Pihkal

by Alexander Shulgin

  (with 14 mg) Very rational, benign, and good humored. The insight and calm common to the 2C-T's are present, with less of the push of body-energy which makes 2C-T-2 difficult for some people. There are no particular visuals, but then I tend to screen them out consistently, except in cases of mescaline and LSD and psilocybin, so I canUt judge what others would experience in the visual area. The eyes-closed imagery is very good without being compelling. The decline is as gradual and gentle as the onset. I am fully capable of making phone calls and other normal stuff. Music is marvelous, and the body feels comfortable throughout.

  (with 14 mg) Persistent cold feet, and an uncertain stomach when moving around. Brilliant color trails reminiscent of 2C-B. But a change is occurring and I canUt talk myself out of it. There are dark corners. If I were with other people, this would bring out the worst in me, which can be pretty bad.

  (with 19 mg) I was caught by the TV. Leonard Bernstein conducting West Side Story. I think I know every note. This was a 1985

  rehearsal with the goofs and the sweat. And now Peter, Paul and Mary, grown older along with the songs we all sang. Where Have All the Flowers Gone Q and an audience of grown-older people singing Puff the Magic Dragon like earnest children and probably crying along with me.

  It is good to have lived through the 60's and not to be in them now.

  Now there's a new song about El Salvador and itUs the battle all over again on a different field, but it will always be so, until and unless. Now, in the 80Us, I donUt get really angry anymore. I am more warrior than angry protester, and that's a much better way to be.

  In fact, I am quite happy to be where I am. I know a lot more about the game, and what it is, and why it is played, and I have a good idea about my part in it, and I like the part IUve chosen.

  (with 22 mg) The transition took place over three hours, an alert in 30 minutes followed by a slow and gentle climb. I found it difficult, not physically but mentally since I was for a while locked into the illogical and disconnected aspects of human experiences and expressions, particularly laws and pronouncements and unseeing prejudices, most of which I was picking up from reading the Sunday paper book reviews. As time went on, things became less pushy and I came to be at ease with very positive feelings about everything going on. No self-rejecting aspect at all. Sleep was excellent, but the next day things went slowly and I had to nap a bit. Next time, maybe 18 milligrams.

  EXTENSIONS AND COMMENTARY: There are shades of the variability of the Alephs. Some observers are overwhelmed with colors and visual activity; others volunteer their absence. And a very wide range of dosages represented, from an estimated 4 or so milligrams for full effects, to something over 20 milligrams without any loss of control.

  That is an unusually wide lattitude of activity. And a rich variety of effects that might be experienced. The same wide range of effective dosages was also observed with the corresponding Tweetio.

  The 2-EtO-homologue of 2C-T-4 is

  2-ethoxy-5-methoxy-4-(i)-propylthiophenethylamine, or 2CT4-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(i-propylthio)benzaldehyde had a melting point of 43-44 !C, the nitrostyrene intermediate a melting point of 77-79 !C, and the final hydrochloride a melting point of 153.5-154 !C. There were practically no differences between trials at 5 milligram increments within the 10 and 25 milligram range. Each produced a gentle plus two level of effect which lasted for some 10

  hours. A code name of RtendernessS was felt to be appropriate, as there was a peaceful meditative inner receptiveness and clarity noted, with an honest connection felt with those who were present during the experience. Sleep was not comfortable.

  I have heard 2C-T-4 referred to as T-4. There is a potent explosive used by terrorists called cyclotrimethylenetrinitramine, known by the code name RDX, or T-4. There is also a T-4 term that refers to thyroxine, an amino acid in the body. The drug 2C-T-4 is neither an explosive nor an amino acid, I am happy to say.

  42 Y-2C-T-4; 2,6-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE) SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an external ice bath, and then treated with 67 mL 1.5 M lithium diisopropylamide in hexane which was added over the course of 10 min.

  The reaction mixture was allowed to return to room temperature and the stirring was continued for 0.5 h. The mixture was poured into dilute H2SO4, the organic layer was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The organic phases were combined, dried over anhydrous K2CO3, and the solvent removed under vacuum. The resulting 4.54 g of almost colorless oil was distilled at 85-95 !C at 0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a colorless oil, showing a single spot on TLC with no indication of starting chlorobenzene. The product formed a picrate salt, but this had an unsatisfactory mp character (partly melting at 45-47 !C, and then completely at about 80-90 !C). The microanalysis for this picrate was low in the carbon value, although the hydrogen and nitrogen were excellent. Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58, 44.45.

  To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl sulfide and 3.5 mL N,N,NU,NU-tetramethylethylenediamine in 25 mL

  anhydrous Et2O that had been cooled to -78 !C with a dry-ice/acetone bath, there was added 10 mL 2.5 M hexane solution of butyllithium.

