Pihkal

by Alexander Shulgin

  DOSAGE: 15 - 25 mg.

  DURATION: 8 - 16 h.

  QUALITATIVE COMMENTS: (with 20 mg) There were some very pleasant visuals starting at 2-2.5 hours and continuing to 4-5 hours after the beginning of the experiment. Open eye visuals seem to come on after staring at particular areas, such as the living room ceiling or at trees. The surroundings tended to move slightly. There was no flowing of the images at all. When looking at the pine trees, the needles appeared crystal clear and sharply defined, with strong contrasts. Though the mental effect is difficult to define, I am not sure it was all that great. I did become tired of the effect (along with the confusion) after 8 hours, and was quite happy to note that it did taper off in the early evening. I am not particularly sure I would want to try this material again.

  (with 20 mg) For the first three or so hours, the beauty of the experience was marred by a strange discomfort. There was some queasiness, and I felt a sluggishness of mind. Then I began moving in and out of a pleasant place, and finally the discomfort completely dissolved and the experience turned full on. Height of beauty, visual perception. Lights below are amazing. Outside, marvelous sense of Presence. There is not an elation, as often with other materials, but a strong, even powerful sense of goodness, inner strength, solidity.

  (with 25 mg) This was quite quick. The onset of the experience was apparent within a half hour, and we were both at +++ within the hour.

  Body load minimal. There was very little visual, compared with some materials. Very interesting eyes-closed, but not continually Q just now and then an intense vision might flash. Very benign and friendly and pleasant and good-humored feeling. Superb for conversation and conceptualization.

  (with 25 mg) The body load was quite noticeable for everyone. But the general state of mind was excellent; everyone was extremely relaxed and funny. Puns, insults, delightful amusement. Not very much insight work possible. Juices were needed and tolerated well, but no one was particularly hungry. Sleep was difficult for most people, not deep and not too refreshing. Excellent material, but body price a bit too much for the mental effects. Pleasant, and I wouldnUt hesitate to take it again, but nothing very memorable except the tremendous humor and laughter, which was truly delightful.

  EXTENSIONS AND COMMENTARY: This compound, BOD, was the first exploratory member of a new family of phenethylamines. This family is called the BOX series because an oxygen atom has been put on the benzylic carbon (the Rbenzyl-oxyS or RBOS) of each of several well studied drugs with recognized substituent patterns on the aromatic ring. The RXS would be RD,S as used here with BOD, making reference to 2C-D, it would be a RBS in BOB making reference to 2C-B, etc.

  Actually the original thought was to make the ROS into an ROMS for methoxy, as this would allow more versatility in the naming of things such as ethoxys (ROES) or hydroxys (ROHS), but the methoxylated 2C-B

  analogue would have come out as BOMB, so the idea was dropped.

  Actually, the concept of naming of drugs with some acronym that is pronounceable has led into some interesting byways. Some examples have been unintended. I have heard DOM pronounced RdomeS and DOET

  pronounced as Rdo it.S And elsewhere I have mentioned the embarrassing occasions where the TOM and TOET families were pronounced Rthe toms and twats.S Some examples have had names that have been contractions of popular names, such as XTC for ecstasy. And there are instances where a name might be proposed simply to irritate the newspaper people. An early street suggestion for PCP was FUK, and a current name for free-base methamphetamine is SNOT. And marijuana is fondly called SHIT by its aficionados. The final RAS on government groups such as the CIA or the DEA or the FDA is strongly reminscent of the final RAS which stands for amphetamine in things such as TMA and MDMA.

  Might there someday be a drug such as 4-cyclopropylmethyl-N-isopropylamphetamine (CIA), or 3,5-dimethoxy-4-ethylamphetamine (DEA)? It has just occurred to me that there is already a 4-fluoro-2,5-dimethoxyamphetamine (FDA), but I have already named it DOF. If all drugs were known only by publicly embarrassing names, there might be less publicity given them by the press.

