From: sender@mit.edu
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 4 of 6

(I'm posting this for a friend.)

This is part 4 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.




#90 IDNNA; 2,5-DIMETHOXY-N,N-DIMETHYL-4-IODOAMPHETAMINE

SYNTHESIS: To a stirred solution of 0.4 g
2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in 12 mL MeOH
containing 4 mL of a 40% formaldehyde solution there was added 1 g
sodium cyanoborohydride.  The pH was kept at about 6 by the occasional
addition of HCl.  When the pH was stable (about 48 h) the reaction
mixture was poured into 250 mL H2O and made strongly basic by the
addition of aqueous NaOH.  This was extracted with 3x75 mL CH2Cl2, the
extracts pooled, and extracted with 2x75 mL dilute H2SO4, and the
pooled acidic extracts again made basic and again extracted with
CH2Cl2.  The solvent was removed under vacuum to give 0.38 g of a
colorless oil.  This was dissolved in 2 mL IPA and treated with a
solution of 0.13 g oxalic acid dihydrate in 1.5 mL warm IPA, and then
anhydrous Et2O was added dropwise until a turbidity persisted.  Slowly
a granular white solid appeared, which was filtered off, Et2O washed,
and air dried to give 0.38 g of
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine oxalate (IDNNA) with a mp
of 145-146 !C.  Anal. (C15H22INO6) C,H.  The hydrochloride salt of
this base proved to be hygroscopic.

DOSAGE: greater than 2.6 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This base, if it were given a code name
based upon its substituents arranged in their proper alphabetical
order, would have to be called something like DNDIA, which is quite
unpronounceable.  But by a rearrangement of these terms, one can
achieve IDNNA (Iodo-Dimethoxy-N,N-dimethyl-Amphetamine) which has a
nice lilt to it.

One of the major goals of research in nuclear medicine is a drug that
can be used to demonstrate the brain blood flow pattern.  To do this
job, a drug should demonstrate four properties.  First, it must carry
a radioactive isotope that is a positron emitter (best, a fluorine or
an iodine atom, for use with the positron camera) that can be put onto
the molecule quickly, synthetically, and which will stay on the
molecule, metabolically.  Second, as to brain entry, the drug should
be rapidly and extensively taken up by brain tissue, without being
selectively absorbed or concentrated at any specific sites.  In other
words, it should go where the blood goes.  Thirdly, the absorption
should be strong enough that it will stay in the brain, and not be
washed out quickly.  This allows time to both locate and count the
radioactivity that was carried in there.  And lastly, the drug must be
without pharmacological action.

IDNNA looked like a promising candidate when tried with a radioactive
iodine label, and there was quite a flurry of interest in using it
both as an ex-perimental drug, and as a prototype material for the
synthesis of structural variants.  It went in quickly, extensively and
quite diffusely, and it stayed in for a long time.

But was it pharmacologically active?  Here one finds a tricky road to
walk.  The animal toxicity and behavioral properties can be determined
in a straightforward manner.  Inject increasing amounts into an
experimental animal and observe him closely.  IDNNA was quite inert.
But, it is a very close analogue to the extremely potent psychedelic
DOI, and it is widely admitted that animal assays are of no use in
trying to determine this specific pharmacological property.  So, a
quiet human assay was called for.  Since it did indeed go into the
brain of experimental animals, it could quite likely go into the brain
of man.  In fact, that would be a needed property if the drug were to
ever become useful as a diagnostic tool.

It was assayed up to levels where DOI would have been active, and no
activity was found.  So one could state that it had none of the
psychedelic properties of DOI at levels where DOI would be active
(this, at 2.6 milligrams orally).  But you donUt assay much higher,
because sooner or later, something might indeed show up.  So it can be
honestly said, IDNNA is less active than DOI itself, in man.  LetUs
wave our hands a bit, and make our statement with aggressive
confidence.  IDNNA has shown no activity in the human CNS at any level
that has been evaluated.  This sounds pretty good.  Just donUt go too
far up there, and donUt look too carefully.  This is not as
unscrupulous as it might sound since, in practical terms, the
extremely high specific activities of the radioactive 122I that would
be used, would dictate that only an extremely small amount of the drug
would be required.  One would be dealing, not with milligram
quantities, but with microgram quantities, or less.

Some fifteen close analogues of IDNNA were prepared, to see if any had
a better balance of biological properties.  A valuable intermediate
was an iodinated ketone that could be used either to synthesize IDNNA
itself or, if it were to be made radio-labelled, it would allow the
preparation of any desired radioactive analogue in a single synthetic
step.  The iodination of p-dimethoxybenzene with iodine monochloride
in acetic acid gave 2,5-diiodo-1,4-dimethoxybenzene as white crystals
from acetonitrile, with a mp of 167-168 !C.  Anal. (C8H8I2O2) C,H.
Treatment of this with an equivalent of butyllithium in ether,
followed with N-methyl formanilide, gave
2,5-dimethoxy-4-iodobenzaldehyde as pale yellow crystals from ethanol,
with a mp of 136-137 !C.  Anal. (C9H9IO3) C,H.  This, in solution in
nitroethane with a small amount of anhydrous ammonium acetate, gave
the nitrostyrene 1-(2,5-dimethoxy-4-iodophenyl)-2-nitropropene as
gold-colored crystals from methanol, mp 119-120 !C.  Anal.
(C11H12INO4) C,H.  This was smoothly reduced with ele-mental iron in
acetic acid to give 2,5-dimethoxy-4-iodophenylacetone as white
crystals from methylcyclopentane.  These melted at 62-63 !C and were
both spec-troscopically and analytically correct.  Anal. (C11H13IO3)
C,H.

This intermediate, when reductively aminated with dimethylamine, gives
IDNNA identical in all respects to the product from the dimethylation
of DOI above.  But it has also been reacted with 131I NaI in acetic
acid at 140 !C for 10 min, giving the radioactive compound by
exchange, and this was reductively aminated with over a dozen amines
to give radioactive products for animal assay.  There was produced in
this way, 2,5-dimethoxy-4-iodo-N-alkyl-amphetamine where the alkyl
group was methyl, isopropyl, cyclopropylmethyl, hexyl, dodecyl,
benzyl, cyanomethyl, and 3-(dimethylaminopropyl).  Several dialkyl
homologue were made, with the alkyl groups being dimethyl (IDNNA
itself), diethyl, isopropyl-methyl, and benzyl-methyl.  These specific
homologues and analogues are tallied in the index, but a number of
other things, such as hydrazine or hydroxylamine derivatives, were
either too impure or made in amounts too small to be valid, and they
are ignored.

The diethyl compound without the iodine is
2,5-dimethoxy-N,N-diethylamphetamine, which was prepared by the
reductive alkylation of DMA with acetaldehyde and sodium
cyanoborohydride.  This product, DEDMA, was a clear white oil, bp
82-92 !C at 0.15 mm/Hg which did not form a crystalline hydrochloride.
An interesting measure of just how different these N,N-dialkylated
homologues can be from the psychedelic primary amines,
pharmacologically, can be seen in the published report that the
beta-hydroxy derivative of DEDMA is an antitussive, with a potency the
same as codeine.

None of these many iodinated IDNNA analogues showed themselves to be
superior to IDNNA itself, in the rat model, and none of them have been
tasted for their psychedelic potential in man.

 

 

 



#91 IM; ISOMESCALINE; 2,3,4-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 8.0 g 2,3,4-trimethoxybenzaldehyde in 125 mL
nitromethane containing 1.4 g anhydrous ammonium acetate was held at
reflux for 1.5 h.  The conversion of the aldehyde to the nitrostyrene
was optimum at this time, with a minimum development of a slow-moving
spot as seen by thin layer chromatography on silica gel plates using
CHCl3 as a developing solvent; the Rf of the aldehyde was 0.31 and the
Rf of the nitrostyrene was 0.61.  The excess nitromethane was removed
under vacuum, and the residue was dissolved in 20 mL hot MeOH.  On
cooling, the yellow crystals that formed were removed by filtration,
washed with cold MeOH and air dried yielding 4.7 g yellow crystals of
2,3,4-trimethoxy-'-nitrostyrene, with a mp of 73-74 !C.  From the
mother liquors, a second crop of 1.2 g was obtained.

A solution of 4.0 g LAH in 80 mL THF under He was cooled to 0 !C and
vigorously stirred.  There was added, dropwise, 2.7 mL of 100% H2SO4,
followed by a solution of 4.7 g 2,3,4-trimethoxy-'-nitrostyrene in 40
mL anhydrous THF.  The mixture was stirred at 0 !C for 1 h, at room
temperature for 1 h, and then brought briefly to a reflux on the steam
bath.  After cooling again, the excess hydride was destroyed with 4.7
mL H2O in THF, followed by the addition of 18.8 mL 15% NaOH which was
sufficient to convert the solids to a white and granular form.  These
were removed by filtration, the filter cake washed with THF, the
mother liquor and filtrates combined, and the solvent removed under
vacuum.  The residue was added to dilute H2SO4, and washed with 2x75
mL CH2Cl2.  The aqueous phase was made basic with 25% NaOH, and
extracted with 2x50 mL CH2Cl2.  The solvent was removed from these
pooled extracts and the amber-colored residue distilled at 95-100 !C
at 0.3 mm/Hg to provide 2.8 g of 2,3,4-trimethoxyphenethylamine as a
white oil.  This was dissolved in 20 mL IPA, neutralized with about 1
mL concentrated HCl, and diluted with 60 mL anhydrous Et2O.  After
filtering, Et2O-washing, and air drying, there was obtained 3.2 g of
2,3,4-trimethoxyphenethylamine hydrochloride (IM) as a white
crystalline product.

DOSAGE: greater than 400 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 300 mg) No effects whatsoever.

(with 400 mg) Maybe a slight tingle at the hour-and-a-half point.
Maybe not.  Certainly nothing an hour later.  Put this down as being
without action.

EXTENSIONS AND COMMENTARY: Some fifty years ago this material was
given the name Rreciprocal mescalineS in that it was believed to
exacerbate the clinical symptoms in schizophrenic patients.  In the
original report, one finds: RThus we have discovered an extremely
remarkable dependency of the intoxicating action upon the position of
the three methoxy groups.  Mescaline, the
3,4,5-trimethoxy-'-phenethylamine, produces in the normal subject a
much stronger over-all intoxication than in the schizophrenic patient,
whereas 2,3,4-trimethoxy-'-phenethylamine has quite the opposite
effect.  It has little action in healthy individuals, being almost
without intoxicating properties, but it is very potent in the
schizophrenic.  The metabolic conversion products of the RreciprocalS
mescaline will be further studied as soon as the study of the
metabolism of the proper mescaline is complete.

This is a pretty rich offering, and one that the present medical
community has no qualms about discarding.  At the bookkeeping level,
the promised further studies have never appeared, so all may be
forgotten as far as potential new discoveries might be concerned.

One recent related study has been reported, tying together
isomescaline and schizophrenia.  Through the use of radioactive
labelling, the extent of demethylation (the metabolic removal of the
methyl groups from the methoxyls) was determined in both schizophrenic
patients and normal subjects.  When there was a loading of the person
with methionine (an amino acid that is the principal source of the
body's methyl groups), the schizophrenics appeared to show a lesser
amount of demethylation.

But might either of these two observations lead to a diagnostic test
for schizophrenia?  At the present time, the conventional thinking is
that this probably cannot be.  The illness has such social and genetic
contributions, that no simple measure of a response to an
almost-psychedelic, or minor shift of some urinary metabolite pattern
could possibly be believed.  No independent confirmation of these
properties has been reported.  But maybe these findings are valid.  A
major problem in following these leads does not involve any complex
research protocols.  What must be addressed are the present regulatory
restrictions and the Federal law structure.  And these are formidable
obstacles.

 

 

 



#92 IP; ISOPROSCALINE; 3,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under
ESCALINE for its preparation) and 13.6 g isopropyl iodide in 50 mL dry
acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and
held at reflux on the steam bath.  After 6 h another 5 mL of isopropyl
iodide was added, and refluxing continued for an additional 12 h.  The
mixture was filtered and the solids washed with acetone.  The mother
liquor and washes were stripped of solvent under vacuum, The residue
was taken up in dilute HCl, and extracted with 3x100 mL CH2Cl2.  The
pooled extracts (they were quite deeply yellow colored) were washed
with 2x75 mL 5% NaOH, and finally once with dilute HCl.  Removal of
the solvent under vacuum yielded 9.8 g of an amber oil, which on
distillation at 125-135 !C at 0.3 mm/Hg provided 6.0 g of
3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile as a pale yellow oil.  A
pure reference sample is a white solid with a mp of 33-34 !C.  Anal.
(C13H17NO3) C,H,N.

A solution of AH was prepared by the cautious addition of 0.84 mL of
100% H2SO4 to 32 mL of 1.0 M LAH in THF, which was being vigorously
stirred under He at ice-bath temperature.  A solution of 5.93 g of
3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile in 10 mL anhydrous THF
was added dropwise.  Stirring was continued for 30 min, then the
reaction mixture was brought up to reflux on the steam bath for
another 30 min.  After cooling again to room temperature, 5 mL IPA was
added to destroy the excess hydride, followed by about 10 mL of 15%
NaOH, sufficient to make the aluminum salts loose, white, and
filterable.  The reaction mixture was filtered, the filter cake washed
with IPA, the mother liquor and washes combined, and the solvent
removed under vacuum.  The residue (7.0 g of an amber oil) was
dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2.  The aqueous
phase was made basic with aqueous NaOH, and the product extracted with
3x75 mL CH2Cl2.  The extracts were evaporated to a residue under
vacuum, and this was distilled at 125-140 !C at 0.3 mm/Hg yielding 3.7
g of a colorless oil.  This was dissolved in 15 mL IPA, neutralized
with 50 drops of concentrated HCl which allowed the deposition of a
white crystalline product.  Dilution with anhydrous Et2O and
filtration gave 3.7 g. of 3,5-dimethoxy-4-(i)-propoxyphenethylamine
hydrochloride (IP) with a mp of 163-164 !C.  Anal. (C13H22ClNO3)
C,H,N.  The catalytic hydrogenation process for reducing the nitrile
that gives rise to escaline, also works with this material.

