(with 100 mg) The material came on fairly rapidly. In about 30
minutes, I was intensely intoxicated, and more deeply than with MDMA.
It was a glorious feeling, and beauty was everywhere enhanced. With eyes closed it felt marvelous, and it was appealing to pursue the inner experience. I did notice an internal dryness which was characteristic of MDMA, and I had similar difficulty in urinating, but not as intense as with MDMA.
(with 120 mg) The colors of the market-place, of all the fresh foods, constituted a beautiful mosaic. Nothing practical, simply a real treasure to be used with individual intention and enjoyment.
Everything was seen with new eyes, new meanings, faces, figures, the colors of the rainbow subconsciously individually applied. A 'soul-scape'. The following day very exhausted, tired, back-pain.
EXTENSIONS AND COMMENTARY: The first time that MDOH was synthesized, it had inadvertently and unknowingly been converted to MDA. And the search for proper dosage and characterization of effects of this product was, of course, the rediscovery of the dosage and the effects of MDA. It is one of the world's most remarkable coincidences that after the second synthesis of MDOH, when MDOH had really and truly been actually prepared, the brand new search for proper dosage and characterization of effects revealed that they were almost identical to the earlier observations for (the inadvertently produced) MDA.
This reminds me of my speculations in the discussion of both FLEA and the HOT compound where they also showed paired molecular structures with their prototypes that differ only by a single oxygen atom.
Again, might there be some metabolic interconversion within the body?
The immediate thought would be that the oxygen atom (the hydroxy group) might be metabolically removed, and the effects of either drug are due to the action of MDA. But the opposite direction is in many ways more appealing, the in vivo conversion of MDA to MDOH. Why more appealing? For one thing, oxidative changes are much more common in the body than reductive changes. For another, the conversion of amphetamine to N-hydroxyamphetamine is an intermediate in the conversion of amphetamine to phenylacetone, a known metabolic process in several animal species. And that intermediate, N-hydroxyamphetamine, is a material that gives the famous cytochrome P-450 complex that has fascinated biochemists studying the so-called NADPH-dependent metabolism.
I would put my money on the likelihood of MDA going to MDOH if it should turn out that the two drugs interconvert in the body. And in that case, it would be MDOH, or another metabolite on down the line that is common to both MDA and MDOH, that is the factor intrinsic to the intoxication that is produced. Human metabolic studies are needed, and they have not yet been done.
115 MDPEA; 3,4-METHYLENEDIOXYPHENETHYLAMINE; HOMOPIPERONYLAMINE
SYNTHESIS: A suspension of 4.0 g LAH in 300 mL anhydrous Et2O was stirred and heated to a gentle reflux in an inert atmosphere. There was added 3.9 g 3,4-methylenedioxy-'-nitrostyrene (see under BOH for its preparation) by allowing the condensing Et2O to leach it out from a Soxhlet thimble. After the addition was complete, the reaction mixture was held at reflux for an additional 48 h. It was then cooled and the excess hydride was destroyed by the cautious addition of 300
mL of 1.5 N H2SO4. When both phases were completely clear, they were separated, and the aqueous phase washed once with 50 mL Et2O. There was then added 100 g potassium sodium tartrate, followed by sufficient base to bring the pH >9. This was extracted with 3x75 mL CH2Cl2, and the solvent from these pooled extracts was removed under vacuum. The residue was dissolved in 150 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was a heavy crystallization of 3,4-methylenedioxyphenethylamine hydrochloride (MDPEA) which weighed 3.0 g and had a mp of 212-213 !C.
DOSAGE: greater than 300 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 200 mg) It was taken twice at different times in a dosage of 200 milligrams each time, without the slightest peripheral or central effects.
(with 300 mg) My tinnitus had disappeared. Probably nothing.
EXTENSIONS AND COMMENTARY: How strange. Even more than DMPEA, this cyclic analogue MDPEA is a potential prodrug to dopamine, and would be a prime candidate for central activity. So why is this drug not active? The usual reason advanced by the pharmacologists is that the body is full of potent enzymes known as monoamine oxidases, and this is a monoamine, and so the body simply chews away on it in an oxidative manner, inactivating it before it ever makes it to some target receptor.
