Pihkal

by Alexander Shulgin

  To a stirred and gently refluxing suspension of 11 g LAH in 750 mL

  anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl chloride in an Et2O solution. The refluxing was maintained for 48 h then, after cooling externally with ice water, the excess hydride was destroyed by the slow addition of 600 mL of 10% H2SO4. The phases were separated, and the aqueous phase extracted with 2x200 Et2O. The organics were pooled, washed once with 200 mL H2O, and the solvent removed under vacuum. The residue was dried azeotropically through the addition and subsequent removal of CH2Cl2. Distillation of the residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil, boiling at 89-92 !C at 0.5 mm/Hg.

  To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH

  there was added a solution of 4 g 85% KOH in 65 mL EtOH. This was followed by the addition of 5 mL methyl iodide, and the mixture was held at reflux for 30 min. This was poured into 200 mL H2O, and extracted with 3x50 mL Et2O. The pooled extracts were washed once with aqueous sodium hydrosulfite, then the organic solvent was removed under vacuum. The residue was distilled to give 8.0 g of 2,4-dimethoxythioanisole as a colorless oil with a bp of 100-103 !C at 0.6 mm/Hg.

  To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been warmed briefly on the steam bath there was added 7.8 g of 2,4-dimethoxythioanisole. The reaction was heated on the steam bath for an additional 20 min and then poured into 200 mL H2O. Stirring was continued until the insolubles had become completely loose and granular. These were removed by filtration, washed with H2O, sucked as dry as possible, and then recrystallized from boiling MeOH. The product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white solid weighing 8.6 g. It could be obtained in either of two polymorphic forms, depending on the concentration of aldehyde in MeOH

  at the time of crystal appearance. One melted at 109-110 !C and had a fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1.

  The other melted at 124.5-125.5 !C and had major fingerprint peaks at 694, 731, 839 and 897 cm-1. Anal. (C10H12O3S) C,H.

  A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL

  nitroethane was treated with 1.8 g anhydrous ammonium acetate and heated on the steam bath for 4 h. Removal of the excess nitroethane under vacuum gave a colored residue which crystallized when diluted with MeOH. Recrystallization of the crude product from boiling EtOH

  gave, after filtration, washing and air drying to constant weight, 8.3

  g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of 112-113 !C. Anal. (C12H15NO4S) C,H,N.

  A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a N2 atmosphere and stirred magnetically and brought to reflux. There was added, dropwise, 8.0 g of

  1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF. The reaction mixture was maintained at reflux for 18 h. After being brought to room temperature, the excess hydride was destroyed by the addition of 6.5 mL H2O in 30 mL THF. There was then added 6.5 mL of 3N NaOH, followed by an additional 20 mL H2O. The loose, white, inorganic salts were removed by filtration, and the filter cake washed with an additional 50 mL THF. The combined filtrate and washes were stripped of solvent under vacuum yielding a residue that was distilled. The free base boiled at 125-128 !C at 0.1 mm/Hg and was a white oil which solidified on standing. It weighed 5.1 g and had a mp of 47-48.5 !C. This was dissolved in 50 mL IPA, neutralized with concentrated HCl (until dampened universal pH paper showed a deep red color) and diluted with anhydrous Et2O to the point of turbidity.

  There was a spontaneous crystallization providing, after filtering, washing with Et2O, and air drying,

  2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a mp of 140.5-142 !C. Anal. (C12H20ClNO2S) C,H,N.

  DOSAGE: greater than 35 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 35 mg) There was a vague awareness of something all afternoon, something that might be called a thinness.

  Possibly some brief cardiovascular stimulation, but nothing completely believable. This is a threshold level at the very most.

  EXTENSIONS AND COMMENTARY: Again, as with the studies with ORTHO-DOT, it is apparent that the activity of META-DOT is going to be way down from the most interesting of these isomers, PARA-DOT (ALEPH-1, or just ALEPH). In the rectal hyperthermia assay (which calculates the psychedelic potential of compounds by seeing how they influence the body temperature of experimental animals in comparison to known psychedelics) the three DOT's were compared with DOM. And the results fell into line in keeping with the activities (or loss of activities) found in man. PARA-DOT was about half as active as DOM, but both ORTHO-DOT and the compound described here, META-DOT, were down by factors of 50x and 30x respectively. These animal studies certainly seem to give results that are reasonable with a view to other known psychedelic drugs, in that mescaline was down from DOM by a factor of more than 1000x, and LSD was some 33x more potent than DOM.