DOSAGE: 40 - 80 mg.

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 75 mg) Starts slowly.  I develop some
queasiness, turning into nausea.  Feels good to lie down and let go,
but the uneasiness remains.  Just beginning to break through in 2
hours.  But the occasional sense of relief, the breaking into the
open, were transient as new sources of discomfort were always being
dredged up.  Then for some reason I chose to dance.  Letting go to
dancing, a marvelous ecstatic experience, flowing with and being the
energy, body feeling completely free.  Noticing how this letting go
got one completely out of the feeling of unease, as though attention
simply needs to be put elsewhere.  Comedown was very slow, gentle,
euphoric; a very signicant experience.  Sleep that night was
impossible, but felt good to simply release to the feelings.  Keeping
mind still, no thinking, just allowing feelings to go where they
wished, became more and more ecstatic.  Tremendous feeling of
confidence in life and the life process.  Complete sense of
resolution.

(with 80 mg) It took about two hours for the body to settle down.
Emotions were true and well felt, a fact that is an all-important
thing to me as it probably is to everyone else I know in this kind of
exploration.  Any sense that there is a dulling of the feeling and
emotional area of the self is a negative, to be watched and noted as
are other things such as disturbed sleep, unpleasant dreams, or
irritability or depression the next day.  I was interacting with
others with a great deal of intensity.  People found themselves
wandering inside and out, listening to music, stirring soup, eating a
bit and enjoying eating, talking, laughing a great deal, and being
silent in great contentment.  It's not a very silent material, though.
Talking is too enjoyable.  There was a slight descent noted at 6-7
hours, but very gentle and smooth.  Slow and pleasant descent until
about 12th hour, when sleep was attempted.  Next day, everyone
slightly irritable but good mood anyway.  The next night I slept
deeply and well, and awoke whole and in excellent mood.

EXTENSIONS AND COMMENTARY: These two excerpts give the color and
complexity of IP.  It has proven to be a completely fascinating
phenethylamine.  And, as with all the phenethylamines, there is an
amphetamine that corresponds to it.  This would be
3,5-dimethoxy-4-isopropoxyamphetamine, or 3C-IP.  The prepa-ration of
it would require access through the O-isopropoxylation product with
syringaldehyde, followed by nitrostyrene formation with nitroethane,
followed by reduction probably with lithium aluminum hydride.  It has
not been synthesized, as far as I know, and so it has probably not
been evaluated in man.  What would be the active level?  It would
probably be more potent than IP, but I would guess not by much.  Maybe
in the 30 milligram area.

A moment's aside for a couple of the words that are so much a part of
the chemist's jargon.  Room temperature, as used above, means the
natural temperature that something comes to if it is put on the table
and is neither heated nor cooled.  The phrase, I discovered during my
year at Gif, is completely un-understandable in French.  A room has no
temperature.  Only things in rooms have temperatures.  Their
expression is more exact.  The object achieves, in the French
terminology, a temperature normale dUinterieur, or about 15 to 16 !C.
But in common laboratory parlance it has become the temperature
dUambiance.

And one finds the prefix RisoS used everywhere.  Considerable care
should be taken in the two different uses of the prefix RisoS in the
nomenclature with the mescaline analogues.  In general, the term RisoS
means the other one of two possibilities.  If you are allowed to paint
a house only with green paint or red paint, and green is the color you
actually use, then red could be called iso-green.  With isoproscaline
(here) there is a rearranging of the propyl group on the 4-oxygen of
mescaline.  It has been replaced with its branched analogue, the other
of two possibilities, the isopropyl group.  Everything is still with
the 3,4,5-orientation on the benzene ring.  However, with IM
(isomescaline) there is a rearrangement of substitution pattern on the
benzene ring, with the repositioning of the trimethoxyl substitution
pattern from the 3,4,5- arrangement to the 2,3,4- arrangement.  It has
been the side-chain that has taken the other of two possible
positions.  The term RisoS must always be interpreted in precise
context.

 

 

 



#93 IRIS; 5-ETHOXY-2-METHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL
95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under
2C-D for its preparation).  This was followed with 23.5 g ethyl
iodide, and the mixture was held at reflux overnight.  The solvent was
removed under vacuum and the residue suspended in 250 mL H2O.  This
was made strongly basic with NaOH and extracted with 3x50 mL CH2Cl2.
Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an
amber oil, which was used in the following step without further
purification.  Acidification of the aqueous phase followed by CH2Cl2
extraction gave, after removal of the solvent, crude recovered
starting phenol as a dark brown crystalline solid.  The reasonably
pure phenol was best isolated by sequential extractions with portions
of 80 !C H2O which, on cooling, deposited the phenol as white
crystals.

A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to
incubate for 1 h and then there was added to it 15.7 g
2-ethoxy-5-methoxytoluene.  This was heated in the steam bath for 2 h,
then poured into 1 L H2O and allowed to stir overnight.  The solids
that formed were removed by filtration and H2O washed, giving 20.7 g
of a crude, amber product.  This was extracted with 2x150 mL boiling
hexane which gave crystals on cooling.  These were filtered and hexane
washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as
pale cream-colored solids with a mp of 75-76 !C.  Recrystallization of
an analytical sample from EtOH two times gave a product with a white
color, and a mp of 81-82 !C.

To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48
mL glacial acetic acid containing 4 g anhydrous ammonium acetate there
was added 10 mL nitroethane, and the mixture heated on the steam bath
for 2 h.  Standing at room temperature overnight allowed a heavy crop
of brilliant crystals to deposit.  These were removed by filtration,
washed cautiously with acetic acid, and air dried to give 8.6 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of
118-120 !C.  Recrystallization of all from 200 mL boiling MeOH gave
8.3 g of lustrous crystals with a mp of 121-122 !C.

To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added 8.1 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  Refluxing was maintained overnight, and the
cooled reaction flask stirred for several additional days.  The excess
hydride was destroyed by the cautious addition of 400 mL H2O
containing 40 g H2SO4.  When the aqueous and Et2O layers were finally
clear, they were separated, and 160 g of potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.
Evaporation of the solvent under vacuum produced an oil that was
dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride
(IRIS) as fine white crystals.  These weighed, after filtration, Et2O
washing, and air drying to constant weight, 5.3 g and had a mp of
192-193 !C.  Recrystallization of an analytical sample from boiling
CH3CN gave lustrous crystals with a mp of 196-197 !C with
decomposition.

DOSAGE: greater than 9 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 7.5 mg) At about three hours I felt that
I was at threshold, but an hour later there was nothing.

(with 9 mg) Maybe a little light headed?  Maybe not.  Little effect
if any.

EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the
ten possible homologues of DOM, which I had discussed under ARIADNE
(the first of the Ladies).  The active level is unknown, but it is
higher than 9 milligrams (the highest dose tried) and since DOM itself
would have been smashingly active at this level, it is obvious that
IRIS is a homologue with decreased potency.

This lack of activity brings up a fascinating point.  I have referred
to a drug's action on the mind, quite frequently in these notes, with
the phrase Rreasonably complex.S By that, I do not mean that a drugUs
action simply shows many facets, and if these were to be tallied, the
drug-mind interaction would become clear.  There is quite a bit of
importance intrinsically implied by the term, complex.  Simple things,
as we have come to appreciate and depend upon them in our day-to-day
living, can have simple explanations.  By this, I mean explanations
that are both completely satisfactory and satisfactorily complete.
Answers that have all the earmarks of being correct.  What is the sum
of two plus three, you ask?  Let's try five.  And for most of our
needs, five is both factual and complete.

But some years ago, a mathematician named Gdel devised a proof for a
theorem that anything that is reasonably complex cannot enjoy this
luxury (I believe he used the word RinterestingS rather than
reasonably complex).  If your collection of information is factual, it
cannot be entirely complete.  And if it is complete, it cannot be
entirely factual.  In short, we will never know, we cannot ever know,
every fact that constitutes an explanation of something.  A complete
book of knowledge must contain errors, and an error-free book of
knowledge must be incomplete.

There is a small warning light deep inside me that starts flashing any
time I hear someone begin to advance an explanation of some reasonably
complex phenomenon with an air of confidence that implies, RHere is
how it works.S What the speaker usually has is an intense familiarity
with one particular discipline or specialty and the phenomenon is
viewed through those eyes, often with the assurance that looking at it
that way, intently enough and long enough, will reveal the complete
explanation.  And be attentive to the phrase, RWe are not yet
com-pletely sure of exactly how it works.S What is really meant is,
RWe havenUt the slightest idea of how it really works.

I must admit to some guilt in this matter, certainly as much as the
next person.  I am a chemist and I suspect that the way that the
psychedelic drugs do their thing can eventually be understood through
a comparison of the structures of the molecules that are active and
those that are inactive.  I put those that have methoxyl groups in
pigeon hole #1, and those that are bicyclic into pigeon hole #2.  And
then, if pigeon hole #2 becomes more and more cluttered, I will
subdivide the contents into pigeon hole #2A for bicyclics with
heteroatoms and pigeon hole #2B for bicyclics without heteroatoms.
The more information I can accumulate, the more pigeon holes I need.

But in the adjoining lab, there is a molecular biologist who feels
that the eventual explanation for the action of the psychedelic drug
will come from the analysis and understanding of the intimate geometry
of the places in the brain where they act.  These classification
pigeon holes are called receptor sites.  But they, too, can become
more and more subdivided as they become cluttered.  One reads of a new
sub-sub type quite regularly in the literature.  The favorite
neurotransmitter of the moment, as far as the current thinking of how
these marvelous drugs work, is serotonin, or 5-HT (for
5-hydroxytryptamine).  There are 5-HT1 and 5-HT2A and 5-HT2B and (for
all I know right now) 5-HT2C and 5-HT2D receptors, and I donUt really
think that either he or I have come much closer to understanding the
mechanism of action.

And, since the mind is a reasonably complex system, Gdel has already
informed us both that neither of us will be completely successful.
Sometimes I feel that the pigeon hole approach to the classification
of knowledge might actually limit our views of the problem.  A Harvard
Professor of Medicine recently noted: RWe must recognize for what it
is, man's predilection for dividing things into tidy categories,
irrespective of whether clarity is gained or lost thereby.

No.  No one will ever have it all together.  It is like sitting down
in front of a jigsaw with a zillion zillion pieces spread all over the
kitchen table.  With diligent searching you will occasionally find a
piece that matches another, but it rarely provides any insight into
the final picture.  That will remain a mystery, unless you had the
chance to see the cover of the box in some other incarnation.  But Oh
my, what fun it is, whenever you do happen to find a new piece that
fits!

This harangue is really a lengthy prelude to the story of putting an
ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of
these psychedelic families.  The making of IRIS was the first move in
this direction, done back in 1976.  One can have a pigeon hole that is
named REthoxy In Place of MethoxyS and toss in there the names of
perhaps twenty pairs of compounds, which differ from one another by
just this feature.  Yet when they are looked at from the potency point
of view, there are some which show a decrease in potency (which is the
case with IRIS and most of the Tweetios) and there are some which seem
to maintain their potency (such as the TMA-2/MEM pair) and there are
some where there is a distinct potency increase (the
mescaline/escaline pair, for example).

What does one do to clarify the contents of this particular pigeon
hole?  The current fad would be to subdivide it into three
subdivisions, maybe something like REthoxy in Place of Methoxy if 2-
or 5-locatedS and REthoxy in Place of Methoxy if 4-located and other
things 2,5S and REthoxy in Place of Methoxy if 4-located, and other
things 3,5.S The end point that soon becomes apparent, down the line,
will be to have as many pigeon holes as compounds!  And at the moment,
this particular piece of the jigsaw puzzle doesnUt seem to fit
anywhere at all.

Perhaps both my neighboring molecular biologist and I are asking the
wrong questions.  I am looking at the molecules and asking, RWhat are
they?S And he is following them and asking, RWhere do they go?S And
neither of us is fully attentive to the question, RWhat do they do?S
It is so easy to replace the word Rmind,S in our inquiries, with the
word Rbrain.

Yup.  The operation of the mind can certainly be classified as a
Rreasonably complexS phenomenon.  I prefer Gdel's term.  The mind is
without question an RinterestingS phenomenon.

 

 

 



#94 J; BDB; 2-AMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;
1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: The Grignard reagent of propyl bromide was made by the
dropwise addition of 52 g 1-bromopropane to a stirred suspension of 14
g magnesium turnings in 50 mL anhydrous Et2O.  After the addition,
stirring was continued for 10 min, and then a solution of 50 g
piperonal in 200 mL anhydrous Et2O was added over the course of 30
min.  The reaction mixture was heated at reflux for 8 h, then cooled
with an external ice bath.  It was quenched with the addition of a
solution of 75 mL cold, saturated aqueous ammonium chloride.  The
formed solids were removed by filtration, and the two-phase filtrate
separated.  The organic phase was washed with 3x200 mL dilute HCl,
dried over anhydrous MgSO4, and the solvent removed under vacuum.  The
crude 62.2 g of 1-(3,4-methylenedioxyphenyl)-2-butanol, which
contained a small amount of the olefin that formed by dehydration, was
distilled at 98 !C at 0.07 mm/Hg to give an analytical sample, but the
crude isolate served well in the next reaction.  Anal. (C11H14O3) C,H.

