. Still others remain to be added.

I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore most of the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes 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.

Although 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.

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