  I have a somewhat jaundiced view of this rabbit rectal hyperthermia business. One is presumably able to tell whether a compound is a stimulant or a psychedelic drug by the profile of the temperature rise, and how potent it will be by the extent of the temperature rise.

  But the concept of pushing thermocouples into the rear ends of restrained rabbits somehow does not appeal to me. I would rather determine both of these parameters from human studies.

  126 METHYL-DMA; DMMA; 2,5-DIMETHOXY-N-METHYLAMPHETAMINE

  SYNTHESIS: To a stirred solution of 28.6 g methylamine hydrochloride in 120 mL MeOH there was added 7.8 g 2,5-dimethoxyphenylacetone followed by 2.6 g sodium cyanoborohydride. HCL was added as needed to maintain the pH at about 6. The reaction was complete in 24 h, but was allowed to stir for another 3 days. The reaction mixture was poured into 600 mL H2O, acidified with HCl (HCN evolution, caution) and washed with 3x100 mL CH2Cl2. Aqueous NaOH was added, making the solution strongly alkaline, and this was then extracted with 3x100 mL

  CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 8.3 g of a clear, off-white oil that distilled at 95-105 !C. at 0.25 mm/Hg. The 6.5 g of colorless distillate was dissolved in 25 mL

  IPA, neutralized with concentrated HCl, and then diluted with anhydrous Et2O to the point of cloudiness. As crystals formed, additional Et2O was added in small increments, allowing clearing crystallization between each addition. In all, 200 mL Et2O was used.

  After filtering,Et2O washing, and air drying, there was obtained 6.2 g of 2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DMA) as fine white crystals with a mp of 117-118 !C. The mixed mp with 2,5-DMA (114-116 !C) was depressed to 96-105 !C. An alternate synthesis gave the same overall yield of an identical product, but started with 2,5-DMA. It required two synthetic steps. The free base amine was converted to the crystalline formamide with formic acid in benzene using a Dean Stark trap, and this intermediate was reduced to METHYL-MDA with LAH.

  DOSAGE: above 250 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 250 mg) There is a slight paresthesia at about 45 minutes, an awareness on the surface of the skin as if I had been touched by a cold draft of air. But nothing more. At three hours, I am completely out, if I was ever in. In the evening I assayed 120 milligrams of MDMA, and it barely produced a threshold effect, so the two materials might be seeing one another.

  EXTENSIONS AND COMMENTARY: This is a difficult compound to pin down in the anthology of drugs. For some reason it has intrigued several independent, quiet researchers, and I have accumulated a number of interesting reports over the years. One person told me that he had felt nothing at up to 60 milligrams. Another had found a threshold at 50 milligrams, and had complete and thorough experiences at both 150

  and 200 milligrams. Yet another person described two incidents involving separate individuals, with intravenous administrations of 0.2 mg/Kg, which would be maybe 15 or 20 milligrams. Both claimed a real awareness in a matter of minutes, one with a tingling in the ge
nitalia and the other with a strange presence in the spine. Both subjects reported increases in body temperature and in blood pressure.

  Apparently the effects were felt to persist for many hours.

  There is an interesting, and potentially informative, convergence of the metabolite of one drug with the structure of another. Under 4-MA, mention was made of a bronchodilator that has been widely used in the treatment of asthma and other allergenic conditions. This compound, 2-methoxy-N-methylamphetamine is known by the generic name of methoxyphenamine, and a variety of trade names with Orthoxine (Upjohn) being the best known. The typical dosage of methoxyphenamine is perhaps 100 milligrams, and it may be used several times a day. It apparently produces no changes in blood pressure and only a slight cardiac stimulation. And one of the major metabolites of it in man is the analogue with a hydroxyl group at the 5-position of the molecule.