  Back to the commentary on BOD. The rationale for this inclusion of a beta-oxygen atom into the structure of a phenethylamine is based directly on the chemistry that occurs naturally in the brain. The phenethylamine neurotransmitter, dopamine, is converted both in the brain and in the body to the equally important transmitter norepinephrine by just this sort of transformation. There is the enzymatic addition of an oxygen atom to the RbenzylicS position of dopamine. And identical chemistry goes on with tyramine in a number of plants and animals, with a similar addition of oxygen to form octopamine, so-named for its discovered presence in the salivary glands of Octopus vulgaris. In the first explorations in the BOX

  series, this oxygen was intentionally blocked with a methyl group, to ease its entry into the brain, and increase the possibilities of its being active as a psychedelic. As mentioned above, the RDS in BOD

  follows from its ring orientation pattern being the same as that of 2C-D (and this, originally from the mimicking of the pattern of DOM).

  All of these D- compounds have the 2,5-dimethoxy-4-methyl ring-substitution pattern.

  An interesting complication is also part of this structure package.

  The added methoxy group (or hydroxy group, see recipe for BOHD) also adds a new asymmetric center, allowing for the eventual separation of the material into two optical isomers. And at such time as the corresponding amphetamine homologues might be made and studied, the presence of yet another chiral center (under the alpha-methyl group) will demand that there be actually two racemic compounds synthesized, and a total of four isomers to contend with, if really careful and thorough work is to be done.

  A parallel chemistry to all of this follows the addition of sodium ethoxide (rather than sodium methoxide) to the nitrostyrene. The final product, then, is the ethoxy homologue 2,5-dimethoxy-'-ethoxy-4-methylphenethylamine, or BOED. It is down in human potency by a factor of three, with a normal dosage being 70-75

  milligrams. It has a ten hour duration, and is both anorexic and diuretic. There have been no visual effects or insights reported, but rather simply a highly intoxicated state.

  Two synonyms, two definitions, and an expression of admiration. The word norepinephrine is synonymous with noradrenalin, and the word epinephrine is synonymous with adrenalin. The distinctions are that the first in each case is American and the second British. And the term RchiralS indicates a potential asymmetry in a molecule that would allow eventual separation into two optical isomers. The term RracemicS refers to a mixture of these two isomers which has not yet been separated into the individual components. A racemic mixture is called a racemate and, from the point of view of the human animal (which is completely asymmetric), must be considered as a mixture of two structurally identical but optically mirror-image isomers, which can be potentially separated and which will certainly have different pharmacologies. And the admiration? This is directed to the explorer who ventured close enough to an octopus to locate its salivary glands and to discover a phenethylamine there!

  15 BOH; '-METHOXY-3,4-METHYLENEDIOXYPHENETHYLAMINE

  SYNTHESIS: To a solution of 30 g piperonal in 100 mL acetic acid there was added 20 mL nitromethane and 10 mL cyclohexylamine. After heating on the steam bath for 1.5 h, the reaction mixture started to crystallize. The mixture was cooled in an ice bath, and the heavy mass of deposited crystals removed by filtration and washed with 20 mL

  acetic acid. All was supended in 100 mL warm MeOH, cooled again, and filtered to give 24.5 g of 3,4-methylenedioxy-'-nitrostyrene as canary-yellow crystals, with a mp of 158-160 !C. Reduction of this compound with LAH gives rise to MDPEA, which is a separate entry with a recipe of its own.

  To a vigorously stirred suspension of 20 g 3,4-methylenedioxy-'-nitro -styrene in 100 mL anhydrous MeOH there was added a freshly prepared solution of 5.5 g elemental sodium in 100 mL MeOH. The nitrostyrene goes into solution over the course of 5 min. There was the
n added, first, 50 mL acetic acid with the stirring continued for an additional 1 min. There was then added 300 mL H2O. An oil separated and was extracted into 200 mL CH2Cl2. The organic extract was washed with 500

  mL dilute aqueous NaHCO3, followed by 500 mL H2O. Removal of the solvent gave a residue that was distilled at 128-145 !C at 0.4 mm/Hg, providing 16.6 g of a yellow viscous liquid which slowly crystallized.

