SYNTHESIS: (from 3,4-methylenedioxyphenylacetone) A solution of 2.1 g N-methylhydroxylamine hydrochloride and 4.4 g 3,4-methylenedioxyphenylacetone in 5.5 mL MeOH was added to a suspension of 4.5 g NaHCO3 in 30 mL boiling MeOH. There was added about 5 mL H2O (which gave a clear solution) followed by another 50 mL H2O which produced a pale yellow color. To this solution of the unisolated nitrone there was added 1.7 g sodium cyanoborohydride, which generated a goodly amount of foaming. There was HCl added as needed to maintain the pH at about neutrality. The reaction appeared to have stopped after a day or two, so all was poured into 500 mL H2O, acidified with HCl, and washed with 2×75 mL CH2Cl2. The addition of base brought the pH >9, and this was then extracted with 3×75 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a residue of 1.65 g of crude N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine. Efforts to obtain solid seed samples of the salts with hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, and with a number of organic acids, all failed. The salt formation from this free-base will be discussed below.
(from 2SO4. This was washed with 2×75 mL CH2Cl2 and then, following the addition of base, this was extracted with 3×75 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a viscous oil residue of 0.53 g. The free-base product from these preparations was distilled at 110–120 °C at 0.2 mm/Hg to give the N-hydroxy-N-methyl product as a white oil. An alternate methylation procedure used a solution of MDOH in a 4:1 MeOH/acetic acid solution containing formaldehyde which was reduced with sodium borohydride at dry ice temperatures. Its work-up is identical to that involving sodium cyanoborohydride.
The distilled product was dissolved in an equal volume of MeOH, and treated with a half-equivalent of oxalic acid dihydrate, dissolved in 10 volumes of MeOH. This combination gave the slow deposition of crystals of the full oxalate salt (one acid, two bases) as a white crystalline product. The mp of the crude salt was in the 130–150 °C range, and after recrystallization from CH3CN, N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine oxalate (FLEA) had a mp of 146–147 °C.
DOSAGE: 100–160 mg.
DURATION: 4–8 h.
QUALITATIVE COMMENTS: (with 90 mg) “The material tastes terrible, like grapefruit juice that has stayed in the can too long. There was no nausea, no feeling of difficulty in swallowing at any time during the day. I felt a dry mouth and was thirsty—sipped water throughout the day. At the beginning of the experiment, there was a glimmer of the
(with 110 mg) “We found this very similar to
(with 110 mg) “The onset was at about a half-hour. The come-on was more gradual and much easier than with
(with 110 mg + 35 mg) “I saw my onset at 20 minutes, and it was subtle, and very pleasant, and had a mild amphetamine-like elevation for me (body lightness, cognitive functions seemed clear and clean, heightened visual awareness and with some enhancement of color). It seemed as if I were on the fringe of
EXTENSIONS AND COMMENTARY: Most people who were involved with the evaluation of FLEA quite logically compared it with
And from the scientific point of view, it lends more weight to a hypothesis that just might be a tremendous research tool in pharmacology. I first observed the intimate connection between an amine and a hydroxylamine with the discovery that N-hydroxy-MDA (
Just how general might this concept be, that an N-hydroxyl analog of an active amine shall be of similar action and duration as the parent drug? What if it really were a generality! What havoc it would wreak in the pharmaceutical industry! If I could patent the concept, then I would be able to make parallel best sellers to all of the primary and secondary amines out there in the industry. Perhaps 90% of all the commercially available drugs that are concerned with the human mental state are amines. And a goodly number of these are primary or secondary amines. And each and every one of these could be converted to its N-hydroxyl analogue, effectively by-passing the patent protection that the originating corporation so carefully crafted. An example, just for fun. A run-away best seller right now is an antidepressant called fluoxetine, with the trade name Prozac. I will make a small wager that if I were to synthesize and taste N-hydroxy-N-methyl-3-phenyl-3-((α,α,α-trifluoro-p-tolyl)oxy)propylamine, I would find it to be an active antidepressant. Remember, Mr. Eli Lilly and Company; you read about it first, right here!
Of course, I was asked, why call it FLEA? The origin was in a classic bit of poetry. A commonly used code name for
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. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.
“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.”
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.
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.
Though 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.Transform Press,
Berkeley, CA 94701
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