A mixture of 65 g crude 1-(3,4-methylenedioxyphenyl)-2-butanol and 1 g
finely powdered potassium bisulfate was heated with a soft flame until
the internal temperature reached 170 !C and H2O was no longer evolved.
The entire reaction mixture was then distilled at 100-110 !C at 0.8
mm/Hg to give 55 g of 1-(3,4-methylenedioxyphenyl)-1-butene as a
colorless oil.  Anal. (C11H12O2) C,H.

To 240 mL of stirred and cooled formic acid there was added 30 mL H2O
followed, slowly, by 45 mL of 35% hydrogen peroxide.  There was then
added a solution of 48 g 1-(3,4-methylenedioxyphenyl)-1-butene in 240
mL acetone at a rate that maintained the internal temperature at less
than 40 !C.  After the addition, the reaction mixture was allowed to
stand and stir for several additional days.  The excess volatiles were
removed under vacuum with the temperature never allowed to exceed 40
!C.  The residue was dissolved in 90 mL MeOH and diluted with 450 mL
15% H2SO4.  This mixture was heated on the steam bath for 2.5 h,
cooled, and then extracted with 3x100 mL Et2O.  The extracts were
pooled, washed with 2x200 mL H2O, 2x200 mL 5% NaOH, 2x200 mL brine,
and then dried over anhydrous MgSO4.  After removal of the solvent
under vacuum, the residue was distilled at 105-135 !C at 0.3 mm/Hg to
give 28.2 g 1-(3,4-methylenedioxyphenyl)-2-butanone as an amber oil.
Redistillation gave a colorless oil, with a bp of 98 !C at 0.11 mm/Hg.
Anal.  (C11H12O3) C,H.  This intermediate ketone could be prepared by
the Wittig reaction between piperonal and the derivative of
triphenylphosphonium propyl bromide and dibutyldisulfide, followed by
hydrolysis in a HCl/acetic acid mixture, but the yields were no
better, Efforts to prepare this ketone by the iron and acid reduction
of the appropriate nitrostyrene
(1-(3,4-methylenedioxyphenyl)-2-nitro-1-butene, mp 64-65 !C) were
thwarted by the consistently unsatisfactory yield of the precursor
from the reaction between piperonal and 1-nitropropane.

A stirred solution of 20 g anhydrous ammonium acetate and 4.6 g
1-(3,4-methylenedioxyphenyl)-2-butanone in 50 mL MeOH was treated with
1.57 g sodium cyanoborohydride.  Droplets of HCl were added as needed
to maintain the pH at approximately 6.  The reaction mixture was made
basic with the addition of 250 mL dilute NaOH and extracted with 3x100
mL CH2Cl2.  The pooled organic extracts were extracted with 2x100 mL
dilute H2SO4, the pooled aqueous extracts made basic again, and
extracted again with 2x100 mL CH2Cl2.  Removal of the solvent gave a
residue which was distilled to give 2.6 g of a colorless oil which was
dissolved in 15 mL IPA, neutralized with concentrated HCl, and diluted
with an equal volume of anhydrous Et2O.  Crystals of
2-amino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (J) separated
slowly.  After filtering, Et2O washing, and air drying there was
obtained 2.8 g of white crystals that melted at 159-161 !C.  Anal.
(C11H16ClNO2) C,H,N.

DOSAGE: 150 - 230 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 175 mg) The first stirrings were evident
in a half hour, pleasant feelings, and without any untoward body
effects.  Within another half hour I was at a plus 2 and there it
leveled off.  I would be reluctant to drive a car, but I could were it
necessary.  There were no visual distortions, no giddiness, no
introspective urges, and no rise to a psychedelic intoxication of any
significance.  After about an hour and a half at this level, I
gradually dropped back over another two hours.  Afterwards I was quite
fatigued and languorous.

(with 200 mg and a 75 mg supplement) RA very strong climb, and a very
good, interior feeling.  It has some of the MDMA properties, but it is
difficult to concentrate on any one point.  There is a tendency to
slide off.  Excellent emotional affect; music is fine but not
gripping.  Someone had used the phrase, mental nystagmus, and there is
something valid there. The supplement was taken at the 2 hour point
when I was already aware of some dropping, and its action was noticed
in about a half hour.

(with 230 mg) Physically, there was a bit of dry mouth but no teeth
clenching, some nystagmus, maybe the slightest bit of dizziness, very
anorexic, and it is not a decongestant.  Mentally, it is extremely
benign and pleasant, funny and good-humored.  No visuals.  Peaceful.
Easy silences, easy talking.  More stoning than MDMA.

EXTENSIONS AND COMMENTARY: In general, all subjects who have explored
J have accepted it and commented favorably.  Perhaps those who have
used supplements (in an imitation of the common MDMA procedure)
achieved an additional period of effect, but also tended to drop to
baseline afterwards more rapidly.  The physical side effects, such as
teeth clench and nystagmus, were infrequent.  The consensus is that J
is a bit more RstoningS than MDMA, more like MDA, but with a
chronology that is very much the same.

Two nomenclature problems have to be faced in the naming of these
compounds.  One deals with the Chemical Abstracts terminology as
contrasted with the logical and intuitive terminology.  The other
invokes the concept of the Muni-Metro, delightfully simple, but
neither Chemical Abstracts-approved nor intuitive in form.  The first
problem is addressed here; the second is discussed where it better
belongs, under the N-methyl homologue of J (see under METHYL-J).

In short, the two-ring system of J, or of any of the MDA-MDMA family
of drugs, can be named as one ring being attached to the other, or by
a single term that encompasses both.  The first procedure, an old
friend with chemists and the one that had been used for years in the
abstracting services, calls the combination methylenedioxybenzene and,
as a prefix, it becomes methylenedioxyphenyl-something.  The benzene
or the phenyl-something is the foundation of the name, and there
happens to be a methylenedioxy-ring attached to it.  On this basis,
this compound J should be named as if it had no methylenedioxy ring
anywhere, and then simply attach the new ring as an afterthought.  So,
the one-ring parent of J is 1-phenyl-2-aminobutane, and J is
1-(3,4-methylenedioxyphenyl)-2-aminobutane (or, to be a purist, the
amino should alphabetically come first, to give
2-amino-1-(3,4-methylene-dioxyphenyl)butane).  The synthesis of the
chemical intermediates given above uses this old-fashioned
nomenclature.

But the name currently in vogue for this two-ring system is
1,3-benzodioxole.  As a prefix it becomes
1,3-benzodioxol-5-yl-something, and so J would be called
1-(1,3-benzodioxol-5-yl)-2-aminobutane.  This is the source of the
code name BDB.  And the N-methyl homologue, the alpha-ethyl analogue
of MDMA, is named MBDB, or METHYL-J, and is with its own separate
entry in this footnote.

There is a psychological nuance to this new nomenclature.  The virtues
and potential medical value of MDMA lie in its most remarkable
property of facilitating communication and introspective states
without an overlay of psychedelic action.  This property has prompted
the coining of a new pharmacological class name, Entactogen, which
comes from the Greek roots for Rtouching within.S But MDMA has been
badly smeared in both the public and the scientific view, by its wide
popular misuse, its precipitous placement into a Schedule I category
of the Federal Drug Law, and a flood of negative neurotoxicological
findings in animal studies.  There are some properties of both this
compound and its methyl-homologue that suggest this RentactogenS
world, so why not avoid the RMDS prefix that, in many eyes, is
pejorative?  Stick with the totally obscure chemical names, and call
them BDB and MBDB.  Or, even more simply, J and METHYL-J.

 

 

 



#95 LOPHOPHINE; 3-METHOXY-4,5-METHYLENEDIOXYPHENETHYLAMINE

SYNTHESIS: A solution of 50 g myristicinaldehyde
(3-methoxy-4,5-methylenedioxybenzaldehyde, see under MMDA for its
preparation) in 200 mL acetic acid was treated with 33 mL nitromethane
and 17.4 g anhydrous ammonium acetate and held on the steam bath for 5
h.  The reaction mixture was diluted with a little H2O and cooled in
an external ice-acetone bath.  A heavy crop of yellow crystals formed,
which were removed by filtration, washed with cold acetic acid, and
dried to constant weight.  There was thus obtained 19.3 g
3-methoxy-4,5-methylenedioxy-'-nitrostyrene with a mp of 210-212 !C.
The mother liquors were diluted with H2O, and extracted with 3x100 mL
CH2Cl2.  The pooled extracts were washed with 5% NaOH, and the solvent
removed under vacuum yielding 34 g of a dark residue that was largely
unreacted aldehyde.  This residue was reprocessed in acetic acid with
nitromethane and ammonium acetate, as described above, and provided an
additional 8.1 g of the nitrostyrene with the same mp.

A suspension of 25 g LAH in 1.5 L anhydrous Et2O in an inert
atmosphere was stirred magnetically, and brought up to a gentle
reflux.  Through a Soxhlet condenser modified to allow Et2O to return
continuously to the reaction mixture, there was added 27.0 g of
3-methoxy-4,5-methylenedioxy-'-nitrostyrene.  The addition require
many h, and when it was completed, the reaction was held at reflux for
an additional 9 days.  After cooling the reaction mixture in an
external ice bath, the excess hydride was destroyed by the cautious
addition of dilute H2SO4.  The final amount used was 1800 mL H2O
containing 133 g H2SO4.  The phases were separated, and the aqueous
phase was washed with 2x100 mL Et2O.  To it was then added 625 g
potassium sodium tartrate, and sufficient base to bring the pH to >9.
This was extracted with 3x250 mL CH2Cl2, and the pooled extracts
stripped of solvent under vacuum.  The residue was dissolved in
anhydrous Et2O and saturated with anhydrous HCl gas, giving a heavy
crystallization of salts.  These were removed by filtration, Et2O
washed, and air dried, to give 17.7 g
3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE) as an
off-white solid with a mp of 160-161 !C.  This was dissolved in CH3CN
containing 5% EtOH, decolorized with activated charcoal, filtered, and
the removed charcoal washed with boiling CH3CN.  Slow cooling of the
solution provided 11.7 g of a white product which melted at 164-164.5
!C.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg) Between two and five hours, very
peaceful and euphoric mood elevation, similar to mescaline, but
without any visual distortion.  Mild enhancement of color perception,
possibly a function of mood elevation.  There was no nausea, no
eyes-closed vision.  Slept easily that evening.

(with 250 mg) Possibly something of a threshold effect from 2:30 to
4:30 of the experiment.  Intangible, and certainly there is nothing an
hour later.

EXTENSIONS AND COMMENTARY: It looks as if this compound is not active.
There is an excellent argument as to why it really should be, and the
fact that it is not active is completely unexpected.  Let me try to
explain.

Quite simply, mescaline is a major component and a centrally active
alkaloid of the Peyote plant.  It is a phenethylamine, which can
undergo a cyclization within the plant to produce a pile of
derivatives (tetrahydroisoquinolines) such as anhalonine and
O-methylanhalonidine that are marvelously complex alkaloids, all
natural components of this magical cactus.  But there is another pile
of derivatives (tetrahydroisoquinolines) such as anhalonine, and
lophophorine, and peyophorine which are the logical cyclization
products of another phenethylamine which does not exist in the cactus.
It should be there, but it is not.  If it were there it would be the
natural precursor to a host of bicyclic alkaloids, but it is absent.
This is 3-methoxy-4,5-methylenedioxyphenethylamine.  I feel that some
day it will be discovered as a plant component, and when it is it can
be given a name that reflects the generic binomial of the plant.  And
since the plant has been known as Lophophora williamsii, why not give
a name to this compound (which should be in the plant), one derived
from the Latin name, but one that has never before been used?  What
about LOPHOPHINE?  And so, I have named it, but I have not found it,
nor has anyone else.  Yet.

It is inevitable that this simple and most appealing precursor will be
found to be present in the cactus, at some future time when we will
have tools of sufficient sensitivity to detect it.  And certainly, it
would be reasonable to expect it to be an active psychedelic, and to
be as interesting in man as its close cousin, mescaline.  But, at the
present time, LOPHOPHINE is not known to be present in the plant, and
it is not known to be active in man.  I am confident that both
statuses will change in the future.

 

 

 



#96 M; MESCALINE; 3,4,5-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 20 g 3,4,5-trimethoxybenzaldehyde, 40 mL
nitromethane, and 20 mL cyclohexylamine in 200 mL of acetic acid was
heated on the steam bath for 1 h.  The reaction mixture was then
diluted slowly and with good stirring, with 400 mL H2O, which allowed
the formation of a heavy yellow crystalline mass.  This was removed by
filtration, washed with H2O, and sucked as dry as possible.
Recrystallization from boiling MeOH (15 mL/g) yielded, after
filtration and air drying, '-nitro-3,4,5-trimethoxystyrene as bright
yellow crystals weighing 18.5 g.  An alternate synthesis was
effective, using an excess of nitromethane as solvent as well as
reagent, if the amount of ammonium acetate catalysis was kept small.
A solution of 20 g 3,4,5-trimethoxybenzaldehyde in 40 mL nitromethane
containing 1 g anhydrous ammonium acetate was heated on the steam bath
for 4 h.  The solvent was stripped under vacuum and the residual
yellow oil was dissolved in two volumes of hot MeOH, decanted from
some insolubles, and allowed to cool.  The crystals formed are removed
by filtration, washed with MeOH and air dried yielding 14.2 g. of
bright yellow crystals of '-nitro-3,4,5-trimethoxystyrene.  The use of
these proportions but with 3.5 g ammonium acetate gave extensive
side-reaction products even when worked up after only 1.5 h heating.
The yield of nitrostyrene was, in this latter case, unsatisfactory.

