SYNTHESIS: A solution of 11.5 g pellet KOH (85%) in 75 mL EtOH was treated with 25 g sesamol followed by 27 g methyl iodide. This was brought to reflux on the steam bath. Salt formation was apparent in 20 min, and refluxing was maintained for a total of 4 h. The solvent was removed under vacuum, and residue poured into 400 mL H2O. This was acidified with HCl and extracted with 3×150 mL CH2Cl2. The pooled extracts were washed with 3×100 mL 5% NaOH, which removed most of the color. The solvent was removed under vacuum to provide 24.0 g of 3,4-methylenedioxyanisole as a pale amber oil.
A mixture of 56.4 g POCl3 and 49.1 g N-methylformanilide was allowed to stand for 40 min and then it was poured into a beaker containing 64 g 3,4-methylenedioxyanisole. There was an immediate exothermic reaction with darkening and the generation of bubbles. This was heated on the steam bath for 1 h, then poured into 1 L H2O with extremely vigorous stirring. The dark brown phase was quite opaque, and then there was a sudden lightening of color with the generation of a fine pale yellow solid. Stirring was continued for 2 h, then these crystals were removed by filtration. This crude product was recrystallized from 400 mL boiling MeOH yielding, after filtering, washing, and air drying to constant weight, 44.1 g 2-methoxy-4,5-methylenedioxybenzaldehyde with a mp of 110–111 °C. Only one positional isomer was visible in the final product by GC, but extraction of the original mother liquors with CH2Cl2 produced, after evaporation of the solvent under vacuum, 2 g of a red oil that showed two earlier peaks on OV-17. These were consistent with about 1% of each of the two alternate positional isomers that could result from the Vilsmeier formylation reaction.
A solution of 43 g 2-methoxy-4,5-methylenedioxybenzaldehyde in 185 g nitroethane was treated with 9.3 g anhydrous ammonium acetate and heated on the steam bath for 4.5 h. The excess nitroethane was removed under vacuum to give a residue that spontaneously crystallized. These solids were washed out mechanically with the aid of 200 mL cold MeOH, and the brilliant orange crystals recovered by filtering and air drying to constant weight. There was obtained 35.7 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of 166–167 °C. This was not improved by recrystallization from IPA. Evaporation of solvent from the methanolic washes gave yellow solids (4.6 g melting at 184–186 °C) which, on recrystallization from THF/hexane, melted at 188–190 °C. This showed a molecular weight of 416 by chemical ionization mass spectroscopy (isobutane at 0.5 torr) and is the C20H20N2O8 adduct of one molecule each of nitrostyrene, aldehyde, and ammonia that frequently appears as a very insoluble impurity in aldehyde-nitroethane condensations that are catalyzed by ammonium acetate.
To a refluxing suspension of 36 g LAH in 1 L anhydrous THF under an inert atmosphere, there was added 44.3 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene in hot THF. The solubility was very low, so that it was necessary to use a heat lamp on the dropping funnel to maintain a clear solution for addition. The addition required 2 h and the reflux was maintained for 36 h. The reaction mixture was then cooled in an ice bath and there was added, in sequence and commensurate with heat evolution, 36 mL H2O, 36 mL 15% NaOH, and finally 108 mL H2O. The granular solids were removed by filtration and washed with THF. The combined filtrate and washes were stripped of solvent under vacuum yielding 58.8 g of a pale amber oil. This was dissolved in 100 mL IPA, neutralized with concentrated HCl (20 mL was needed) and diluted with 500 mL anhydrous Et2O. More IPA was required to keep an oil phase from appearing. After the crystalline product was completely formed, it was removed by filtration, washed with IPA/Et2O, and finally with Et2O. Air drying gave 31.1 g of 2-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA-2) with a mp of 186–187 °C.
DOSAGE: 25–50 mg.
DURATION: 8–12 h.
QUALITATIVE COMMENTS: (with 25 mg) “Had some not-too-pleasant jangly effects—this is not the smoothest of drugs. Duration: onset at 1 1/2 hours (dose after lunch), acute 3 to 4 hours, Seconal at 11 hours to stop residual effects so I could sleep. Occasionally from 5 to 10 hours acute abdominal distress, resembling gas pains but unable to defecate. Abdominal muscles tight and hard. This occurred for about 15 minutes every hour or so. Rather unpleasant.”
(with 30 mg) “There was the first subtle note at 45 minutes, and the slow development makes the changes easy to assimilate, but difficult to quantitate. My awareness is truly enhanced. Nothing is distorted, so there can be no misrepresentation as a result. This would be a good material to introduce someone to the slow-on slow-off type of experience. It would be impossible for any person, at this level, on this drug, to have a bad experience. This is very much like a slow MDA, perhaps 80 milligrams of it, and fully as controllable. The N-methyl of this is a must.”
