(with 0.3 mg of the RRS isomer) Maybe slightly wiry? No effects.
(with 0.5 mg of the RRS isomer) There is a real effect, and it is significant that the first effects of the racemate were noted at 1.0
milligram. There is a trace of time slowing and in general a pretty full manic state. There is some mydriasis. Everything had pretty much cleared up by evening.
(with 2.0 mg of theSSS isomer) No effects. There was an unexpected slight tachycardia at the two hour point, but nothing suggesting psychotropic action.
(with 2.6 mg of the RSS isomer) There are signs of both pulse increase and blood pressure increase. There is some teeth-rubbiness, but still no psychological turn on at all.
EXTENSIONS AND COMMENTARY: The rationale for the design and making of DOM has already been discussed. One could predict that it could have been, theoretically, a totally inactive compound and maybe an effective blocker for whatever receptor sites are being occupied by other psychoactive drugs and even for strange things that some unbalanced people might actually make within their bodies, using their own personal chemistry. On the other hand, it could have been a potent psychedelic in its own rights, and if so, probably long lived.
The latter Rcould have beenS proved to be so.
The very modest amount of study of the individual optical isomers clearly indicates that the RRS isomer is the more active. The sparse comments suggest that some of the heavier physical aspects of the racemate might be due to contributions from the RinactiveS RSS isomer.
It is, after all, the RSS isomer of amphetamine that carries the major punch of that stimulant. Maybe if that isomer were removed, and one were to explore the pure RRS isomer of DOM, the dramatic visual aspects of the larger dosages might not be complicated with a troublesome physical component.
This compound, unbeknownst to me, was scattered widely and plentifully in the heyday of the Haight-Ashbury in San Francisco, in mid-1967. It was distributed under the name STP, which was said to stand for Serenity, Tranquility, and Peace. It was also claimed to represent Super Terrific Psychedelic, or Stop The Police. The police called it: Too Stupid to Puke. Actually, the name was taken from the initials of a motor additive which was completely unrelated chemically.
Incredibly, and sadly, one of the avowed experts in the area of the Rsensuous drugsS actually stated that STP, the motor oil additive, was really one and the same as STP, the highly dangerous psychedelic. The motor oil additive, he wrote in a book of his, had properties somewhat related to those of LSD, mescaline, and the amphetamines. How fortunate that the love children of the time didnUt do much reading, for they might have gotten into yet deeper pharmacological troubles with drug raids on the local gasoline stations.
Two complications became apparent during this first appearance and they led to serious difficulties. One, there was no equation made between STP and DOM. No one knew what this drug was which had been distributed in a cavalier way throughout the city. There could be no educated guess as to the best treatment of overdose emergencies. And secondly, the initial tablets that had been distributed apparently contained 20 milligrams of DOM per tablet; later, it was dropped to 10
milligrams. Either of these, in retrospect, is now known to be a thoroughly whopping dose. The overdose situation was aggravated by the slow onset of DOM. The user may be aware of some initial effects at the half-hour point, there will be what might be called a + or ++
at the end of the first hour, and the full impact of the drug is not appreciated until some two hours have elapsed. But many of the recipients of the free handouts of DOM were familiar with LSD which can show its alert in 15 to 20 minutes, or even sooner with a large dose, and there is already a deep and compelling intoxication felt at the half-hour point. They, quite reasonably, expected this familiar activity pattern with STP and assumed, when there was little if any activity noted at the half-hour point, that the potency was less than expected. They took one or even two additional dosage units. Thus, some of the overdose victims of that period may well have taken as much as 30 mg of DOM. The slow onset of action, coupled with the remarkably long duration, caught many innocent users unprepared.
Clinical studies have documented the rapid tolerance development from repeated exposures to DOM. Five volunteers were given 6 milligrams daily for three days. Objectively, psychological tests showed a decrease in responses. Subjectively, all found extremely intense effects on the first day, and all but one found it unpleasant. By the third exposure on the third day, all had diminished responses, ranging from only Rmoderately strongS to Rfelt absolutely nothing.S One actually slept during the experience on the third day.
The hexadeutero-analogue (deuterium atoms on the two methoxyl groups) has been prepared as an internal standard for analytical work, but there are no reports of its human pharmacology. A study with this sort of derivative would be a fine companion to the studies already underway with the mescaline analogues that are similarly substituted.
A difference exists, however. With mescaline, it is believed that the loss of a methoxyl group is a step towards the inactivation of the compound, whereas with DOM this loss may be associated with the formation of an active metabolite. The several fascinating questions raised by possible differences in both the rates and the degree of demethylation of these two compounds are well worth trying to answer.
A number of compounds related to DOM had been synthesized and studied at the University of California at San Francisco, at about this time.
Two of these were simply the juggling of the two methoxyl groups and the methyl group on the ring, still maintaining the 2,4,5-ness relative to the amphetamine chain. These are 2,4-dimethoxy-5-methylamphetamine and 4,5-dimethoxy-2-methylamphetamine. Since the slang name for DOM in and about the medical center was STP, and since STP was the name of a motor oil additive, it is not unreasonable that the first of these to be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by the name of another motor oil additive popular at that time, F-310.