To a gently refluxing suspension of 2 g LAH in 200 mL Et2O, there was
added 2.4 g '-nitro-3,4,5-trimethoxystyrene as a saturated Et2O
solution by use of a Soxhlet extraction condenser modified to allow
the continuous return of condensed solvent through the thimble.  After
the addition was complete, the refluxing conditions were maintained
for another 48 h.  After cooling the reaction mixture, a total of 150
mL of 1.5 N H2SO4 was cautiously added, destroying the excess hydride
and untimately providing two clear phases.  These were separated, and
the aqueous phase was washed once with 50 mL Et2O.  There was then
added 50 g potassium sodium tartrate, followed by sufficient NaOH to
bring the pH >9.  This was then extracted with 3x75 mL CH2Cl2, and the
solvent from the pooled extracts was removed under vacuum.  The
residue was distilled at 120-130 !C at 0.3 mm/Hg giving a white oil
that was dissolved in 10 mL IPA and neutralized with concentrated HCl.
The white crystals that formed were diluted with 25 mL Et2O, removed
by filtration, and air dried to provide 2.1 g
3,4,5-trimethoxyphenethylamine hydrochloride (M) as glistening white
crystals.  The sulfate salt formed spectacular crystals from water,
but had a broad and uncharacteristic mp.  An alternate synthesis can
employ 3,4,5-trimethoxyphenylacetonitrile, as described under '-D.

DOSAGE: 200-400 mg (as the sulfate salt), 178-256 mg (as the
hydrochloride salt).

DURATION: 10-12 h

QUALITATIVE COMMENTS: (with 300 mg) I would have liked to, and was
expecting to, have an exciting visual day, but I seemed to be unable
to escape self-analysis.  At the peak of the experience I was quite
intoxicated and hyper with energy, so that it was not hard to move
around.  I was quite restless.  But I spent most of the day in
considerable agony, attempting to break through without success.  I
learned a great deal about myself and my inner workings.  Everything
almost was, but in the final analysis, wasnUt.  I began to become
aware of a point, a brilliant white light, that seemed to be where God
was entering, and it was inconceivably wonderful to perceive it and to
be close to it.  One wished for it to approach with all one's heart.
I could see that people would sit and meditate for hours on end just
in the hope that this little bit of light would contact them.  I
begged for it to continue and come closer but it did not.  It faded
away not to return in that particular guise the rest of the day.
Listening to Mozart's Requiem, there were magnificent heights of
beauty and glory.  The world was so far away from God, and nothing was
more important than getting back in touch with Him.  But I saw how we
created the nuclear fiasco to threaten the existence of the planet, as
if it would be only through the threat of complete annihilation that
people might wake up and begin to become concerned about each other.
And so also with the famines in Africa.  Many similar scenes of joy
and despair kept me in balance.  I ended up the experience in a very
peaceful space, feeling that though I had been through a lot, I had
accomplished a great deal.  I felt wonderful, free, and clear.

(with 350 mg) Once I got through the nausea stage, I ventured
out-of-doors and I was aware of an intensification of color and a
considerable change in the texture of the cloth of my skirt and in the
concrete of the sidewalk, and in the flowers and leaves that were
handed me by an observer.  I experienced the desire to laugh
hysterically at what I could only describe as the completely
ridiculous state of the entire world.  Although I was afraid of
motion, I was persuaded to take a ride in a car.  The driver turned on
the radio and suddenly the music 'The March of the Siamese Children'
from 'The King and I' became the most perfect background music for the
parody of real life which was indeed the normal activity of Telegraph
Avenue on any Saturday morning.  The perfectly ordinary people on
their perfectly ordinary errands were clearly the most cleverly
contrived set of characters all performing all manners of eccentric
activities for our particular hilarity and enjoyment.  I felt that I
was at the same time both observing and performing in an outrageous
moving picture.  I experienced one moment of transcendant happiness
when, while passing Epworth Hall, I looked out of the window of the
car and up at the building and I was suddenly in Italy looking up at a
gay apartment building with its shutters flung open in sunshine, and
with its window boxes with flowers.  We stopped at a spot overlooking
the bay, but I found the view uninteresting and the sun uncomfortable.
I sat there on the seat of the car looking down at the ground, and the
earth became a mosaic of beautiful stones which had been placed in an
intricate design which soon all began to move in a serpentine manner.
Then I became aware that I was looking at the skin of a beautiful
snake Q all the ground around me was this same huge creature and we
were all standing on the back of this gigantic and beautiful reptile.
The experience was very pleasing and I felt no revulsion.  Just then,
another automobile stopped to look at the view and I experienced my
first real feeling of persecution and I wanted very much to leave.

(with 400 mg) During the initial phase of the intoxication (between 2
and 3 hours) everything seemed to have a humorous interpretation.
People's faces are in caricature, small cars seem to be chasing big
cars, and all cars coming towards me seem to have faces.  This one is
a duchess moving in regal pomp, that one is a wizened old man running
away from someone.  A remarkable effect of this drug is the extreme
empathy felt for all small things; a stone, a flower, an insect.  I
believe that it would be impossible to harm anything Q to commit an
overt harmful or painful act on anyone or anything is beyond oneUs
capabilities.  One cannot pluck a flower Q and even to walk upon a
gravel path requires one to pick his footing carefully, to avoid
hurting or disturbing the stones.  I found the color perception to be
the most striking aspect of the experience.  The slightest difference
of shade could be amplified to extreme contrast.  Many subtle hues
became phosphorescent in intensity.  Saturated colors were often
unchanged, but they were surrounded by cascades of new colors tumbling
over the edges.

(with 400 mg) It took a long time to come on and I was afraid that I
had done it wrong but my concerns were soon ended.  The world soon
became transformed where objects glowed as if from an inner
illumination and my body sprang to life.  The sense of my body, being
alive in my muscles and sinews, filled me with enormous joy.  I
watched Ermina fill to brimming with animal spirit, her features
tranformed, her body cat-like in her graceful natural movement.  I was
stopped in my tracks.  The world seemed to hold its breath as the cat
changed again into the Goddess.  As she shed her clothes, she shed her
ego and when the dance began, Ermina was no more.  There was only the
dance without the slightest self-consconciousness. How can anything so
beautiful be chained and changed by other's expectations?  I became
aware of myself in her and as we looked deeply into one another my
boundaries disappeared and I became her looking at me.

EXTENSIONS AND COMMENTARY: Mescaline is one of the oldest psychedelics
known to man.  It is the major active component of the small dumpling
cactus known as Peyote.  It grows wild in the Southwestern United
States and in Northern Mexico, and has been used as an intimate
component of a number of religious traditions amongst the native
Indians of these areas.  The cactus has the botanical name of
Lophophora williamsii or Anhalonium lewinii and is immediately
recognizable by its small round shape and the appearance of tufts of
soft fuzz in place of the more conventional spines.  The dried plant
material has been classically used with anywhere from a few to a
couple of dozen of the hard tops, called buttons, being consumed in
the course of a ceremony.

Throughout the more recently published record of clinical human
studies with mescaline, it has been used in the form of the synthetic
material, and has usually been administered as the sulfate salt.
Although this form has a miserable melting point (it contains water of
crystallization, and the exact melting point depends on the rate of
heating of the sample) it nonetheless forms magnificent crystals from
water.  Long, glistening needles that are, in a sense, its signature
and its mark of purity.  The dosages associated with the above
Rqualitative commentsS are given as if measured as the sulfate,
although the actual form used was usually the hydrochloride salt.  The
conversion factor is given under RdosageS above.

Mescaline has always been the central standard against which all other
compounds are viewed.  Even the United States Chemical Warfare group,
in their human studies of a number of substituted phenethylamines,
used mescaline as the reference material for both quantitative and
qualitative comparisons.  The Edgewood Arsenal code number for it was
EA-1306.  All psychedelics are given properties that are something
like Rtwice the potency of mescalineS or Rtwice as long-lived as
mescaline.S This simple drug is truly the central prototype against
which everything else is measured.  The earliest studies with the
Rpsychotomimetic amphetaminesS had quantitative psychological numbers
attached that read as Rmescaline units.S Mescaline was cast in
concrete as being active at the 3.75 mg/kg level.  That means for a 80
kilogram person (a 170 pound person) a dose of 300 milligrams.  If a
new compound proved to be active at 30 milligrams, there was a M.U.
level of 10 put into the published literature.  The behavioral
biologists were happy, because now they had numbers to represent
psychological properties.  But in truth, none of this represented the
magic of this material, the nature of the experience itself.  That is
why, in this Book II, there is only one line given to Rdosage,S but a
full page given to Rqualitative comments.

Four simple N-modified mescaline analogues are of interest in that
they are natural and have been explored in man.

The N-acetyl analogue has been found in the peyote plant, and it is
also a major metabolite of mescaline in man.  It is made by the gentle
reaction of mescaline with acetic anhydride (a bit too much heat, and
the product N-acetyl mescaline will cyclize to a dihydroisoquinoline,
itself a fine white crystalline solid, mp 160-161 !C) and can be
recrystallized from boiling toluene.  A number of human trials with
this amide at levels in the 300 to 750 milligrams range have shown it
to be with very little activity.  At the highest levels there have
been suggestions of drowsiness.  Certainly there were none of the
classic mescaline psychedelic effects.

If free base mescaline is brought into reaction with ethyl formate (to
produce the amide, N-formylmescaline) and subsequently reduced (with
lithium aluminum hydride) it is converted to the N-methyl homologue.
This base has also been found as a trace component in the Peyote
cactus.  And the effects of N-methylation of other psychedelic drugs
have been commented upon elsewhere in these recipes, all with
consistently negative results (with the noteworthy exception of the
conversion of MDA to MDMA).  Here, too, there is no obvious activity
in man, although the levels assayed were only up to 25 milligrams.

N,N-Dimethylmescaline has been given the trivial name of Trichocerine
as it has been found as a natural product in several cacti of the
Trichocereus Genus but, interestingly, never in any Peyote variant.
It also has proven inactive in man in dosages in excess of 500
milligrams, administered parenterally.  This observation, the absence
of activity of a simple tertiary amine, has been exploited in the
development of several iodinated radiopharmaceuticals that are
mentioned elsewhere in this book.

The fourth modification is the compound with the nitrogen atom
oxidatively removed from the scene.  This is the mescaline metabolite,
3,4,5-trimethoxyphenylacetic acid, or TMPEA.  Human dosages up to 750
milligrams orally failed to produce either physiological or
psychological changes.

One additional manipulation with some of these structures has been
made and should be mentioned.  These are the analogues with an oxygen
atom inserted between the aromatic ring and the aliphatic chain.  They
are, in essence, aminoethyl phenyl ethers.  The first is related to
mescaline itself, 2-(3,4,5-trimethoxyphenoxy)ethylamine.  Human trials
were conducted over the dose range of 10 to 300 milligrams and there
were no effects observed.  The second is related to trichocerine,
N,N-dimethyl-2-(3,4,5-trimethoxyphenoxy)ethylamine.  It was inactive
in man over the range of 10 to 400 milligrams.  Mescaline, at a dose
of 420 milligrams, served as the control in these studies.

 

 

 



#97 4-MA; PMA; 4-METHOXYAMPHETAMINE

SYNTHESIS: A solution of 27.2 g anisaldehyde and 18.0 g nitroethane in
300 mL benzene was treated with 2.0 mL cyclohexane and refluxed using
a Dean Stark trap until H2O ceased to accumulate.  A total of 3.8 mL
was generated over about 5 days.  After the removal of the solvent
under vacuum, the viscous red oily residue was cooled and it
spontaneously crystallized.  This was ground under an equal volume of
MeOH, producing lemon-yellow crystals of
1-(4-methoxyphenyl)-2-nitropropene.  The final yield was 27.4 g of
product with a mp of 45-46 !C.  Recrystallization from 4 volumes MeOH
did not improve the mp.  An excellent alternate synthesis with a
comparable yield involved letting a solution of equimolar amounts of
the aldehyde and nitro-ethane and a tenth mole of n-amylamine stand in
the dark at room temperature for a couple of weeks.  The product
spontaneously crystal-lized, and could be recrystallized from MeOH.
The more conventional synthesis involving acetic acid as a solvent and
ammonium acetate as a catalyst, produced a poor yield of the
nitrostyrene and it was difficult to separate from the white diacetate
of the starting anisaldehyde, mp 59-60 !C.

A suspension of 32 g LAH in 1 L anhydrous Et2O was well stirred and
32.6 g 1-(4-methoxyphenyl)-2-nitropropene in Et2O was added at a rate
that maintained a reflux.  After the addition was complete, reflux was
continued for 48 h.  The reaction mixture was cooled, and the excess
hydride was destroyed by the cautious addition of dilute H2SO4.  The
Et2O was separated, and extracted with additional aqueous H2SO4.  A
solution of 700 g potassium sodium tartrate in 600 mL H2O was added,
and the pH brought to >9 with 25% NaOH.  This aqueous phase was
extracted with 3x200 mL CH2Cl2 which provided, after removal of the
solvent, 32.5 g of a clear amber oil.  This was dissolved in 100 mL
IPA, neutralized with concentrated HCl, and then diluted with 300 mL
anhydrous Et2O.  There was obtained white crystals of
4-methoxyamphetamine hydrochloride (4-MA) that weighed, after
filtering, Et2O washing and air drying, 22.2 g and had a mp of 208-209
!C.  The amphetamine metabolite, 4-hydroxyamphetamine hydrochloride
(4-HA), was prepared by heating 5.0 g 4-MA in 20 mL concentrated HCl
at 15 lbs/in.  After recrystal-lization from aqueous EtOH, the product
weighed 3.8 g and had a mp of 171-172 !C.