That is the pitch given in the textbooks. Phenethylamines are subject to easy enzymatic oxidation, hence they are not active. The presence of an alpha-methyl group (the corresponding amphetamines) blocks the compound from easy access to the enzyme, and since that protects them from oxidative destruction, they are active. The oft-quoted exception is mescaline, and even it is largely destroyed, as evidenced by the large amount needed for activity (a fraction of a gram). Sorry, I canUt buy it. This entire book is peppered with phenethylamines that are active at the few-milligram area. Why arenUt they also destroyed as well? The textbooks simply are not right.
MDPEA was one of the seven compounds evaluated as to toxicity and animal behavior at the University of Michigan under contract from the Army Chemical Center. Its Edgewood Arsenal code number was EA-1297.
The number for MDA itself was EA-1298.
The beta-hydroxy analogue of MDPEA is the ethanolamine MDE, standing for methylenedioxyethanolamine. This is an old term, and in the more recent literature, since 1975 certainly, MDE has been used to represent methylenedioxyethylamphetamine. The ethanolamine compound is discussed in the recipe for DME.
There is a family of compounds, to be discussed elsewhere, that is called the Muni-Metro (see under METHYL-J). The simplest member is this compound, MDPEA, and under its chemically acceptable synonym, homopiperonylamine, it can be called RHS. Following that code, then, the N-methyl homologue of MDPEA is METHYL-H, and it has been looked at, clinically, as an antitussive agent. N-METHYL-MDPEA, or METHYL-H, or N-methyl-3,4-methylenedioxyphenethylamine is effective in this role at dosages of about 30 milligrams, but I have read nothing that would suggest that there were any central effects. I have tried it at this level and have found a little tightness of the facial muscles, but there was nothing at all in the mental area.
116 MDPH; a,a-DIMETHYL-3,4-METHYLENEDIOXY-
PHENETHYLAMINE; 3,4-METHYLENEDIOXYPHENTERMINE
SYNTHESIS: To 150 mL of THF, under an atmosphere of nitrogen, there was added 11.2 g diisopropylamine, and the solution was cooled with external dry ice/IPA. There was then added 48 mL of a 2.3 M solution of butyllithium in hexane, dropwise, with good stirring. This was warmed to room temperature, stirred for a few min, and then all was cooled again in the dry ice bath. Following the dropwise addition of 4.4 g of isobutyric acid there was added 10.5 mL
hexamethylphosphoramide. Again, the stirred reaction mixture was brought to room temperature for about 0.5 h. There was then added, drop-wise, 8.5 g 3,4-methylenedioxybenzyl chloride and the mixture allowed to stir overnight at room temperature. The reaction mixture was poured into 100 mL 10% HCl, and the excess THF was removed under vacuum. The acidic aqueous residue was extracted with 2x150 mL Et2O.
These extracts were pooled, washed with 10% HCl, and then extracted with 3x75 mL of 4 N Na2CO3. These extracts were pooled, made acidic with HCl, and again extracted with Et2O. After drying the pooled extracts with anhydrous MgSO4, the solvent was removed under vacuum to give a residue that spontaneously crystallized. Recrystallization from hexane yielded 6.5 g of
2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid as white crystals with a mp of 71-73 !C. The NMR spectrum in CDCl3 showed the alpha-dimethyl groups as a sharp singlet at 1.18 ppm. Anal.
(C12H14O4) C,H.
The triethylamine salt of
2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid (5.4 g amine, 11.4 g acid) was dissolved in 10 mL H2O and diluted with sufficient acetone to maintain a clear solution at ice-bath tempera
ture. A solution of 6.4 g ethyl chloroformate in 40 mL acetone was added to the 0 !C solution over the course of 30 min, followed by the addition of a solution of 4.1 g sodium azide in 30 mL H2O. Stirring was continued for 45 min while the reaction returned to room temperature.
The aqueous phase was extracted with 100 mL toluene which was washed once with H2O and then dried with anhydrous MgSO4. This organic solution of the azide was heated on a steam bath until nitrogen evolution had ceased, which required about 30 min. The solvent was removed under vacuum and the residue was dissolved in 30 mL benzyl alcohol. This solution was heated on the steam bath overnight.
Removal of the excess benzyl alcohol under vacuum left a residue 13.5
g of
1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane as an amber oil. The dimethyl group showed, in the NMR, a sharp singlet at 1.30 ppm in CDCH3. Anal. (C19H21NO4) C,H. This carbamate was reduced to the primary amine (below) or to the methylamine (see under MDMP).