  An analytical sample was recrystallized from four volumes of MeOH to give 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane as bright yellow crystals with a mp of 58-59 !C. Anal. (C10H11NO5) C,H.

  A solution of LAH (100 mL of 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 2.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 12 g

  1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane over the course of 2 min. There was an immediate loss of color. After a few minutes further stirring, the temperature was brought up to a reflux with a heating mantle. There was a gentle gas evolution for a few min, followed by an exothermic reaction that exceeded the capacity of the condenser. Once the reaction had subsided, the unreacted hydride was destroyed with a minimum of IPA, and 15% NaOH was added to convert the inorganics to a loose white filterable mass. The reaction mixture was filtered, and the filter cake washed thoroughly with THF. The combined filtrate and washes were stripped of solvent under vacuum, providing an orange oil. This was dissolved in 400 mL dilute H2SO4, which was washed with 3x75 mL CH2Cl2. After making the aqueous phase basic, it was extracted with 2x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue distilled at 103-112 !C at 0.5 mm/Hg. There was obtained 2.5 g of a colorless, viscous oil which was dissolved in 25 mL IPA, neutralized with 45

  drops of concentrated HCl, and finally diluted with 30 mL anhydrous Et2O. There was thus formed

  '-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (BOH) as a fine white crystalline product. The mp was 105-106.5 !C, with bubbling and darkening. The mp properties proved to be inconsistent, as the salt was a hydrate. Recrystallization from CH3CN, or simply heating to 100 !C in toluene, converted the salt to an anhydrous form, with mp of 152-153 !C. Anal. (C10H14ClNO3) C,H.

  DOSAGE: 80 - 120 mg.

  DURATION: 6 - 8 h.

  QUALITATIVE COMMENTS: (with 90 mg) Distinct body awareness in an hour. The threshold is mostly physical. Faint sense of inside warmth, skin prickling, cold feet, loose bowels, anorexia. By the fifth hour, I was on the downslope, and in retrospect I found it good humored but not insightful.

  (with 100 mg) There was a vague nausea, and a chilling of the feet.

  It reached a real plus two, with dilated pupils and quite a thirst.

  How can one describe the state? There were no visuals, and I was not even stoned. I was just very turned on. And I was completely back to baseline by hour number six.

  EXTENSIONS AND COMMENTARY: There are several reports of a nice, mild mood enhancement in the 20-40 milligram dosage area, but searches for psychedelic effects at higher levels gave a strange mix of some sort of an altered state along with bodily discomfort. The BOH name for this member of the BOX family follows the convention discussed in the BOD recipe Q with RHS for homopiperonylamine, the simplest of the muni-metro family, q.v. The demethylated homologue of BOH is BOHH, and is the methylenedioxy analogue of norepinephrine. It might well hydrolytically open up in the body to provide this neurotransmitter, and serve as some sort of transmitter in its own right. It is discussed under DME.

  Maybe there is something to the concept that when you imitate a neurotransmitter too closely, you get a hybrid gemisch of activity.

  The term Rpro-drugS is used to identify a compound that may not be intrinsically active, but one which metabolizes in the body to provide an active drug. I feel the term should have been pre-drug, but pro-drug was the word that caught on. BOH may well act in the body as a pro-drug to norepinephrine, but with the temporary blocking of the polar functions with ether groups, it can gain access to the brain.

  And once there, it can be stripped of these shields and play a direct neurological role. I uncovered a very similar analogy in the tryptamine world some years ago. Just as norepinephrine is a neurotransmitter, so is serotonin. And I found that by putting an O-ether on the indolic phenol (to hide its polarity) and an alpha-methyl group next to the primary amine (to protect it from metabolic deaminase), it became an extremely potent, and most complex, psychedelic. This was the compound alpha,O-dimethylserotonin, or a,O-DMS. There is an uncanny analogy between this tryptamine and the phenethylamine BOH.

  Somehow the quiet voice deep inside me says, donUt use too much, too quickly. Maybe one of the optical isomers is the body thing, and the other isomer is the mind thing. So far, only the racemic mixture has been tasted, to the best of my knowledge.