DOSAGE: 50 - 80 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 60 mg) At just over an hour, there was a
sudden blood pressure rise, with the systolic going up 55 mm.  This
was maintained for another hour.  I found the effects reminiscent of
DET, distinct after-images, and some parasthesia.  I was without any
residue by early evening (after 5 hours).

(with 70 mg) It hit quite suddenly.  I had a feeling of druggedness,
almost an alcohol-like intoxication, and I never was really high in
the psychedelic sense.

EXTENSIONS AND COMMENTARY: This is another of the essential
amphetamines, because of the appearance of the 4-methoxy group in two
most important essential oils.  These are the allylbenzene (estragole
or esdragol) and the propenyl isomer (anethole).  Their natural
sources have been discussed under TMA.

Two comments are warranted concerning 4-MA, one of scientific
interest, and the other about a social tragedy.

A major metabolites of amphetamine is 4-hydroxyamphetamine, from
oxidation at the 4-position.  It has been long known that with chronic
amphetamine usage there is the generation of tolerance, which
encourages ever-increasing doses to be used.  When the daily load gets
up around one or two hundred milligrams, the subject can become quite
psychotic.  The question was asked: might the chronic amphetamine user
be methylating his endogenously produced 4-hydroxyamphet-amine to
produce 4-methoxyamphetamine (4-MA), and maybe this is the agent that
promotes the psychosis?  To address this question, several studies
were done with normal subjects, about 20 years ago, to see if 4-MA
might produce a psychotic state (it didnUt at the highest levels
tried, 75 milligrams) and to see if it was excreted to some extent
unchanged in the urines of these normal subjects (it was seen even at
the lowest dosage tried, 10 milligrams).  It produced excitation and
other central effects, it produced adrenergic pressor effects, and it
consistently produced measur-able quantities of 4-MA in the urine, but
it produced no amphetamine-like crazies.  And since the administration
of up to 600 milligrams of amphetamine produced no detectable 4-MA in
the urine, this theory of psychotomimesis is not valid.

On the tragic side, a few years later, 4-MA became widely distributed
in both the US (as the sulfate salt) and in Canada (as the
hydrochloride), perhaps in-spired by some studies in rats that had
reported that it was second only to LSD in potency as a hallucinogen.
The several deaths that occurred probably followed overdose, and it
was clear that 4-MA was involved as it had been isolated from both
urine and tissue during post mortems.  It had been sold under the
names of Chicken Power and Chicken Yellow, and was promoted as being
MDA.  I could find no record of a typical street dosage, but comments
collected in association with the deaths implied that the ingested
quantites were in the hundreds of milligrams.  Rrecently, the ethoxy
homologue, 4-EA, appeared on the streets of Canada.  The dosage,
again, was not reported.  It was promptly illegalized there.

The two positional analogues of 4-MA are known; vis., 2-MA and 3-MA.
Their synthesis is straightforward, in imitation of that for 4-MA
above.  The meta-compound, 3-MA, has been metabolically explored in
man, but no central effects were noted at a 50 milligram dose (2x25
milligrams, separated by three hours).  There appears to be no report
of any human trial of 2-MA.  The N-methyl homologue of 2-MA is a
commercial adrenergic bronchodilator called Methoxyphenamine, or
Orthoxine.  It has been used in the prevention of acute asthma attacks
in doses of up to 200 milligrams, with only slight central
stimulation.  The N-methyl homologues of 3-MA and 4-MA are known, and
the latter compound is the stuff of a separate entry in this book.

 

 

 



#98 MADAM-6; 2,N-DIMETHYL-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A mixture of 102 g POCl3 and 115 g N-methylformanilide was
allowed to stand for 0.5 h at room temperature during which time it
turned a deep claret color.  To this there was added 45 g
3,4-methylenedioxytoluene and the mixture was held on the steam bath
for 3 h.  It was then added to 3 L H2O.  Stirring was continued until
the oil which had separated had become quite firm.  This was removed
by filtration to give a greenish, somewhat gummy, crystalline solid,
which was finely ground under 40 mL MeOH and again filtered giving,
when air dried, 25 g of an almost white solid.  Recrystallization of a
small sample from methylcyclopentane gave ivory-colored glistening
crystals of 2-methyl-4,5-methylenedioxybenzaldehyde with a mp of
88.5-89.5 !C.  In the infra-red, the carbonyl was identical to that of
the starting piperonal (1690 cm-1) but the fingerprint was different
and unique, with bands at 868, 929, 1040 and 1052 cm-1.

A solution of 23 g 2-methyl-4,5-methylenedioxybenzaldehyde in 150 mL
nitroethane was treated with 2.0 g anhydrous ammonium acetate and
heated on the steam bath for 9 h.  The excess solvent was removed
under vacuum to give a dark yellow oil which was dissolved in 40 mL
hot MeOH and allowed to crystallize.  The solids were removed by
filtration, washed modestly with MeOH and air dried, to give 21.2 g of
1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene as beautiful
yellow crystals with a mp of 116-118 !C.  Recrystallization of an
analytical sample from MeOH gave lustrous bright yellow crystals with
a mp of 120-121 !C.  Anal. (C11H11NO4) C,H,N.

A suspension of 54 g electrolytic elemental iron in 240 g glacial
acetic acid was warmed on the steam bath, with frequent stirring.
When the reaction between them started, there was added, a portion at
a time, a solution of 18.2 g
1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene in 125 mL warm
acetic acid.  The orange color of the nitrostyrene solution became
quite reddish, white solids of iron acetate appeared, and a dark
tomato-colored crust formed which was continuously broken back into
the reaction mixture.  Heating was continued for 1.5 h, and then all
was poured into 2 L H2O.  All the insolubles were removed by
filtration, and these were washed well with CH2Cl2.  The filtrate and
washes were combined, the phases separated, and the aqueous phase
extracted with 2x100 mL additional CH2Cl2.  The combined organics were
washed with 5% NaOH, and the solvent removed under vacuum.  The
residue weighed 15.9 g, and was distilled at 90-110 !C at 0.4 mm/Hg to
give 13.9 g of 2-methyl-4,5-methylenedioxyphenylacetone that
spontaneously crystallized.  A small sample from methylcyclopentane
had a mp of 52-53 !C, another from hexane a mp of 53-54 !C, and
another from MeOH a mp of 54-55 !C.  Anal. (C11H12O3) H; C calcd,
68.73; found 67.87, 67.84.

To a stirred solution of 30 g methylamine hydrochloride in 200 mL warm
MeOH there was added 13.5 g 2-methyl-4,5-methylenedioxyphenylacetone
followed, after returning to room temperature, by 7 g sodium
cyanoborohydride.  There was added HCl as needed to maintain the pH at
approximately orange on external damp universal pH paper.  After a few
days, the reaction ceased generating base, and all was poured into 2 L
dilute H2SO4 (caution, HCN evolved).  This was washed with 3x75 mL
CH2Cl2, made basic with 25% NaOH, and the resulting mixture extracted
with 3x100 CH2Cl2.  The pooled extracts were stripped of solvent under
vacuum and the residue, 15 g of a pale amber oil, was distilled at
95-110 !C at 0.4 mm/Hg.  There was obtained 12.3 g of a white oil that
was dissolved in 60 mL IPA, neutralized with approximately 5.5 mL
concentrated HCl, and crystals of the salt formed spontaneously.
These were loosened with the addition of another 10 mL IPA, and then
all was diluted by the addition of an equal volume of anhydrous Et2O.
The white crystals were separated by filtration, Et2O washed, and air
dried to give 14.1 g of 2,N-dimethyl-4,5-methylenedioxyamphetamine
hydrochloride (MADAM-6) as a brilliant white powder with a mp of
206-207 !C.  Anal. (C12H18ClNO2) C,H.

DOSAGE: greater than 280 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 180 mg) There is a hint of good things
there, but nothing more than a hint.  At four hours, there is no
longer even a hint.

(with 280 mg) I took 150 milligrams, waited an hour for results,
which was niente, nada, nothing.  Took supplements of 65 milligrams
twice, an hour apart.  No effect.  Yes, we giveth up.

EXTENSIONS AND COMMENTARY: The structure of MADAM-6 was designed to be
that of MDMA, with a methyl group attached at what should be a
reasonably indifferent position.  In fact, that is the genesis of the
name.  MDMA has been called ADAM, and with a methyl group in the
6-position, MADAM-6 is quite understandable.  And the other
ortho-position is, using this nomenclature, the 2-position, and with a
methyl group there, one would have MADAM-2.  I should make a small
apology for the choice of numbers.  MDMA is a 3,4-methylenedioxy
compound, and the least ambiguous numbering scheme would be to lock
the methylenedioxy group inescapably at the 3,4-place, letting the
other ring position numbers fall where they may.  The rules of
chemistry ask that if something is really a 3,4,6-orientation it
should be renumbered as a 2,4,5-orientation.  Let's quietly ignore
that request here.

How fascinating it is, that a small methyl group, something that is
little more than one more minor bump on the surface of a molecule that
is lumpy and bumpy anyway, can so effectively change the action of a
compound.  A big activity change from a small structure change usually
implies that the bump is at a vital point, such as a target of
metabolism or a point of critical fit in some receptor site.  And
since 6-MADAM can be looked upon as 6-bump-MDMA, and since it is at
least 3x less potent than MDMA, the implication is that the action of
MDMA requires some unbumpiness at this position for its particular
action.  There are suggestions that the body may want to put a
hydroxyl group right there (a 6-hydroxy-dopamine act), and it couldnUt
if there was a methyl group right there.  The isopropylamine side
chain may want a certain degree of swing-around freedom, and this
would be restricted by a methyl bump right next to it.  And there are
all kinds of other speculations possible as to why that position
should be open.

Anyway, MADAM-6 is not active.  And the equally intriguing positional
isomer, the easily made MADAM-2, will certainly contribute to these
speculations.  A quiz for the reader!  Will
2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be: (1) Of much
reduced activity, akin to MADAM-6, or (2) Of potency and action
similar to that of MDMA, or (3) Something unexpected and
unanticipated?  I know only one way of finding out.  Make the SchiffsU
base between piperonal and cyclohexylamine, treat this with butyl
lithium in hexane with some TMEDA present, add some
N-methylformanilide, convert the formed benzaldehyde to a nitrostyrene
with nitroethane, reduce this with elemental iron to the
phenylacetone, reduce this in the presence of methylamine with sodium
cyanoborohydride, then taste the result.

 

 

 



#99 MAL; METHALLYLESCALINE;
3,5-DIMETHOXY-4-METHALLYLOXYPHENETHYLAMINE)

SYNTHESIS: To a solution of 5.8 g of homosyringonitrile (see under
ESCALINE for its preparation) in 50 mL of acetone containing 100 mg of
decyltriethylammonium iodide there was added 7.8 mL methallyl chloride
followed by 6.9 g of finely powdered anhydrous K2CO3.  The suspension
was kept at reflux by a heating mantle, with effective stirring.
After 6 h an additional 4.0 mL of methallyl chloride was added, and
the refluxing was continued for an additional 36 h.  The solvent and
excess methallyl chloride was removed under vacuum and the residue was
added to 400 mL H2O.  This solution was extracted with 3x75 mL CH2Cl2.
The extracts were pooled, washed with 2x50 mL 5% NaOH, and the solvent
removed to provide a dark brown oil.  This was distilled at 120-130 !C
at 0.4 mm/Hg to provide 6.1 g of
3,5-dimethoxy-4-methyallyloxyphenylacetonitrile as a lemon-colored
viscous oil.  Anal. (C14H17NO3) C,H.

A suspension of 4.2 g LAH in 160 mL anhydrous THF under He was
stirred, cooled to 0 !C, and treated with 2.95 ml of 100% H2SO4 added
dropwise.  This was followed by the addition of 6.0 g of
3,5-dimethoxy-4-methallyloxy-phenylacetonitrile dissolved in 10 mL
anhydrous THF, at a slow rate with vigorous stirring.  The reaction
mixture was held at reflux on the steam bath for 0.5 h, brought back
to room temperature, and the excess hydride destroyed with IPA.
Sufficient 15% NaOH was added to convert the formed solids to a loose,
granular texture, and the entire mixture filtered and washed with THF.
The filtrate and washings were pooled, the solvent removed under
vacuum, and the residue added to 500 mL dilute HCl.  This solution was
washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and
extracted with 3x75 mL CH2Cl2.  The extracts were pooled, the solvent
removed under vacuum, and the residual pale amber oil distilled at
120-130 !C at 0.3 mm/Hg to provide 1.5 g of a white oil.  This was
dissolved in 8.0 mL of IPA and neutralized with 25 drops of
concentrated HCl.  The addition of 40 ml of anhydrous Et2O with
stirring produced, after a few moments delay, a spontaneous
crystallization of 3,5-dimethoxy-4-methallyloxyphenethylamine
hydrochloride (MAL) as fine white needles.  After standing overnight
these were removed by filtration, washed with an IPA/Et2O mixture,
then with Et2O, and allowed to air dry to constant weight.  The
product weighed 1.1 g, and had a mp of 153-154 !C.  Anal.
(C14H22ClNO3) C,H.

DOSAGE: 40 - 65 mg.

DURATION: 12 - 16 h.

QUALITATIVE COMMENTS: (with 45 mg) Too much overload. I am
sur-rounded with unreality.  I do not choose to repeat the
experiment.

(with 45 mg) I am basically favorably impressed.  I believe the
initial discomfort would be alleviated by taking two 30 milligram
doses separated by an hour.

(with 45 mg) Much too much too much.  There are shades of what might
become amnesia.  I am losing immediate contact.  I will not repeat.