The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp 117-118 !C) with a yellow malononitrile derivative from EtOH with a mp of 193-194 !C. The nitrostyrene from this and nitroethane formed yellow crystals from CH3CN, with a mp 138-139 !C. The amine formed easily with LAH in ether, and the product F-310 (or 5-DOM) gave white crystals from CH3CN with a mp of 182-183 !C.
And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became known familiarly as F-320, or sometimes simply 2-DOM. Its preparation followed an identical procedure, starting from 3,4-dimethoxytoluene.
I have been told that F-310 is not active even at 20 milligrams in man, which would make it several times less potent than DOM (STP). I know of no trials with F-320. The use of the letter RFS does not imply any relationship between these two compounds and the series described elsewhere with the RFS code followed by other numbers, such as F-2 and F-22. These latter are F's because they are furans, not motor oil additives. And yet another oil additive, well known at the time as Z-7, became associated with the synthesis of the DOM (STP) isomer with its groups in the 2,4,6-positions. This is entered separately under y-DOM.
69 Y-DOM; Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE
SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp 92-93 !C from the lithiation of 3,5-dimethoxytoluene followed by reaction with N-methylformanilide) in 10 mL nitroethane, there was added 0.1 g anhydrous am-monium acetate and the mixture was heated on the steam bath for 16 h. Removal of the solvent under vacuum gave a slightly oily red-orange crystalline mass which was finely ground under 1 mL of MeOH. Filtration and a sparing wash with MeOH gave, after air drying, 0.8 g of a light yellow crystalline solid with a mp of 121-122.5 !C. Recrystallization from 4 mL boiling absolute EtOH
gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very light yellow platelets, which melted at 123-124 !C.
To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and un
der He, there was added a solution of 0.3 g 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF. Upon the completion of the addition, the reaction mixture was held at reflux for 48 h. After cooling with an external ice bath there was added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL
H2O. The inorganic solids were removed by filtration, and the filter cake washed with THF. The solvent from the combined filtrate and washings was removed under vacuum, and the residue (0.3 g) was a crystal clear colorless oil with a high refractive index. This was dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted with 35 mL of anhydrous Et2O. After a minute's standing, the solution became turbid, followed by the slow deposition of very fine white crystals. After standing 1 h at room temperature, these were removed by filtration, Et2O washed, and air dried to constant weight. There was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine hydrochloride (y-DOM) with a mp of 203 !C. sharp.
DOSAGE: 15 - 25 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey. I can go from a train of thought straight up into thin air. Then, to get to another one there must be a careful choice of words. Logic has nothing to do with any of it. There is no trace of the MDMA-like magic. This is an interpretive drug, not simply an ASC [altered state of consciousness] opening.
(with 18 mg) There is a light-headedness, and a somewhat starry-eyed stoned state. Nothing visual, and no body concern except for what seems to be a very fine inner tremor. I think that with a little more, things might very well begin to move in the visual field. But I have no feeling of great concern about taking a somewhat higher dosage.
(with 25 mg) I was at a +++ for about three hours, and it was a very weird place. There were some visuals, but they were not at all commensurate with the degree to which I was simply stoned. The erotic does not knit, and it's hard to get involved with music. It is as if you were going down some totally unknown street in a completely familiar city. You know the territory, but yet it is strangely all new. Eyes closed fantasy and shaped imagery was quite remarkable.
But some heart arrhythmias and a pretty constant diarrhea made the experience less than totally ideal. My sleep was good and with good dreams.
EXTENSIONS AND COMMENTARY: I canUt remember the exact names of the companies that went with the oil additives. STP was, I believe, itUs own thing, and originally stood for Scientifically Treated Petroleum.
And F-310 was, I believe, a Chevron Oil product. F-320 was, of course, the product of the wild and happy chemists at the Pharmaceutical Chemistry Department at the University of California in San Francisco, playing with what they fondly called Rfunny drugs.S And when the 2,4,6-orientation became an obvious positional isomer, the Pennzoil Oil Company's additive, Z-7, was a natural to have its name volunteered to the cause. There was one additional isomer possible, with the methyl in the 2-position and the methoxyl groups at the 4-
and 6-positions. This followed the more conventional aldehyde made from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and N-methylformanilide. This material
(2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 !C from cyclohexane or from MeOH) is completely distinct from the isomer used above (2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 !C from MeOH).
The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine, and had been christened by the chemistry crowd as Z-7.1.
Much effort had been put forth in research by this medical school group of graduate students and graduate advisors, to try to explain the biological activity of the 2,4,5-things such as TMA-2 and DOM
(STP). And a considerable investment had been made in the attempt to tie together the amphetamine world of psychedelics with the indole world of psychedelics. The convenience of having two methoxy groups para to one another was a clear invitation to speculate upon the formation of a benzoquinone intermediate of some kind, and this would require the loss of the methyl groups which were already known to be metabolically labile. This Rquinone-likeS intermediate was the cornerstone of a Rhydroquinone hypothesis,S as it allowed further condensation within the molecule itself involving the primary amine group, to form something called an indolene which, with some arcane electron pushing and removal, could eventually become an indole.