  This phenolic amine, 5-hydroxy-2-methoxy-N-methylamphetamine is just a methyl group away from METHYL-DMA; it could either be methylated to complete the synthesis, or METHYL-DMA could be demethylated to form this phenol. There is plentiful precedent for both of these reactions occuring in the body. It is always intriguing when drugs which show distinctly different actions can, in principle, intersect metabolically at a single structure. One wonders just what the pharmacology of that common intermediate might be.

  Three additional N-methylated homologues of known psychedelics warrant mention, but do not really deserve separate recipes. This is because they have had only the most cursory assaying, which I have learned about by personal correspondence. All three were synthesized by the reduction of the formamide of the parent primary amine with LAH.

  METHYL-TMA (or N-methyl-3,4,5-trimethoxyamphetamine) had been run up in several trials to a maximum of 240 milligrams, with some mental disturbances mentioned only at this highest level. METHYL-TMA-2 (or N-methyl-2,4,5-trimethoxyamphetamine) had been tried at up to 120

  milligrams without any effects. METHYL-TMA-6 (or N-methyl-2,4,6-

  trimethoxyamphetamine) had been tried at up to 30 milligrams and it, too, was apparently without effects. These are reports that I have heard from others, but I have had no personal experience with them.

  Those that I can describe from personal experience are entered separately as recipes of their own. And there are many, many other N-methyl homologues which have been prepared and characterized in the literature, and have yet to be tasted. So far, however, the only consistent thing seen is that, with N-methylation, the potency of the psychedelics is decreased, but the potency of the stimulants appears to be pretty much maintained.

  127 METHYL-DOB; 4-BROMO-2,5-DIMETHOXY-N-METHYLAMPHETAMINE

  SYNTHESIS: To a solution of 6.0 g of the free base of 2,5-dimethoxy-N-methyl-amphetamine (see recipe under METHYL-DMA) in 30

  mL glacial acetic acid there was added, dropwise and with good stirring, a solution of 5.5 g bromine in 15 mL acetic acid. The reaction became quite warm, and turned very dark. After stirring an additional 45 min, the mixture was poured into 200 mL H2O and treated with a little sodium hydrosulfite which lightened the color of the reaction. There was added 20 mL concentrated HCl, and the reaction mixture was washed with 2x100 mL CH2Cl2 which removed most of the color. The aqueous. phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. The removal of the solvent from the pooled extracts under vacuum gave 1.8 g of an oil which was dissolved in 10

  mL IPA, neutralized with concentrated HCl, and diluted with 100 mL

  anhydrous Et2O. No crystals were obtained, but rather an oily and somewhat granular insoluble lower phase. The Et2O was decanted, and the residue washed by grinding up under 3x100 mL Et2O. The original decanted material was combined with the three washes, and allowed to stand for several h. The product

  4-bromo-2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DOB) separated as fine white crystals which weighed, after filtering and air drying, 0.3 g and had a mp of 149-150 !C. The Et2O-insoluble residue finally set up to a pale pink mass which was finely ground under a few mL acetone. Filtration and air drying gave a second crop of product as 0.9 g of pale lavender solids, with a mp of 143-145 !C.

  DOSAGE: greater than 8 mg.

  DURATION: probably rather long.

  QUALITATIVE COMMENTS: (with 8.0 mg) At an hour and twenty minutes, I was suddenly quite light headed. An hour later I must say that the effects are real, and generally good. I am spacey Q nothing tangible.

  And a couple of hours yet later I am still aware. My teeth are somewhat rubby, and as things have been pretty steady for the last three hours, this will prove to be long lasting. There are a lot of physical effects that may be kidding me into providing myself some of the mental. At the sixth hour, I find that this is almost entirely physical. My teeth are tight, there is a general physical tenseness, my reflexes seem exaggerated, and my eyes are quite dilated. All of these signs are lessened by the eighth hour, and do not interfere with sleep at the twelfth hour. There is no desire to proceed any further, at least at the present time. Mental (+) physical (++). Next day, slight impression of persistence of toxicity.

  (with 10 mg) Nothing psychedelic, but awfully hard on the bod. The next day (24 hours later) I had a severe response to 5 milligrams of psilocybin.