(with 50 mg) A good level.  I found myself totally caught up in the
visual theater.  Although I had trouble sleeping, I would willingly
repeat the experiment at the same level.

(with 60 mg) Extremely restless.  Am very impressed with all the
activity.  But if I repeated it would be at a lower dose.

(with 60 mg) Friendly territory.  There is much kaleidoscopic TneonU
colors.  Eyes closed very active.  Eyes open there is considerable
visual distortions seen in melted wax.  Faces are distorted (friendly)
but the sinister is not far away.

(with 65 mg) Completely involved Q good psychedelic state Q visual
entertainment with alternation (i.e., depth and movement) at the
retinal level Q detail in watercolors.  Later in the experience (the 8
hour point) easy childhood memory recall.

(with 65 mg) Beautiful.  To a +2 by the 1st hr and continued
climbing.  Intense +3 within 2 hrs.  Quite strong body.  Diuretic.
Fantasy, imagery, erotic.  Way up, good connections between parts of
self.  Slight slowing of pulse in 7th to 8th hour.  Excellent solid
sleep with strong, clear, balancing dreams.  But not until after 12
hrs.

EXTENSIONS AND COMMENTARY: This testimony can be accurately described
as a mixed bag!

This base, MAL, lies as a hybrid of two other compounds, AL and CPM.
It is an olefin (as is AL) which means that it has a place of
unsaturation in its structure.  And it is an isostere of CPM which
means that the carbon atoms are all in the same location, but just the
connecting electrons (called the chemical bonds) are in different
places.  Actually there is yet a third compound in this same picture,
called PROPYNYL.  And yet, although all of them have extremely close
structural similarities, there are such great differences in action
that one does not dare to generalize.  CPM leads largely to fantasy,
MAL largely to visual imagery, AL is twice as potent as either of
these but it doesnUt show either effect, and PROPYNYL is almost
without any action at all.

Speaking of generalization, I am glad that there are always
exceptions.  Some years ago, I had a most difficult experience with a
strain of marijuana that was known by the name of DRED.  The only word
that I can use to describe my response to it is to say that I felt I
had been poisoned.  From this I warned myself to beware (and to
believe in) whatever common name a drug might have been given.
Fortunately, MAL did not live up to its name (at least for me),
although some of the experimental subjects might disagree!

One additional compound was suggested by these parallels.  Each of
these three drugs can be viewed as having a negative something hanging
out a-ways from the molecular center.  With AL and MAL, this is the
olefin double bond.  With CPM this is a very strained three-member
ring.  What about an oxygen?  The reaction between homosyringonitrile
and methoxyethyl chloride produced the precursor to such a product
(3,5-dimethoxy-4-(2-methoxyethoxy)-phenethylamine) but the yield was
so bad that the project was abandoned.  This same grouping has
successfully been put into the 4-position of the sulfur-containing
analog, and the result (2C-T-13) has proved to be quite a potent and
interesting material.  Maybe someday hang a sulfur atom out there at
the end of that chain.

The name methallylescaline actually is completely unsound.  There is
no union of a methallyl with an escaline.  What is really there is not
an escaline at all, but rather a mescaline with a 2-propene attached
to the methyl of the methoxy on the 4-position.  There is no way of
naming the thing in that manner, so the only logical solution is to
take off the methyl entirely, and then put the methallyl on in its
place.  The name of this would then be
4-methylallyldesmethylmescaline.  That would have received the
abbreviation MAD which would have been even more difficult to deal
with.  MAL is preferable.

 

 

 



#100 MDA; 3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from piperonal) To a solution of 15.0 g piperonal in 80 mL
glacial acetic acid there was added 15 mL nitroethane followed by 10 g
cyclohexylamine.  The mixture was held at steam-bath temperature for 6
h, diluted with 10 mL H2O, seeded with a crystal of product, and
cooled overnight at 10 !C.  The bright yellow crystals were removed by
filtration, and air dried to yield 10.7 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene with a mp of 93-94 !C.
This was raised to 97-98 !C by recrystallization from acetic acid.
The more conventional efforts of nitrostyrene synthesis using an
excess of nitroethane as a solvent and anhydrous ammonium acetate as
the base, gives impure product in very poor yields.  The nitrostyrene
has been successfully made from the components in cold MeOH, with
aqueous NaOH as the base.

A suspension of 20 g LAH in 250 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically.  There was added, dropwise,
18 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in solution in THF
and the reaction mixture was maintained at reflux for 36 h.  After
being brought back to room temperature, the excess hydride was
destroyed with 15 mL IPA, followed by 15 mL of 15% NaOH.  An
additional 50 mL H2O was added to complete the conversion of the
aluminum salts to a loose, white, easily filtered solid.  This was
removed by filtration, and the filter cake washed with additional THF.
The combined filtrate and washes were stripped of solvent under
vacuum, and the residue dissolved in dilute H2SO4.  Washing with 3x75
mL CH2Cl2 removed much of the color, and the aqueous phase was made
basic and reextracted with 3x100 mL CH2Cl2.  Removal of the solvent
yielded 13.0 g of a yellow-colored oil that was distilled.  The
fraction boiling at 80-90 !C at 0.2 mm weighed 10.2 g and was
water-white.  It was dissolved in 60 mL of IPA, neutralization with
concentrated HCl, and diluted with 120 mL of anhydrous Et2O which
produced a lasting turbidity.  Crystals formed spontaneously which
were removed by filtration, washed with Et2O, and air dried to provide
10.4 g of 3,4-methylenedioxyamphetamine hydrochloride (MDA) with a mp
of 187-188 !C.

(from 3,4-methylenedioxyphenylacetone) To a solution of 32.5 g
anhydrous ammonium acetate in 120 mL MeOH, there was added 7.12 g
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 2.0 g sodium cyanoborohydride.  The resulting yellow
solution was vigorously stirred, and concentrated HCl was added
periodically to keep the pH of the reaction mixture between 6 and 7 as
determined by external damp universal pH paper.  After several days,
undissolved solids remained in the reaction mixture and no more acid
was required.  The reaction mixture was added to 600 mL of dilute HCl,
and this was washed with 3x100 mL CH2Cl2.  The combined washes were
back-extracted with a small amount of dilute HCl, the aqueous phases
combined, and made basic with 25% NaOH.  This was then extracted with
3x100 mL CH2Cl2, these extracts combined, and the solvent removed
under vacuum to provide 3.8 g of a red-colored residue.  This was
distilled at 80-90 !C at 0.2 mm/Hg to provide 2.2 g of an absolutely
water-white oil.  There was no obvious formation of a carbonate salt
when exposed to air.  This was dissolved in 15 mL IPA, neutralized
with 25 drops of concentrated HCl, and diluted with 30 mL anhydrous
Et2O.  Slowly there was the deposition of white crystals of
3,4-methylenedioxyamphetamine hydrochloride (MDA) which weighed 2.2 g
and had a mp of 187-188 !C.  The preparation of the formamide (a
precursor to MDMA) and the acetamide (a precursor to MDE) are
described under those entries.

DOSAGE: 80 - 160 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 100 mg) The coming on was gradual and
pleasant, taking from an hour to an hour and one half to do so.  The
trip was euphoric and intense despite my having been naturally
depleted from a working day and having started so late.  One thing
that impressed itself upon me was the feeling I got of seeing the play
of events, of what I thought to be the significance of certain people
coming into my life, and why my TdanceU, like everyone elseUs, is
unique.  I saw that every encounter or event is a potential for
growth, and an opportunity for me to realize my completeness at where
I am, here and now, not at some future where I must lug the pieces of
the past for a final assemblage Tthere.U I was reminded of living the
moment to its fullest and I felt that seeing this was indicative that
I was on the right track.

(with 128 mg) Forty-five minutes after the second dosage, when I was
seated in a room by myself, not smoking, and where there was no
possible source of smoke rings, an abundance of curling gray smoke
rings was readily observed in the environment whenever a relaxed
approach to subjective observation was used.  Visually these had
complete reality and it seemed quite unneccessary to test their
properties because it was surely known and fully appreciated that the
source of the visual phenomena could not be external to the body.
When I concentrated my attention on the details of the curling gray
forms by trying to note how they would be affected by passing a finger
through their apparent field, they melted away.  Then, when I relaxed
again, the smoke rings were there.  I was as certain that they were
really there as I am now sure that my head is on top of my body.

(with 140 mg) I vomited quite abruptly, and then everything was OK.
I had been drinking probably excessively the last two days, and maybe
the body needed to unpoison itself.  The tactile sense is beautiful,
but there seems to be some numbness as well, and I feel that nothing
erotic would be do-able.  Intimacy, yes, but no performance IUm pretty
sure.  I saw the experience start drifting away only four hours into
it, and I was sad to see it go.  It was an all around delightful day.

(with 200 mg, 2x100 mg spaced 1 h) RThe first portion was apparent at
one-half hour.  There was microscopic nausea shortly after the second
portion was taken, and in an hour there was a complete +++ developed.
The relaxation was extreme.  And there seemed to be time distortion,
in that time seemed to pass slowly.  There was a occasional LSD-like
moment of profoundness, but by and large it was a simple intoxication
with most things seeming quite hilarious.  The intoxication was also
quite extreme.  Some food was tried later in the experiment, and it
tasted good, but there was absolutely no appetite.  None at all.

(with 60 mg of the RRS isomer) There was a light and not too gentle
development of a somewhat brittle wound-up state, a + or even a ++.
Chills, and I had to get under an electric blanket to be comfortable.
The effects smoothed out at the fourth hour, when things started to
return to baseline.  Not too entertaining.

(with 100 mg of the RRS isomer) Rapid development from the 40 minute
point to an hour and a quarter; largely a pleasant intoxication, but
there is something serious there too.  No great insights, and not too
much interference with the day's goings-on.  Completely clear at the 8
hour point.

(with 120 mg of the RRS isomer) This is a stoning intoxicant.  I
would not choose to drive, because of possible judgement problems, but
my handwriting seems to be clear and normal.  The mental excitement
dropped rapidly but I was aware of physical residues for several
additional hours.

(with 80 mg of the RSS isomer) A very thin, light threshold, which is
quite delightful.  I am quite willing to push this a bit higher.

(with 120 mg of the RSS isomer) Perhaps to a one +.  Very light, and
very much like MDMA, but perhaps shorter lived.  I am pretty much
baseline in three hours.

(with 160 mg of the RSS isomer) The development is very rapid, and
there is both muscular tremor and some nausea.  The physicals are
quite bothersome.  With eyes closed, there are no effects noticeable,
but with eyes open, things are quite bright and sparkling.  The
muscular spasms persist, and there is considerable teeth clenching.  I
feel that the mental is not worth the physical.

EXTENSIONS AND COMMENTARY: There are about twenty different synthetic
routes in the literature for the preparation of MDA.  Many start with
piperonal, and employ it to make methylenedioxyphenylacetone or a
methylenedioxydihydro-cinnamic acid amide instead of the nitrostyrene.
The phenylacetone can be reduced in several ways other than the
cyanoborohydride method mentioned here, and the amide can be
rearranged directly to MDA.  And there are additional methods for the
reduction of the nitrostyrene that use no lithium aluminum hydride.
Also there are procedures that have safrole or isosafrole as starting
points.  There is even one in the underground literature that starts
with sassafras root bark.  In fact, it is because safrole is one of
the ten essential oils that MDA can humorously be referred to as one
of the Ten Essential Amphetamines.  See the comments under TMA.

There is a broad and checkered history concerning the use and abuse of
MDA, and it is not the case that all the use was medical and all the
abuse was social.  One of the compulsive drives of both the military
and the intelligence groups, just after World War II, was to discover
and develop chemical agents which might serve as Rtruth serumsS or as
incapacitating agents.  These government agencies considered the area
of the psychedelics to be a fertile field for searching.  The giving
of relatively unexplored drugs in a cavalier manner to knowing and
unknowing subjects was commonplace.  There was one case in 1953,
involving MDA and a psychiatric patient named Howard Blauer that
proved fatal.  The army had contracted with several physicians at the
New York State Psychiatric Institute to explore new chemicals from the
Edgewood Arsenal and one of these, with a chemical warfare code number
of EA-1298, was MDA.  The last and lethal injection into Blauer was an
intravenous dose of 500 milligrams.

There have been a number of medical explorations.  Under the code
SKF-5 (and trade name of Amphedoxamine) it was explored as an anorexic
agent.  It has been found promising in the treatment of psychoneurotic
depression.  There are several medical reports, and one book (Claudio
Naranjo's The Healing Journey), that describe its values in
psychotherapy.

MDA was also one of the major drugs that was being popularly used in
the late 1960's when the psychedelic concept exploded on the public
scene.  MDA was called the Rhug-drugS and was said to stand for Mellow
Drug of America.  There was no difficulty in obtaining unending
quantities of it, as it was available as a research chemical from
several scientific supply houses (as were mescaline and LSD) and was
sold inexpensively under its chemical name.

A few experimental trials with the pure optical isomers show a
consistency with all the other psychedelic compounds that have been
studied in their separated forms, the higher potency with the RRS
isomer.  The less potent RSS isomer seemed to be more peaceful and
MDMA-like at lower doses, but there were worrisome toxic signs at
higher levels.

The structure of MDA can be viewed as an aromatic ring (the
3,4-methylenedioxyphenyl ring) with a three carbon chain sticking out
from it.  The amine group is on the second of the three carbon atoms.
The isomers, with the amine function moved to the first of these
carbons atoms (a benzylamine) and with the amine function moved to the
third (furthest out atom) of these carbon atoms (a (n)-propylamine),
are known and both have been assayed.