  16 BOHD; 2,5-DIMETHOXY-'-HYDROXY-4-METHYLPHENETHYLAMINE

  SYNTHESIS: A solution of 0.4 g

  1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane (see preparation in the recipe for BOD) in 3.0 mL acetic acid was heated to 100 !C on a steam bath. There was added 1.0 g powdered zinc, followed by additional acetic acid as needed to maintain smooth stirring.

  After 0.5 h there was added 1.0 mL concentrated HCl and, following an additional few minutes heating, the reaction mixture was poured into 300 mL H2O. After washing the aqueous phase with 3x75 mL CH2Cl2, the mixture was made basic with 25% NaOH, and extracted with 3x50 mL

  CH2Cl2. Removal of the solvent and distillation of the residue at 130-140 !C 0.25 mm/Hg gave an oil that, on dissolving in IPA, neutralization with concentrated HCl, and the addition of anhydrous Et2O, gave beautiful white crystals of 2,5-dimethoxy-'-hydroxy-4-methylphenethylamine hydrochloride (BOHD).

  The yield was 0.2 g, and the mp was 180-181 !C. The infrared spectrum was that of an amine salt with a strong OH group present. Anal.

  (C11H18ClNO3) C,H.

  DOSAGE: greater than 50 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 50 mg) At about the two hour point, there was a precipitous drop of blood pressure (from 120/72 to 84/68) although the pulse stayed steady at 60. This trend had been apparent in earlier trials, and was being watched carefully. No further tests are planned.

  EXTENSIONS AND COMMENTARY: The usual method of making beta-ethanolamine such as this is through the reduction of the cyanohydrin of the corresponding benzaldehyde and, in fact, that method is described in the recipe for DME. This above procedure was actually part of an exploration of different agents that might be used in the reduction of the intermediate nitroalkane. This product was the unexpected result of trying zinc.

  Why the potent cardiovascular effect seen by this compound? There are a couple of points that might argue for some adrenolytic toxicity.

  This material is a beta-ethanolamine and, with maybe one or two exceptions, clinically used beta-receptor blockers are beta-ethanolamines. In fact, a few of these so-called beta-blockers actually have two methoxy groups on the aromatic rings, also a property of BOHD. The antidiabetic drug Butaxamine (BW 64-9 in the code of Burroughs Wellcome) is identical to BOHD except that the 4-methyl group is on the alpha-carbon instead, and there is a tertiary butyl group on the nitrogen atom. Another point involves the proximity of the beta-hydroxy group and the methoxyl oxygen atom in the 2-position of the ring. There is going to be a strong hydrogen-bonding with this orientation, with the formation of a stable six-membered ring. This might help obscure the hydrophilic nature of the free hydroxyl group and allow the compound to pass into the brain easily. If this group is masked by an easily removed group such as an acetate ester, one gets the compound

  beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is similar to BOHD as a hypotensive.

  The code-naming procedure used here (and elsewhere here in Book II) is: (1) to use RBOS as the alert to there being an oxygen on the benzyl carbon of a phenethylamine (it is a benzyl alcohol); (2) if there is j
ust one more letter (a third and last letter) it will identify the 2C-X parent from which it has been derived [RBS comes from 2C-B, RDS comes from 2C-D, RHS comes from homopiperonylamine (MDPEA) rather than from 2C-H, RMS comes from mescaline, and in every case the beta-substituent is a methoxy group]; and (3) if there are four letters, then the fourth letter is as above, and the third letter (the next to last letter) is the substituent on that benzylic oxygen.

  With a three letter code, the substituent is a methyl group, an RHS

  for a third letter of four makes it a hydroxyl group, and an RAS for the third letter is an acetyl group, and an RES is for an ethyl group.

  A similar sort of cryptographic music was composed by Du Pont in their three-number codes for the Freons. The first number was one less than the number of carbons in the molecule, the second number was one more than the number of hydrogens in the molecule, the third number was the exact number of fluorines in the molecule, and the rest of the bonds were filled with chlorines, Thus Freon 11 (really Freon 011) was trichlorofluoromethane and Freon 116 was hexafluoroethane.