(with 40 mg) “The chemical is primarily a visual enhancer with only an extremely modest amount of visual distortion. The retinal activity was of a minor and non-threatening nature. The chemical seemed to facilitate empathic communication and the emotions felt strong and clean. Conversation flowed easily, without inhibitions or defensiveness. Anorexia accompanied experience. There was no impotence. There was some restless movement which dissipated with exercise (walking and playing frisbee). Next day woke feeling energetic, no muscular stiffness, alert. I would repeat this experience.”
(with 50 mg) “I was coming on within 40–60 minutes, easy and slow, but the body was +3 before the mind. The mental was strange for the first 2–3 hours—I called it ‘High Sierras’—realistic, dispassionate, not kind. Some dark areas are persistent. Watched last half of Circus of Dr. Lao and the whole feeling changed from pornographic to erotic. Delightful. Some fantasy. On coming down, sleep was difficult. The body feels unexpectedly depleted. Rubber legs and handwriting jerky.”
EXTENSIONS AND COMMENTARY: A comparison of this material to MDA was often made by subjects who were familiar with both. But it is hard to separate that which is intellectualized from that which is felt. An awareness of the chemical structure immediately shows, of course, the close resemblance. There is the complete MDA molecule, with the addition of a methoxy group. And for the non-chemist, the name itself (MMDA-2) represents the second possible methoxy-MDA. Certainly one property that is shared with MDA is the broad variety of opinions as to the quality of its action. Some like it much, and some like it not at all. The N-methyl homologue was indeed made, for direct evaluation in comparison to N-methyl MDA (which is MDMA).
The phenethylamine analog of MMDA-2 has been prepared by the condensation of the above benzaldehyde with nitromethane (in acetic acid with ammonium acetate catalyst, giving an equal weight of the nitrostyrene as deep orange crystals with a mp of 166–167 °C from ethyl acetate) followed by lithium aluminum hydride reduction (in ether). The product, 2-methoxy-4,5-methylenedioxyphenethylamine hydrochloride (
2C-2 ) melted at 218–219 °C. There were no effects observed at up to 2.6 milligrams, but no higher trials were made. The 4-carbon homologue was made similarly (from the aldehyde and nitropropane but using tert-butylammonium acetate as a reagent in 100% excess and isopropanol as solvent, giving orange crystals melting at 98–99 °C from methanol) followed by reduction (with lithium aluminum hydride in ether) to give 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-aminobutane hydrochloride ( 4C-2 ) with a mp of 172–174 °C. This material has never even been tasted.
The Tweetio homologue of MMDA-2 has been tasted, however. This is 2-ethoxy-4,5-methylenedioxyamphetamine, or EMDA-2. The allyl ether of sesamol (3,4-methylenedioxyallyloxybenzene) was rearranged to the 2-allyl phenol which was, in turn, converted to the ethyl ether. Reaction with tetranitromethane gave the nitrostyrene intermediate which had a mp of 120–121 °C. The final hydrochloride salt of EMDA-2 had a mp of 188–188.5 °C. At 135 milligrams, there have been reported eyes-closed visual phenomena, with intense colors. The overall duration is similar to MMDA-2 (some 10 hours) and there are reported sleep disturbances. At 185 milligrams, the feelings were intensified, there were “marvelous eyes-closed visuals (the colors were incredible), good concentration, but distinct body-tingles and rushes.” The time span was about 12 hours from start to finish, but it proved to be impossible to sleep afterwards. This homologue is thus about a third the potency of MMDA-2.
Shulgin, AT; Sargent, T; Naranjo, C. Structure-activity relationships of one-ring psychotomimetics. Nature, 1 Jan 1969, 221, 537–541. 537 kB. doi:10.1038/221537a0
Shulgin, AT. Chemistry and structure-activity relationships of the psychotomimetics. In Psychotomimetic Drugs; Efron, DH, Ed., Raven Press, New York, 1 Jan 1970; pp 21–41. 8647 kB.
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Nichols, DE; Hoffman, AJ; Oberlender, RA; Riggs, RM. Synthesis and evaluation of 2,3-dihydrobenzofuran analogues of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: Drug discrimination studies in rats. J. Med. Chem., 1 Jan 1986, 29 (2), 302–304. 441 kB. doi:10.1021/jm00152a022
McKenna, DJ; Guan, AM; Shulgin, AT. 3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine. Pharmacol. Biochem. Behav., 1 Jan 1991, 38 (3), 505–12. 783 kB. doi:10.1016/0091-3057(91)90005-M
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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.
“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
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.
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.Transform Press,