The benzylamine counterpart (as if one were to move the amine function
from the beta-carbon to the alpha-carbon of the three carbon chain of
the amphetamine molecule) is alpha-ethyl-3,4-methylenedioxybenzylamine
or 1-amino-1-(3,4-methylenedioxyphenyl)propane, ALPHA.  The
hydrochloride salt has a mp of 199-201 !C.  At low threshold levels
(10 milligram area) there were eyes-closed RdreamsS with some body
tingling.  The compound was not anorexic at any dose (up to 140
milligrams) and was reported to produce a pleasant, positive feeling.
It is very short-lived (about 3 hours).  The N-methyl homologue is
alpha-ethyl-N-methyl-3,4-methylenedioxybenzylamine or
1-methylamino-1-(3,4-methylenedioxy-phenyl)propane, M-ALPHA.  It is
similar in action, but is perhaps twice as potent (a plus one or plus
two dose is 60 milligrams) and of twice the duration.

The (n)-propylamine counterpart (as if one were to move the amine
function the other direction, from the beta-carbon to the gamma-carbon
of the three carbon chain of the amphetamine molecule) is
gamma-3,4-methylenedioxyphenylpropylamine or
1-amino-3-(3,4-methylenedioxyphenyl)propane, GAMMA.  The hydrochloride
salt has a mp of 204-205 !C.  At oral levels of 200 milligrams there
was some physical ill-at-ease, possible time distortion, and a feeling
of being keenly aware of one's surroundings.  The duration of effects
was 4 hrs.

The phenethylamine that corresponds to MDA (removing the alpha-methyl
group) is 3,4-methylenedioxyphenethylamine, or homopiperonylamine, or
MDPEA, or simply H in the vocabulary of the Muni-Metro world.  This
compound is an entry in its own rights.  The adding of another carbon
atom to the alpha-methyl group of MDA gives compound J, and leads to
the rest of the Muni-Metro series (K, L etc).  All of this is
explained under METHYL-J.  The bending of this alpha-methyl group back
to the aromatic ring gives an aminoindane, and with J one gets an
aminotetralin.  Both compounds react in animal discrimination studies
identically to MDMA, and they appear to be free of neurochemical
toxicity.

The two possible homologues, with either one or two methyl groups on
the methylene carbon of the methylenedioxy group of MDA, are also
known.  The ethylidene compound (the acetaldehyde addition to the
catechol group) has been encoded as EDA, and the acetone
(isopropylidine addition to the catechol group) is called IDA.  In
animal discrimination studies, and in in vitro neurotransmitter
studies, they both seem to be of decreased potency.  EDA is down two
to three-fold from MDA, and IDA is down by a factor of two to
three-fold again.  Human trials of up to 150 milligrams of the
hydrochloride salt of EDA producd at best a threshold
light-headedness.  IDA remains untested as of the present time.  The
homologue of MDA (actually of MDMA) with the added carbon atom in,
rather than on, the methylenedioxy ring, is a separate entry; see
MDMC.

A final isomer to be mentioned is a positional isomer.  The
3,4-methylene-dioxy group could be at the 2,3-position of the
amphetamine skeleton, giving 2,3-methylenedioxyamphetamine, or
ORTHO-MDA.  It appears to be a stimulant rather than another MDA.  At
50 milligrams, one person was awake and alert all night, but reported
no MDA-like effects.

 

 

 



#101 MDAL; N-ALLYL-MDA; 3,4-METHYLENEDIOXY-N- ALLYLAMPHETAMINE

SYNTHESIS: A total of about 20 mL allylamine was introduced under the
surface of 20 mL concentrated HCl, and the mixture stripped of
volatiles under vacuum The resulting 24 g of wet material did not
yield any crystals with either acetone or Et2O.  This was dissolved in
75 mL MeOH, treated with 4.45 g 3,4-methylenedioxy-phenylacetone (see
under MDMA for its preparation), and finally with 1.1 g sodium
cyanoborohydride.  Concentrated HCl was added as needed over the
course of 5 days to keep the pH constant at about 6.  The reaction
mixture was then added to a large amount 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 3.6 g of an amber oil which, on
distillation at 90-95 !C at 0.2 mm/Hg, yielded 2.6 g of an off-white
oil.  This was dissolved in 10 mL IPA, neutralized with about 25 drops
of concentrated HCl, and the resulting clear but viscous solution was
diluted with Et2O until crystals formed.  These were removed by
filtration, washed with IPA/Et2O (1:1), then with Et2O, and air dried
to constant weight.  There was thus obtained 2.5 g of
3,4-methylenedioxy-N-allylamphetamine hydrochloride (MDAL) with a mp
of 174-176 !C and a proton NMR spectrum that showed that the allyl
group was intact.  Anal. (C13H18ClNO2) N.

DOSAGE: greater than 180 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Here is another inactive probe, like MDPR,
that could possibly serve as a primer to LSD.  The three carbon chain
on the nitrogen seen with MDPR is almost identical to the three carbon
chain on the nitrogen atom of MDAL.  And yet, where an RinactiveS
level of 180 milligrams of MDPR is a rather fantastic enhancer of LSD
action, the same weight of this compound not only does not enhance,
but actually seems to somewhat antagonize the action of LSD.  All this
difference from just a couple of hydrogen atoms.  Identical carbon
atoms, identical oxygen atoms, and an identical nitrogen atom.  And
all in identical places.  Simply C13H18ClNO2 rather than C13H20ClNO2.

So, apparently, almost identical is not good enough!

 

 

 



#102 MDBU; N-BUTYL-MDA; 3,4-METHYLENEDIOXY-N-BUTYLAMPHETAMINE

SYNTHESIS: A total of 30 mL butylamine was introduced under the
surface of 33 mL concentrated HCl, and the mixture stripped of
volatiles under vacuum.  The resulting glassy solid was dissolved in
160 mL MeOH and treated with 7.2 g 3,4-methylenedioxyphenylacetone
(see under MDMA for its preparation).  To this there was added 50%
NaOH dropwise until the pH was at about 6 as determined by the use of
external dampened universal pH paper.  The solution was vigorously
stirred and 2.8 g sodium cyanoborohydride was added.  Concentrated HCl
was added as needed, to keep the pH constant at about 6.  The addition
required about two days, during which time the reaction mixture first
became quite cottage-cheese like, and then finally thinned out again.
All was dumped into 1 L H2O acidified with HCl, and extracted with
3x100 mL CH2Cl2.  These extracts were combined, extracted with 2x100
mL dilute H2SO4, which was combined with the aqueous fraction above.
This latter mixture was made basic with 25% NaOH, and extracted with
3x150 mL CH2Cl2.  Evaporation of the solvent yielded 4.0 g of an amber
oil which, on distillation at 90-100 !C at 0.15 mm/Hg, yielded 3.2 g
of a white clear oil.  This was dissolved in 20 mL IPA, neutralized
with 30 drops of concentrated HCl, and the spontaneously formed
crystals were diluted with sufficient anhydrous Et2O to allow easy
filtration.  After Et2O washing and air drying, there was obtained 2.8
g of 3,4-methylenedioxy-N-butylamphetamine hydrochloride (MDBU) as
white crystals with a mp of 200-200.5 !C.  Anal. (C14H22ClNO2) N.

DOSAGE: greater than 40 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Straight chain homologues on the nitrogen
atom of MDA longer than two carbons are probably not active.  This
butyl compound provoked no interest, and although the longer chain
counterparts were made by the general sodium cyanoborohydride method
(see under MDBZ), they were not tasted.  All mouse assays that
compared this homologous series showed a consistent decrease in action
(anesthetic potency and motor activity) as the alkyl chain on the
nitrogen atoms was lengthened.

This synthetic procedure, using the hydrochloride salt of the amine
and sodium cyanoborohydride in methanol, seems to be quite general for
ketone compounds related to 3,4-methylenedioxyphenylacetone.  Not only
were most of the MD-group of compounds discussed here made in this
manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P)
itself appears to be equally effective.  The reaction of butylamine
hydrochloride in methanol, with phenyl-2-propanone and sodium
cyanoborohydride at pH of 6, after distillation at 70-75 !C at 0.3
mm/Hg, produced N-butylamphetamine hydrochloride (23.4 g from 16.3 g
P-2-P).  And, in the same manner with ethylamine hydrochloride there
was produced N-ethylamphetamine (22.4 g from 22.1 g P-2-P) and with
methylamine hydrochloride there was produced N-methylamphetamine
hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple
ammonia (as ammonium acetate) gives consistently poor yields in these
reactions.

 

 

 



#103 MDBZ; N-BENZYL-MDA; 3,4-METHYLENEDIOXY-N-BENZYLAMPHETAMINE

SYNTHESIS: To a suspension of 18.6 g benzylamine hydrochloride in 50
mL warm MeOH there was added 2.4 g of 3,4-methylenedioxyphenylacetone
(see under MDMA for its preparation) followed by 1.0 g sodium
cyanoborohydride.  Concentrated HCl in MeOH was added over several
days as required to maintain the pH at about 6 as determined with
external, dampened universal paper.  When the demand for acid ceased,
the reaction mixture was added to 400 mL H2O and made strongly acidic
with an excess of HCl.  This was extracted with 3x150 mL CH2Cl2 (these
extracts must be saved as they contain the product) and the residual
aqueous phase made basic with 25% NaOH and again extracted with 4x100
mL CH2Cl2.  Removal of the solvent under vacuum and distillation of
the 8.7 g pale yellow residue at slightly reduced pressure provided a
colorless oil that was pure, recovered benzylamine.  It was best
characterized as its HCl salt (2 g in 10 mL IPA neutralized with about
25 drops concentrated HCl, and dilution with anhydrous Et2O gave
beautiful white crystals, mp 267-268 !C).  The saved CH2Cl2 fractions
above were extracted with 3x100 mL dillute H2SO4.  These pooled
extracts were back-washed once with CH2Cl2, made basic with 25% NaOH,
and extracted with 3x50 mL CH2Cl2.  The solvent was removed from the
pooled extracts under vacuum, leaving a residue of about 0.5 g of an
amber oil.  This was dissolved in 10 mL IPA, neutralized with
concentrated HCl (about 5 drops) and diluted with 80 mL anhydrous
Et2O.  After a few min, 3,4-methylenedioxy-N-benzylamphetamine
hydrochloride (MDBZ) began to appear as a fine white crystalline
product.  After removal by filtration, Et2O washing and air drying,
this weighed 0.55 g, and had a mp of 170-171 !C with prior shrinking
at 165 !C.  Anal. (C17H20ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The benzyl group is a good ally in the
synthetic world of the organic chemist, in that it can be easily
removed by catalytic hydrogenation.  This is a trick often used to
protect (for a step or series of steps) a position on the molecule,
and allowing it to become free and available at a later part in a
synthetic scheme.  In pharmacology, however, it is often a
disappointment.  With most centrally active alkaloids, there is a
two-carbon separation between the weak base that is called the
aromatic ring, and the strong base that is called the nitrogen.  This
is what makes phenethylamines what they are.  The phen- is the
aromatic ring (this is a shortened form of prefix phenyl which is a
word which came, in turn, from the simplest aromatic alcohol, phenol);
the ethyl is the two carbon chain, and the amine is the basic
nitrogen.  If one carbon is removed, one has a benzylamine, and it is
usually identified with an entirely different pharmacology, or is most
often simply not active.  A vivid example is the narcotic drug,
Fentanyl.  The replacement of the phenethyl group, attached to the
nitrogen atom with a benzyl group, virtually eliminates its analgesic
potency.

Here too, there appears to be little if any activity in the N-benzyl
analogue of MDA.  A number of other variations had been synthesized,
and none of them ever put into clinical trial.  With many of them
there was an ongoing problem in the separation of the starting amine
from the product amine.  Sometimes the difference in boiling points
could serve, and sometimes their relative polarities could be
exploited. Sometimes, ion-pair extraction would work wonders.  But
occasionally, nothing really worked well, and the final product had to
be purified by careful crystallization.

Several additional N-homologues and analogues of MDA are noted here.
The highest alkyl group on the nitrogen of MDA to give a compound that
had been assayed, was the straight-chain butyl homologue, MDBU.  Six
other N-alkyls were made, or attempted.  Isobutylamine hydrochloride
and 3,4-methylenedioxyphenylacetone were reduced with sodium
cyanoborohydride in methanol to give
3,4-methylenedioxy-N-(i)-butylamphetamine boiling at 95-105 !C at 0.15
mm/Hg and giving a hydrochloride salt (MDIB) with a mp of 179-180 !C.
Anal. (C14H22ClNO2) N.  The reduction with sodium cyanoborohydride of
a mixture of (t)-butylamine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol produced
3,4-methylenedioxy-N-(t)-butylamphetamine (MDTB) but the yield was
miniscule.  The amyl analog was similarly prepared from (n)-amylamine
hydrochloride and 3,4-methylenedioxyphenylacetone in methanol to give
3,4-methylenedioxy-N-amylamphetamine which distilled at 110-120 !C at
0.2 mm/Hg and formed a hydrochloride salt (MDAM) with a mp of 164-166
!C.  Anal. (C15H24ClNO2) N.  A similar reaction with (n)-hexylamine
hydrochloride and 3,4-methylenedioxyphenylacetone in methanol, with
sodium cyanoborohydride, produced after acidification with dilute
sulfuric acid copious white crystals that were water and ether
insoluble, but soluble in methylene chloride!  This sulfate salt in
methylene chloride was extracted with aqueous sodium hydroxide and the
remaining organic solvent removed to give a residue that distilled at
110-115 !C at 0.2 mm/Hg to give
3,4-methylenedioxy-N-(n)-hexylamphetamine which, as the hydrochloride
salt (MDHE) had a mp of 188-189 !C.  Anal. (C16H26ClNO2) N.  An
attempt to make the 4-amino-heptane analogue from the primary amine,
3,4-methylenedioxyphenylacetone, and sodiumcyanoborohydride in
methanol seemed to progress smoothly, but none of the desired product
3,4-methylenedioxy-N-(4-heptyl)-amphetamine could be isolated.  This
base has been named MDSE, with a SE for septyl rather than HE for
heptyl, to resolve any ambiguities about the use of HE for hexyl.  In
retrospect, it had been assumed that the sulfate salt would have
extracted into methylene chloride, and the extraordinary partitioning
of the sulfate salt of MDHE mentioned above makes it likely that the
sulfate salt of MDSE went down the sink with the organic extracts of
the sulfuric acid acidified crude product.  Next time maybe ether as a
solvent, or citric acid as an acid.  With (n)-octylamine hydrochloride
and 3,4-methylenedioxyphenylacetone in methanol, with sodium
cyanoborohydride, there was obtained
3,4-methylenedioxy-N-(n)-octylamphetamine as a water-insoluble,
ether-insoluble sulfate salt.  This salt was, however, easily soluble
in methylene chloride, and with base washing of this solution, removal
of the solvent, and distillation of the residue (130-135 !C at 0.2
mm/Hg) there was eventually gotten a fine hydrochloride salt (MDOC) as
white crystals with a mp of 206-208 !C.  Anal. (C18H30ClNO2) N.

