SYNTHESIS: A solution of 33 g 3,4-dimethoxybenzaldehyde in 140 mL acetic acid was treated with 23 mL nitromethane and 12.5 g anhydrous ammonium acetate, and heated on the steam bath for 45 min. To this there was slowly added, with good stirring, 300 mL H2O, and the resulting solids were removed by filtration. The product was finely ground under a small amount of MeOH, filtered again, and air dried to give 13.5 g 3,4-dimethoxy-β-nitrostyrene with a mp of 142–143 °C.
To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O that was at a gentle reflux and under an inert atmosphere, there was added 11.45 g 3,4-dimethoxy-β-nitrostyrene by leaching it from a thimble in a modified Soxhlet condenser. The addition took 2 h and the refluxing was maintained for another 16 h. After cooling to room temperature, the excess hydride was destroyed by the cautious addition of 500 mL 1.5 N H2SO4. The phases were separated, and to the aqueous phase there was added 250 g potassium sodium tartrate. The pH was brought to >9, and the clear solution was extracted with 3×100 mL CH2Cl2. Removal of the solvent from the combined extracts under vacuum gave 5.2 g of a pale yellow oil. This was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly sticky off-white solid. This was recrystallized from 75 mL of boiling CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA) as beautiful white crystals.
DOSAGE: greater than 1000 mg.
QUALITATIVE COMMENTS: (with 500 mg) “Nothing.”
(with 1000 mg) “Nothing.”
(with 10 mg i.v.) “Nothing.”
(with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human metabolite of DMPEA) “Nothing.”
(with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human metabolite of DMPEA) “Nothing.”
EXTENSIONS AND COMMENTARY: Why all the interest? Why keep pursuing a compound that is so obviously without activity? Or a metabolite that is also without activity? The answer is that these are totally fascinating compounds just because they have no activity! By the way, in this instance, I actually made up most of the quotations. I am not sure that the subjects actually said, “Nothing,” but they did report that there were no effects. In my own experiments, my notes record the phrase, “No effects whatsoever.”
A little background: one of the transmitter heavyweights in the brain is dopamine. Dopamine is called dopamine because it is an amine that comes from an amino acid that is 3,4-dihydroxyphenylalanine and this, in German, is Di-Oxo-Phenyl-Alanine, or DOPA. The levo-optical (or L-) isomer of DOPA has rather cutely been called the punch-drunk Spanish matador, or El Dopa. But that is not part of the story.
The story is really about the “Pink Spot of Schizophrenia.” Many years ago, an observation was made in a biochemical laboratory on the East Coast that stirred up a rolling controversy. It had been found that if the urines of schizophrenic patients (sloppily called “schizophrenic urines”) were extracted in such and such a way, and the extracts chromatographed, a pink spot would develop at a particular place on the chromatogram. Well, if this proved to be true with urines of a sick population, and were this proved to be different from the urines of a healthy population, it would constitute an objective diagnosis of schizophrenia. A simple chemical test to confirm a pathology that had defied all efforts to achieve consensus amongst the psychiatrists of the world.
The literature was suddenly filled with dozens of papers. Researcher A confirmed that the pink spot was found with schizophrenics, and not with normal controls. Researcher B found the pink spot in all urines, regardless of pathology. Researcher C found it in no urines at all. Researcher D argued that it was a factor from the hospital diet. Researcher E found that the pink spot reflected the time of day that the urine sample was collected. Researcher F drew a conclusion about where truth might lie by tallying the number of papers that supported argument A, B, C, D, or E.
The only confirmable fact that endured was that the pink spot was due to DMPEA. So a bright spotlight was directed towards its possible role in mental illness. And this expressed itself in the simple question: would it produce schizophrenia in a normal subject? No. And in a way I am comforted that that did not evolve into a simple litmus test for a schizophrenic diagnosis. There are so many cultural, political, and social factors that come to bear on the assignment of a diagnosis of mental illness, that I would have been forever skeptical of a neat biochemical marker.