  EXTENSIONS AND COMMENTARY: The mention above, of the 10 milligrams of METHYL-DOB followed by 5 milligrams of psilocybin, leads to some interesting speculation. The usual pattern that is seen when two psychedelic drugs are taken too closely together is that the second experience is less effective than would have been expected. This is the property that is called tolerance, and it is frequently seen in pharmacology. The two exposures may be to a single drug, or they may be to two different drugs which usually have some properties in common. It is as if the spirit of the receptor site had become a little tired and needed a while to rest up and recuperate. When there is a demand for a repeat of full effectiveness, the user will customarily increase the dosage of the drug that is used. It is one of the built-in protections, in the area of psychedelics that, after one experience, you must wait for a period of time to lose the refractoriness that has set in.

  The measure of the degree of tolerance that can be shared between different drugs, called cross-tolerance, can be used as an estimate of the similarities of their mechanisms of action. In other words, if A and B are somehow seen by the body as being similar, then a normally effective dose of A will make a next-day's normally effective dose of B weaker than expected. Or not active at all. And B will do the same job on A. If two drugs are different in their ways of doing things in the body, there is most often no cross-tolerance seen. This was described for MDMA and MDA, and is the basis of the argument that they act by distinctly separate mechanisms. A person who used what would be held as an active dose of MDMA for several days lost all response to the drug. He was tolerant to its effects. But an exposure to an effective dose of MDA at the time that tolerance to MDMA was complete, provided a normal response to the MDA. The drugs are not cross-tolerant and the body recognizes them as distinct individuals.

  But for one drug to promote, or to exaggerate, the effect of another is called potentiation, and can be a clue to the dynamics going on in the brain or body. Here, admittedly in only a single report, METHYL-DOB had somehow sensitized the subject to a rather light dosage of psilocybin. But there have been other reports like this that I have heard of, from here and there. I have been told of an experiment with the dextro-isomer of DOM (this is the inactive optical isomer) at a level that was, not surprisingly, without any effects. The researcher had a severe reaction the following day with what was referred to as RpoorS hashish. A similar form of potentiation has been commented upon under the recipe for TOMSO, where an inactive drug, and a most modest amount of alcohol, add together to create an unexpectedly intense intoxication. But note that in each of these cases, it is a phenethylamine interacting with a non-phenethylamine (psilocybin is an indole, hashish is a non-alkaloid terpene thing, and alcohol is, well, alcohol).

&nb
sp; The bottom line with METHYL-DOB is, as with the other N-methylated psychedelics, that it is way down in potency, and probably not worth pursuing.

  128 METHYL-J; MBDB; EDEN;

  2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE; N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

  SYNTHESIS: A solution of 0.12 g mercuric chloride in 180 mL H2O was added to 5 g aluminum foil that had been cut into 1 inch squares, and amalgamation allowed to proceed for 0.5 h. The gray cloudy aqueous phase was decanted, and the resulting aluminum washed with 2x200 mL

  H2O. After shaking as dry as possible, there was added, in sequence, a solution of 7.6 g methylamine hydrochloride in an equal weight H2O, 23 mL IPA, 18.3 mL 25% NaOH, 6.72 g

  1-(3,4-methylenedioxyphenyl)-2-butanone (see under the recipe of J for its preparation), and finally 44 mL additional IPA. The mixture was occasional swirled, and cooled externally as needed to keep the temperature below 50 !C. After the reduction was completed (no metallic aluminum remaining, only gray sludge), it was filtered and the residues washed with MeOH. The combined filtrate and washes were stripped of organic volatiles under vacuum, the residue treated with 100 mL Et2O, and this was extracted with 2x50 mL 3 N HCl. After washing the pooled aqueous extracts with 3x100 mL CH2Cl2, they were made basic with an excess of 25% NaOH and extracted with 5x50 mL

  CH2Cl2. Drying of these extracts with anhydrous MgSO4 and removal of the solvent gave a residue that was distilled at 88 !C at 0.08 mm/Hg to give a colorless oil that was dissolved in IPA and neutralized with concentrated HCl. The solids that separated were removed by filtration, Et2O washed, and air dried to provide 6.07 g 2-methylamino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (METHYL-J or MBDB) as white crystals with a mp of 156 !C. Anal.