  The mixture was allowed to return to room temperature, and there was added 3.5 mL DMF which caused the yellow color to progressively darken. The reaction mixture was poured into dilute H2SO4, the Et2O

  layer was separated, and the aqueous phase extracted with 3x75 mL

  EtOAc. The solvent was removed from the combined organic phases, and the residue distilled at 0.15 mm/Hg to give two fractions. One, boiling at 120-140 !C, was 0.98 g of a pale yellow mobile liquid, which was part starting sulfide and part product aldehyde by TLC. The second cut, boiling at 160-180 !C, was a viscous liquid, weighed 1.66

  g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This formed a crystalline anil with 4-methoxyaniline (by fusing equimolar amounts of the two with a flame) which, after recrystallization from MeOH, gave fine yellow crystals with a mp of 87.5-89 !C. Anal.

  (C19H23NO3S) C,H.

  A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL

  nitromethane was treated with 0.2 g anhydrous ammonium acetate and heated on the steam bath for 1 h. The excess reagent/solvent was removed under vacuum, and the residue spontaneously solidified. This was recrystallized from 5 mL MeOH to give 0.70 g 2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy solid, with a mp of 83-84.5 !C. Anal. (C13H17NO4S) C,H.

  A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He to 0 !C with an external ice bath. With good stirring there was added 0.54 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.54 g

  2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene in a small volume of anhydrous THF. The color was discharged immediately. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for about 10 min, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of IPA followed by sufficent 15% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed well with THF. The filtrate was stripped of solvent under vacuum and the residue dissolved in 100 mL of dilute H2SO4. This was washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2. The residue remaining after the removal of the solvent was distilled at 130-140 !C at 0.05 mm/Hg to give 0.11 g of a white oil. This was dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl and diluted with 50 mL anhydrous Et2O. After filtration of the formed crystals, Et2O washing, and air drying, there was obtained 80 mg of 2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (y-2C-T-4) as fine white crystals. The removal of the solv
ent from the CH2Cl2

  washes of the dilute H2SO4 solution gave a H2O-soluble white solid that proved to be the sulfate salt of the product. This provided, after making the H2O solution basic, extraction with CH2Cl2, and solvent removal, the free base that was converted, as described above, to a second crop of the hydrochloride salt.

  DOSAGE: above 12 mg.

  DURATION: probably short.

  QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1, and with a very good feeling. But I cannot say how long it lasted, and it was probably pretty short. It just sort of faded away.

  (with 12 mg) At the 25 minute point I am reminded of the experiment, and in another quarter hour I am into something. Will this be another forever threshold? I feel very good, but there is no sparkle.

  EXTENSIONS AND COMMENTARY: Here is another example of the presentation of a compound for which there has not yet been an effective level determined. Why? For a very good reason. This is an example of a whole class of compounds that I have called the pseudos, or the y-compounds. Pseudo- as a prefix in the literary world generally stands for Rfalse.S A pseudopod is a thing that looks like a foot, but isnUt one. A pseudonym is a fictitious name. But in chemistry, it has quite a different meaning. If something has a common name, and there is a second form (or isomer, or shape, or orientation) that is possible and it doesnUt have a common name, it can be given the name of the first form with a Rpseudo-S attached. Ephedrine is the erythro-isomer of N-methyl-'-hydroxyamphetamine. There is a second stereoisomer, the threo- isomer, but it has no trivial name. So it is called pseudoephedrine, or the RSudafedS of sinus decongestant fame.

  The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of the 2,4,5-trisubstituted psychedelics. Almost all of the 2,5-dimethoxy-4-something-or-other compounds are active and interesting whether they be phenethylamines or amphetamines, and it is an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds are going be just as active and just as interesting. A number of examples have already been mentioned. TMA-2 is 2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with a methoxyl at the 4-position). The pseudo- analogue is TMA-6

  (2,4,6-trimethoxyamphetamine) and it is every bit as potent and fascinating. Z-7 could be called pseudo-DOM, and although it is quite a bit down in potency, it is an active drug and will both demand and receive much more clinical study some day.

  Will the other 2,4,5-things spawn 2,4,6-things that are active?

  Without a shadow of a doubt. Chemically, they are much more difficult to synthesize. The 2,5-dimethoxy orientation made the 4-position a natural and easy target. The 2,6-dimethoxy orientation pushes for 3-substitution, and the 4-position is completely unnatural. Tricks are needed, but tricks have now been found. The above synthesis of pseudo-2C-T-4 shows one such trick. This is, in my opinion, the exciting chemistry and psychopharmacology of the next decade. Well over half of all the psychedelic drugs mentioned in Book II are 2,4,5-trisubstituted compounds, and every one of them has a (potentially active) 2,4,6-pseudo-counterpart.

  It goes yet further. The antidepressant series of RAriadneS compounds are 1-phenyl-2-aminobutanes. But the 1-phenyl is again a 2,4,5-trisubstituted compound. The 2,4,6-isomer will give rise to a pseudo-Ariadne family, and I will bet that they too will be antidepressants. The 1-phenyl-2-aminobutane analog of y-2C-T-4 is the 2,4,6-analogue and it has been prepared as far as the nitrostyrene.