A chemical modification of DMPEA that has been explored in this question of pink spots, mental pathology, and diagnostic markers, is the corresponding acetamide. One of the metabolites of DMPEA was found to be the N-acetyl derivative, N-acetyl-3,4- dimethoxyphenethylamine. It was found to be demethylated in man, and to have pharmacological activity in animals. Maybe this was the active compound that could be involved in the schizophrenic process. But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man.
Another chemical modification is the beta-hydroxy analogue of DMPEA. It has been explored separately, and is the subject of its own recipe, in its own rights. See DME.
Pink was not the only colorful spot associated with schizophrenia. Somewhere at about this same time, a research paper from Canada reported the observation of a mauve spot in the chromatographic analysis of urines of schizophrenic patients. This had nothing to do with DMPEA. I was working closely with a researcher at the psychiatric institute and we were fascinated by, again, a possible diagnostic marker. We assayed the urines of the next 10 patients being admitted as acute schizophrenics. No trace of mauve. We wrote to Canada, and verified the analytical procedure. We were told that the whatzis should have been added after, rather than before, the whosey, and that we should have heated for 30, not 10 minutes. Okay. We assayed the urines of the next 10 patients being admitted using these new directions. No trace of mauve. Another call to Canada, and we were informed that we still weren’t doing it right. They were consistently batting a 100% positive correlation between mauve spots and schizophrenics, and 0% with healthy controls. In fact, they actually gave this positive test the name of a disease, Malvaria.
Then, that little burst of insight! Aha! What if, just what if, they had been seeing something given to their schizophrenics? Chlorpromazine was the popular treatment of the day. We took a whopping dose of chlorpromazine, and over the next couple of days did manage (barely) to collect our urine samples. Both of us were positive Malvarians! And three days later, we were again negative. We were most likely seeing a metabolite of chlorpromazine. One last call to Canada with the ultimate question—had you given any medication to your schizophrenics before your urine analysis? Of course (came the answer)—it would not be ethical to leave them untreated. Another color down the drain, and still no objective measure for mental illness.
By the way, I cannot say I like the chlorpromazine trip. There is no real communication either with others or with yourself, with that stuff. You are a zombie, but if you are both schizophrenic and a zombie, you cannot possibly be troublesome for anybody in the emergency room.
Shulgin, AT; Sargent, T; Naranjo, C. Role of 3,4-dimethoxyphenethylamine in schizophrenia. Nature, 1 Jan 1966, 212, 1606–1607. 267 kB. doi:10.1038/2121606a0
Sargent, TW; Israelstam, DM; Shulgin, AT; Landaw, SA; Finley, NN. A note concerning the fate of the 4-methoxyl group in 3,4-dimethoxyphenethylamine (DMPEA). Biochem. Biophys. Res. Commun., 1 Jan 1967, 29 (1), 126–130. 262 kB. doi:10.1016/0006-291X(67)90552-9
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
Ghosal, S; Srivastava, RS. β-Phenethylamine, tetrahydroisoquinoline and indole alkaloids of Desmodium tiliaefolium. Phytochem., 1 Jan 1973, 12 (1), 193–197. 552 kB. doi:10.1016/S0031-9422(00)84646-4
Butterick, JR; Unrau, AM. Studies on theoretical psychotogens. Synthesis of O-methylated analogs of catecholamine neurotransmitters and metabolic precursors. Can. J. Chem., 1 Jan 1974, 52 (16), 2873–2879. 305 kB. doi:10.1139/v74-418
Butterick, JR. Synthesis of O-transmethylated catecholamines and psychodysleptic β-phenylisopropylamines. Ph. D. Thesis, Simon Faser University, Burnaby, BC, Canada, 11 Mar 1975. 6069 kB. External examiner: A. T. Shulgin!.
Sargent, T; Shulgin, AT; Kusubov, N. Quantitative measurement of demethylation of C-methoxyl labeled DMPEA and TMA-2 in rats. Psychopharmacol. Commun., 1 Jan 1976, 2 (3), 199–206. 8643 kB.
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Altun, A; Golcuk, K; Kumru, M; Jalbout, AF. Electron-conformation study for the structure-hallucinogenic activity relationships of phenylalkylamines. Bioorg. Med. Chem., 1 Dec 2003, 11 (24), 3861–3868. 577 kB. doi:10.1016/S0968-0896(03)00437-1
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,