A solution of 3.27 g of
1-[N-(benzyloxycarbonyl)amino]-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane in 250 mL absolute ethanol was treated with 0.5 g 10% palladium on carbon. This mixture was shaken under hydrogen at 35 pounds pressure for 24 h. The carbon was removed by filtration through Celite, and the filtrate titrated with HCl. The solvent was removed under vacuum, and the residue allowed to crystallize. This produce was recrystallized from an EtOH/EtOAc mixture to provide a,a-dimethyl-3,4-methylenedioxyphenethylamine hydrochloride (MDPH).
The white crystals weighed 1.63 g and had a mp of 180-181 !C. Anal.
(C11H16ClNO2) C,H,N.
DOSAGE: 160 - 240 mg.
DURATION: 3 - 5 h.
QUALITATIVE COMMENTS: (with 120 mg) The alert was felt in forty minutes and I was pretty much there at an hour and twenty. Quite like MDA, simple, with no lines, no colors, no motion, no fantasy. I am pleasantly stoned. The anorexia is real, as is the impotency. The drop from the 4th to the 6th hour was softened by a modest amount of wine, and this proved to be extremely intoxicating. My speech was slurred, and there was later amnesia for the rather aggressive and uninhibited behavior that occurred. I felt that there was more drug than alcohol contributing to this episode. My dream patterns were disturbingly unreal.
(with 160 mg) A very quiet development. There was no body load whatsoever. And no visual, and I saw it fading away all too soon.
This might be a good promoter, like MDPR. I felt refreshed and relaxed on the following morning.
(with 200 mg) This has an inordinately foul taste. I felt slightly queasy. There were short daydreams which were quickly forgotten. I see no values that are worth the hints of physical problems, a little eye mismanagement and some clenching of teeth, and a tendency to sweat. I was able to sleep at only five hours into it, but there were a couple of darts. This is not as rewarding (stoning) as MDA, and has none of the magic of MDMA. It was a short-lived plus two.
EXTENSIONS AND COMMENTARY: What is the train of thought that leads from the structure of a known compound (which is active) to the structure of an unknown one (which may or may not be active)?
Certainly the extrapolations involve many what-if's and maybeUs. The path can be humorous, it certainly can be tortuous, and it often calls for special things such as faith, insight, and intuition. But can one say that it is logical?
Logic is a tricky thing to evaluate. One of the earliest approaches was laid down by Aristotle, in the form of the syllogism.
In it there are three lines consisting of two premises and a conclusion, a form that is called a Rmood.S All are statements of relationships and, if the premises are true, there are only certain conclusions that may logically follow. For example: Every man is a lover.
Every chemist is a man.
Therefore, every chemist is a lover.
Letting lover be the major term RaS and letting chemist be the minor term RbS and letting man be the middle term RmS, this reduces to: Every m is a,
Every b is m.
Therefore, every b is a
and it is a valid mood called Barbara.
Of the 256 possible combinations of all's and someUs and noneUs and are's and are-notUs, only 24 moods are valid. The reasoning here with MDPH goes:
Some stimulants when given a methylenedioxy ring are MDMA-like.
Some ring-unsubstituted 1,1-dimethylphenylethylamines are stimulants.
Therefore, some ring-unsubstituted
1,1-dimethylphenylethyl amines when given a methylenedioxy ring are MDMA-like.
In symbolic form this is:
Some m is a, and
Some b is m, then
Some b is a
and this is not one of the 24 valid moods. Given the first premise as some m is a, there is only one valid syllogism form that can follow, and this is known as Disamis, or:
Some m is a, and
Every m is b, then
Some b is a
which translates as:
Some stimulants when given a methylenedioxy group are MDMA-like.
Every stimulant is a ring-unsubstituted 1,1-dimethylphenyl ethylamine.
Therefore, some ring-unsubstituted
1,1-dimethylphenylethyl amines when given a methylenedioxy group are MDMA-like.
The conclusion is the same. But the second premise is false so the entire reasoning is illogical. What is the false second premise? It is not a fact that every stimulant is a phentermine. There are lots of stimulants that are not phentermines.
So much for applying syllogistics to pharmacology.
117 MDPL; N-PROPARGYL-MDA; N-PROPYNYL-MDA; 3,4-METHYLENEDIOXY-N-PROPARGYLAMPHETAMINE) SYNTHESIS: A solution of 10.5 g propargylamine hydrochloride in 40 mL
MeOH was treated with 2.0 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 0.55 g sodium cyanoborohydride.