  It has not yet been reduced, so it is not yet been evaluated, but it could be a most remarkable psycho-pharmacological probe.

  And it goes yet yet further. Think back to the six possible TMAUs.

  TMA and TMA-3 were relatively inactive. And TMA-2 and TMA-6 were the interesting ones. The first gave rise to the last twenty years of psychedelic chemistry, and the other (as speculated upon above) will give rise to the forthcoming ten years. But what of TMA-4 and TMA-5?

  Both showed activity that was more than TMA but less than that of the -2 or -6 isomers. Could they, some day, provoke yet other families of psychedelics? Maybe the 3-position of these two might be focal points of leverage as to psychological activity. What are the letters that follow y in the Greek alphabet? If I remember correctly, the next letter is the last letter, omega. So, I guess that Nature is trying to tell us something, that the -4 and -5 isomers will not engender interesting families. What a pity. The chemistry is so unthinkably difficult that it would have been a true challenge. My next incarnation, maybe?

  43 2C-T-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE

  SYNTHESIS: To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under the recipe for 2C-T-2 for its preparation) and 7.4 g (n)-propylbromide dissolved in 20 mL MeOH. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for 0.5

  h, added to 800 mL H2O, additional aqueous NaOH added until the pH was basic, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with dilute NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl (n)-propyl sulfide which was obtained as a pale yellow oil, and which weighed 8.9 g. It had a light pleasant fruity smell, and was sufficiently pure for use in the next reaction without distillation.

  A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 8.9 g of 2,5-dimethoxyphenyl (n)-propyl sulfide, and the mixture heated an additional 25 min on the steam bath. This was then added to 800 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued until the oily phase had completely solidified (about 15

  minutes). The resulting brown sugar-like solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, they were dissolved in an equal weight of boiling MeOH

  which, after cooling in an ice-bath, deposited pale ivory colored crystals. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 8.3 g of 2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde with a mp of 73-76 !C.

  Recrystallization from 2.5 volumes of MeOH provided a white analytical sample with mp 76-77 !C. The NMR spectrum in CDCl3 was textbook perfect, with the two aromatic protons showing singlet signals at 6.81

  and 7.27 ppm, giving assurance that the assigned location of the introduced aldehyde group was correct.

  To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde in 20

  g of nitromethane there was added 0.23 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The clear orange solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. The orange-yellow crystalline material that remained was crystallized from 70 mL boiling IPA which, on slow cooling, deposited 2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene as orange crystals.

  After their removal by filtration and air-drying to constant weight, they weighed 3.6 g, and had a mp of 120-121 !C. Anal. (C13H17NO4S) C,H.

  A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.4 g

  2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene in 50 mL anhydrous THF.

  There was an immediate loss of color. After a few min further stirring, the tem-perature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of IPA (21 mL required) followed by sufficent 5% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (15 mL was used).

  The reaction mixture was filtered and the filter cake washed first with THF and then with IPA. The filtrate and washes were combined and stripped of solvent under vacuum providing about 6 g of a pale amber oil. Without any further purification, this was distilled at 140-150

  !C at 0.25 mm/Hg to give 4.8 g of pro
duct as a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. An equal volume of anhydrous Et2O was added, and after complete grinding and mixing,

  2,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (2C-T-7) was removed by filtration, Et2O washed, and air dried to constant weight. The resulting spectacular white crystals weighed 5.2 g.

  DOSAGE: 10 - 30 mg.

  DURATION: 8 - 15 h.

  QUALITATIVE COMMENTS (with 20 mg) A wonderful day of integration and work. Took about 2 hours for the onset. Some nausea on and off Q

  that seemed to cycle periodically throughout the day. Visuals were great, much like mescaline but less sparkly. Lots of movement and aliveness Q velvety appearance and increased depth perception. Neck and shoulder tension throughout the day along with legs. I would periodically notice extreme tightness of muscles, and then relax.

  Working was very integrative. Back and forth constantly between wonderful God-space Q similar to MDMA but more grounded Q then always back to sadness. I felt that it really showed me where I was unfinished, but with self-loving and tolerance. Tremendous processing and letting go. Seeing things very clearly and also able to laugh at my trips. Lots of singing. In spite of shoulder tension, vocal freedom and facility were very high. I felt my voice integrated and dropped in a way it never had before, and that remained for several days. Able to merge body, voice, psyche and emotions with music and then let go of it as a role. I also realized and gave myself permission to do whatever it takes to get free. I let go of Dad with tragic arias. The next day I let go of Mom by singing Kaddish for her, and merging with it.

  (with 20 mg) I lay down with music, and become engrossed with being as still as possible. I feel that if I can be totally, completely still, I will hear the inner voice of the universe. As I do this, the music becomes incredibly beautiful. I see the extraordinary importance of simply listening, listening to everything, to people and to nature, with wide open receptivity. Something very, very special happens at the still point, so I keep working on it. When I become totally still, a huge burst of energy is released. And it explodes so that it takes enormous effort to quiet it all down in order to be still again. Great fun.