There. We now have a tie-in to the tryptamine world, and to serotonin, and that entire neurotransmitter magic.
There was only one small fly in the ointment. No matter how the 2,4,5-things were explained, none of the proposed mechanisms could allow for the 2,4,6-things to also be active.
How can one accommodate such blasphemy? The first and obvious approach was the simplest. Denial. The 2,4,6-things arenUt really active at all. Placebo stuff. There is a commonly used phrase, Rbad scienceS which is an in-famous term used to belittle findings that do not fit with one's theories or purposes. But that simply didnUt wash, because I knew, as did a few others who chose not to identify themselves too publicly, that TMA-2 and TMA-6 were both fully active in the 40 to 50 milligram area. And although not as potent as DOM, the compound of this recipe, y-DOM or Z-7, was certainly an active one. So, since approach number one didnUt work, try approach number two. Make the shoe fit the wearer, without respect to the size of his foot. One single size shoe fits all. One single mechanistic hypothesis explains all. It was obvious that for the RhydroquinoneS
hypothesis to survive, Z-7 would have to undergo some metabolic oxidation Q phenol formation Q in the 3-position.
And guess who was actually euchred into embarking onto the synthesis of this hypothetical metabolic Lucy [that's the anthropological-type, not the LSD-type Lucy]? Moi! On to a new methoxylated amphetamine which would be called Z-7.2. Oxidation of the above 2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH, CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59-62 !C at 0.1 mm/Hg. This formed the anion between the meta-methoxy groups with butyllithium, and N-methylformanilide gave the new compound 2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 !C at 0.7 mm/Hg) with an excellent NMR spectrum. This formed the 3-carbon nitrostyrene with nitroethane, as bright yellow crystals from methanol with a mp 67-68.5 !C (and excellent NMR and microanalysis, C,H,N).
Lithium aluminum hydride reduction gave rise to what I was assuming would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine or Z-7.2. This formed a hydrochloride salt which, although analytically excellent, insisted in remaining as an ether and chloroform-soluble oil which had an excellent NMR spectrum. This was certainly MY target compound, but it was not THEIR target compound.
The upper echelons who were running the show were serious about this hydroquinone thing. Therefore, this product Z-7.2, that should have been entered into human evaluation, was instead processed further by the substitution of a t-BOC on the amine group, oxidation to the quinone with ceric ammonium nitrate, reduction to the hydroquinone with dithionite, and finally deprotection of the blocking t-BOC group by hydrochloric acid. The final product, 2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an extremely light-sensitive solid which was looked at by NMR (excellent spectrum in D2O) and by cyclic voltimetry (destructive and uninformative) but which would have been totally worthless to have tasted.
In fact, the whole 2,4,6 substitution concept is just now beginning to explode. Fully half of the drugs described in this Book II are of the classical 2,4,5-trisubstitution pattern, and it is becoming evident that every one of them will have a 2,4,6-trisubstituted counterpart that bids fair to be an active psychedelic. Diligence could thus easily double the number of known psychedelics. The nickname RpseudoS
is really the Greek letter RpsiS which looks like a candelabrum standing on the table holding up three candles. If I can find the type in some font, I will simply precede each known drug with this letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness.
Therefore, Z-7 is also pseudo-DOM.
Z-7.2 might have been an interesting compound to taste. But the academic climate was not appropriate at that time (early 1977) for such honesty. The Rhydro-quinone hypothesisS is now not much more than a minor bit of history. And anyhow, it was just about this time that I had uncovered a slick way of getting a sulfur atom into the amphetamine molecule. I quickly lost interest in the pursuit of other people's hypotheses that didnUt seem to lead anywhere. Maybe, someday, some single earth-shaking mechanism will emerge to explain everything. But in the meantime, the best contribution I can make to this Rgrand unified theory of psychedelic activityS is to continue to make new and unexpected things which, if they are active, will effectively destroy any hypothesis that just happens to be popular at the moment. It is a lot more exciting, too.
70 DON; 2,5-DIMETHOXY-4-NITROAMPHETAMINE
SYNTHESIS: A solution of 8.4 g 2,5-dimethoxyamphetamine base in 40 mL
acetic acid was added dropwise over the course of 0.5 h to 43 mL of 50% nitric acid which was well stirred and cooled with an external ice bath. The resulting solution was quenched with ice water, made basic with aqueous NaOH, and extracted with a benzene-ether mixture. The residue that remained after the removal of the solvent was dissolved in dilute HCl which, upon evaporation of the H2O, yielded a nearly colorless residue. Recrystallization from an ethanol/ether mixture gave, after drying, 10.5 g of 2,5-dimethoxy-4-nitroamphetamine hydrochloride (DON) with a mp of 206-207 !C. The acetamide derivative melted at 166-168 !C. The formamide derivative was easily hydrolyzed with 3N HCl. And the R-isomer of DON hydrochloride had a mp of 231-232 !C.
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