Concentrated HCl was added as needed, to keep the pH constant at about 6. The reaction seemed to progress very slowly. After about five days, the reaction mixture was added to 400 of H2O, acidified with HCl, and extracted with 3x100 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from these extracts yielded 1.6 g of a clear amber, strong smelling oil which, on distillation at 105-110 !C at 0.2 mm/Hg, yielded 1.0 g of an almost colorless oil. This was dissolved in 20 mL
IPA, neutralized with about 10 drops of concentrated HCl, and the spontaneously formed crystals were diluted with 50 mL anhydrous Et2O.
After filtration, Et2O washing and air drying, there was obtained 1.1
g white crystals of 3,4-methylenedioxy-N-propargylamphetamine hydrochloride (MDPL) with a mp of 189-190 !C. Anal. (C13H16ClNO2) N.
DOSAGE: greater than 150 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: There is a continuing uncertainty about the name for the three-carbon radical that contains a triple bond. The hydrocarbon is propyne, although it has been referred to as methylacetylene in the older literature. The adjective, going from the triple bond out to the point of attachment, is called propargyl, as in propargyl chloride. When the adjective must be built on the parent hydrocarbon, the double bond is on the outside and one reads away from it, as in 2-propynyl something. However, when the hydrocarbon is essentially the entire structure, then things get named going towards the triple bond, as in 3-chloro-1-propyne. Wait. IUm not done yet! When the actual hydrocarbon name becomes distorted into the derivative, then the triple bond is again at the high end of the numbering scheme. Propynol is 2-propyn-1-ol, which is, of course, the same as 3-hydroxypropyne, or propargyl alcohol. The code MDPL takes the first and last letter of the two of them, both propargyl and propynyl.
118 MDPR; N-PROPYL-MDA; 3,4-METHYLENEDIOXY-N-PROPYLAMPHETAMINE
SYNTHESIS: A total of 20 mL concentrated HCl was added beneath the surface of 20 mL propylamine, and when the addition was complete, the mixture was stripped of volatiles under vacuum. The slightly yellow residual oil weighed 20.7 g and
set up to crystals on cooling. It was dissolved in 75 mL MeOH, and there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.1 g sodium cyanoborohydride. Concentrated HCl in MeOH
was added as required to maintain the pH at about 6 as determined with external, dampened universal pH paper. When the generation of base had stopped, the MeOH was allowed to evaporate and the residue was suspended in 1 L water. This was made strongly acidic with an excess of HCl. After washing with CH2Cl2, the aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum yielded 3.3 g of a pale amber oil that was distilled at 85-90 !C at 0.2 mm/Hg. This fraction was water-white and weighed 2.3 g. It was dissolved in 10 mL IPA and neutralized with 25 drops concentrated HCl which produced crystals spontaneously. These were diluted with anhydrous Et2O, removed by filtration, washed with additional Et2O, and air dried. In this way there was obtained 2.3 g of 3,4-methylenedioxy-N-propylamphetamine hydrochloride (MDPR) with a mp of 190-192 !C. Recrystallization from IPA gave a mp of 194-195 !C. The NMR spectrum was completely consistent with the assigned chemical structure. Anal. (C13H20ClNO2) N.
DOSAGE: greater than 200 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 200 mg) There are the slightest hints of physical response, maybe a smidgin of a lightheadedness at the one hour point. Perhaps a slight teeth clench. Certainly there is no central mental effect.
EXTENSIONS AND COMMENTARY: This particular drug, considering that it was without activity, has proven one of the richest veins of pharmacological raw material. Two clues suggested its potential value. A number of reports in the 150 to 200 milligram area suggested that something was taking place in the periphery even without any clear central effects. The term Rbody windowS was used occasionally by experimenters, an outgrowth of the term RwindowS that was used (at that time, the mid-1970Us) to describe the mental effects of MDMA. It was as if the body was opened up and made receptive, instead of the mind. The second clue came from many anecdotal reports that methedrine (a potent central nervous system stimulant) would augment the effects of an LSD dosage which followed it. The putting of a drug on top of an inactive drug is the RprimerS concept. It turned out that MDPR was an extraordinary primer to some following psychedelic, especially LSD, even at modest doses. The putting of a drug on top of an active drug, usually during the latter part of its effectiveness is, as previously stated, called Rpiggy-backing.S A third drug-drug interaction has also been studied; the simultaneous administration of two active drugs, to study synergism. There may be an enhancement, or an inhibition, of one with the other. Let's now re-enter the subsection RQualitative CommentsS again, with this primer concept in mind.
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