As to N,N-dialkylhomologues of MDA, the N,N-dimethyl has been
separately entered in the recipe for MDDM.  Two efforts were made to
prepare the N,N-diethyl homologue of MDA.  The reasonable approach of
reducing a mixture of diethylamine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol with sodium
cyanoborohydride was hopelessly slow and gave little product.  The
reversal of the functionality was successful.  Treatment of MDA (as
the amine) and an excess of acetaldehyde (as the carbonyl source) with
sodium borohydride in a cooled acidic medium gave, after acid-base
workup, a fluid oil that distilled at 85-90 !C at 0.15 mm/Hg and was
converted in isopropanol with concentrated hydrochloric acid to
3,4-methylenedioxy-N,N-diethylamphetamine (MDDE) with a mp of 177-178
!C.  Anal. (C14H22ClNO2) N.

And two weird N-substituted things were made.  Aminoacetonitrile
sulfate and 3,4-methylenedioxyphenylacetone were reduced in methanol
with sodium cyanoborohydride to form
3,4-methylenedioxy-N-cyanomethylamphetamine which distilled at about
160 !C at 0.3 mm/Hg and formed a hydrochloride salt (MDCM) with a mp
of 156-158 !C after recrystallization from boiling isopropanol. Anal.
(C12H15ClN2O2) N.  During the synthesis of MDCM, there appeared to
have been generated appreciable ammonia, and the distillation provided
a fore-run that contained MDA.  The desired product had an acceptable
NMR, with the N-cyanomethylene protons as a singlet at 4.38 ppm.  A
solution of t-butylhydrazine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol was reduced with sodium
cyanoborohydride and gave, after acid-basing and distillation at
95-105 !C at 0.10 mm/Hg, a viscous amber oil which was neutralized in
isopropanol with concentrated hydrochloric acid to provide
3,4-methylenedioxy-N-(t)-butylaminoamphetamine hydrochloride (MDBA)
with a mp of 220-222 !C with decomposition.  Anal. (C14H23ClN2O2); N:
calcd, 9.77; found, 10.67, 10.84.

 

 

 



#104 MDCPM; CYCLOPROPYLMETHYL-MDA;
3,4-METHYLENEDIOXY-N-CYCLOPROPYLMETHYLAMPHETAMINE

SYNTHESIS: A solution of 9.4 g cyclopropylmethylamine hydrochloride in
30 mL MeOH was treated with 1.8 g 3,4-methylenedioxyphenylacetone (see
under MDMA for its preparation) followed by 0.5 g sodium
cyanoborohydride.  Concentrated HCl was added as needed to keep the pH
constant at about 6.  After several days stirring, the reaction
mixture was added to H2O, acidified with HCl, and washed with 2x100 mL
CH2Cl2.  The aqueous phase was made basic with 25% NaOH, and extracted
with 3x150 mL CH2Cl2.  Removal of the solvent from these extracts
under vacuum yielded 2.8 g of a crude product which, on distillation
at 90-100 !C at 0.1 mm/Hg, yielded 0.4 g of a clear white oil.  This
was dissolved in a small amount of IPA, neutralized with a few drops
of concentrated HCl, and diluted with anhydrous Et2O to the point of
turbidity.  There was obtained a small yield of crystalline
3,4-methylenedioxy-N-cyclopropylmethylamphetamine hydrochloride
(MDCPM) which was filtered off, Et2O washed and air dried.  The mp was
218-220 !C, with extensive darkening just prior to melting.  Anal.
(C14H20ClNO2) N.

DOSAGE: greater than 10 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The record of the tasting assay of this
compound is pretty embarrassing.  The highest level tried was 10
milligrams, which showed no hint of activity.  But in light of the
rather colorful activities of other cyclopropylmethyl things such as
CPM and 2C-T-8 , this compound might someday warrant reinvestigation.
It is a certainty that the yield could only be improved with a careful
resynthesis.

 

 

 



#105 MDDM; N,N-DIMETHYL-MDA;
3,4-METHYLENEDIOXY-N,N-DIMETHYLAMPHETAMINE

SYNTHESIS: To a well stirred solution of 9.7 g dimethylamine
hydrochloride in 50 mL MeOH there was added 3.56 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 0.88 g sodium cyanoborohydride.  A 1:1 mixture of
concentrated HCl and MeOH was added as required to maintain the pH at
about 6 as determined with external, dampened universal paper.  Twenty
drops were called for over the first four h, and a total of 60 drops
were added over the course of two days at which time the reduction was
complete.  After the evaporation of most of the MeOH solvent, the
reaction mixture was added to 250 mL H2O and made strongly acidic with
an excess of HCl.  After washing with 2x100 mL CH2Cl2 the aqueous
phase was made basic with 25% NaOH, and extracted with 3x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded a nearly
colorless oil that was distilled at 85-90 !C at 0.3 mm/Hg.  There was
obtained 1.5 g of a water-white oil that was dissolved in 8 mL IPA,
neutralized with concentrated HCl and then diluted with 10 mL
anhydrous Et2O.  The slightly turbid solution deposited a light lower
oily layer which slowly crystallized on scratching.  With patience, an
additional 75 mL of Et2O was added, allowing the formation of a white
crystalline mass.  This was removed by filtration and washed with
additional Et2O.  After air drying there was obtained 1.3 g of
3,4-methylenedioxy-N,N-dimethylamphetamine hydrochloride (MDDM) with a
mp of 172-173 !C.  The NMR spectrum (60 mH) of the hydrochloride salt
(in D2O and with external TMS) was completely compatible with the
expected structure.  The signals were: 1.25, 1.37 (d) CCH3, 3H; ArCH2
under the N(CH3)2, 2.96, 8H; CH (m) 3.65; CH2O2 (s) 6.03 2H; ArH 6.93
(3H).  Anal: (C12H18ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg)  No effects whatsoever.

(with 150 mg) The effects, if any, were so-so.  Perhaps a threshold.
But my libido was non-existent for three days.

(with 550 mg) I took 550 milligrams of it Saturday night and I had a
pretty bad trip.  On a scale of positive 10 to negative 10 it was
about a negative 6.  It really downed me.  Two other friends took 200
milligrams.  They found it very pleasant after about 20 minutes.  It
was a plus 3 [on the -10 to +10 scale].  Then it wore off a little
bit; and then, 4 hours later, it hit them even stronger and was about
a plus 5.

(with 1000 mg) I took up to a gram of it and absolutely nothing.

EXTENSIONS AND COMMENTARY: I cannot attest for the actual drug that
had been used in the two larger-dose reports above.  These are from an
anonymous source associated with clandestine syntheses.  If this
material does eventually prove to be active, it is going to require a
pretty hefty dose.  But it may well have some activity, as there have
been reports in the forensic literature of its preparation, or at
least its intended preparation, in illicit laboratories.  It seems
unlikely that much effort would be directed towards the synthesis of a
completely inactive compound.

The reduced potency of MDDM has been exploited in an unexpected way.
Based on the premise that the dialkylation of the amine group of
amphetamine makes the parent compound intrinsically less active but
without interfering with its ability to enter the brain, a large
number of materials have been explored to take advantage of this very
property.  There is a need in medical diagnosis for agents that can
allow various organs of the body to be visualized.  One of the most
powerful modalities for this work is the positron camera, and the use
of the unusual properties of the positron that allow it to work.  In
the art of positron emission tomography (PET), an emitted positron
(from a radioactive and thus unstable atom) will quickly interact with
a nearby electron and all mass disappears with the complete conversion
to energy.  The detection of the produced pair of annihilation gamma
rays will establish with great exactness the line along which this
interaction occurred.  So if one were to put an unstable atom into a
compound that went to the tissue of the brain, and this atom were to
decay there, the resulting gamma rays would allow a RphotographS to be
made of the brain tissue.  One could in this way visualize brain
tissue, and observe abnormalities.

But what is needed is a molecule that carries the unstable atom (and
specifically one that emits positrons) and one which goes to the brain
as well.  One of the very best unstable atoms for the formation of
positrons is iodine, where there is an isotope of mass 122 which is
perfect for these needs.  And, of course, the world of the psychedelic
drugs is tailor-made to provide compounds that go to the brain.  But,
the last thing that the physician wants, with the diagnostic use of
such tools, would be to have the patient bouncing around in some
turned-on altered state of consciousness.

So the completely logical union of these requirements is to take a
compound such as DOI (carrying the needed atom and certainly going to
the brain) and put two methyl groups on the nitrogen (which should
reduce the chances for conspicuous biological activity).  This
compound was made, and it does label the brain, and it has shown
promise as a flow indicator in the brain, and it and several of its
close relatives are discussed in their own separate recipe, called
IDNNA.

 

 

 



#106 MDE; MDEA; EVE; N-ETHYL-MDA;
3,4-METHYLENEDIOXY-N-ETHYLAMPHETAMINE

SYNTHESIS: (from MDA) To a solution of 3.6 g of the free base of
3,4-methylenedioxyamphetamine (MDA) in 20 g pyridine, there was added
2.3 g acetic anhydride, and the mixture stirred at room temperature
for 0.5 h.  This was then poured into 250 mL H2O and acidified with
HCl.  This aqueous phase was extracted with 3x75 mL CH2Cl2, the
extracts pooled and washed with dilute HCl, and the solvent removed
under vacuum.  The pale amber residue of
N-acetyl-3,4-methylenedioxyamphetamine weighed 5.2 g as the crude
product, and it was reduced without purification.  On standing it
slowly formed crystals.  Recrystallization from a mixture of
EtOAc/hexane (1:1) gave white crystals with a mp of 92-93 !C.

A stirred suspension of 4.8 g LAH in 400 mL anhydrous THF was brought
up to a reflux, and then treated with a solution of 5.0 g of the
impure N-acetyl-3,4-methylenedioxyamphetamine in 20 mL anhydrous THF.
Reflux conditions were maintained for 3 days, and then after cooling
in an ice bath, the excess hydride was destroyed with the careful
addition of H2O.  The 4.8 mL H2O (in a little THF) was followed with
4.8 mL of 15% NaOH, and finally an additional 15 mL H2O.  The white,
granular, basic mass of inorganic salts was removed by filtration, the
filter cake washed with additional THF, and the combined filtrate and
washings stripped of solvent under vacuum.  The residue was dissolved
in 20 mL IPA, made acidic with 40 drops of concentrated HCl, and
diluted with 150 mL anhydrous Et2O.  The crystalline product was
removed by filtration, washed with 80% Et2O (containing IPA) followed
by Et2O itself, and then air dried to provide 3.0 g of
3,4-methylenedioxy-N-ethylamphetamine hydrochloride (MDE) as fine
white crystals with a mp of 198-199 !C.

(from 3,4-methylenedioxyphenylacetone with aluminum amalgam) To 40 g
of thin aluminum foil cut in 1 inch squares (in a 2 L wide mouth
Erlenmeyer flask) there was added 1400 mL H2O containing 1 g mercuric
chloride.  Amalgamation was allowed to proceed until there was the
evolution of fine bubbles, the formation of a light grey precipitate,
and the appearance of occasional silvery spots on the surface of the
aluminum. This takes between 15 and 30 min depending on the freshness
of the surfaces and the temperature of the H2O.  The H2O was removed
by decantation, and the aluminum was washed with 2x1400 mL of fresh
H2O.  The residual H2O was removed as thoroughly as possible by
shaking, and there was added, in succession and with swirling, 72.5 g
ethylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145
mL 25% NaOH, 53 g 3,4-methylenedioxy-phenylacetone (see under MDMA for
its preparation), and finally 350 mL IPA.  The exothermic reaction was
kept below 60 !C with occasional immersion into cold water and, when
it was thermally stable, it was allowed to stand until it had returned
to room temperature and all the insolubles settled to the bottom as a
grey sludge.  The clear yellow overhead was decanted and the sludge
removed by filtration and washed with MeOH.  The combined decantation,
mother liquors, and washes, were stripped of solvent under vacuum, the
residue suspended in 1500 ml of H2O, and sufficient HCl added to make
the phase distinctly acidic.  This was then washed with 2x100 mL
CH2Cl2, made basic with 25% NaOH, and extracted with 3x100 mL of
CH2Cl2.  After removal of the solvent from the combined extracts,
there remained 59.5 g of an amber oil which was distilled at 145-150
!C at 0.5 mm/Hg, producing 40.3 g of an off-white oil.  This was
dissolved in 600 mL IPA, neutralized with about 20 mL of concentrated
HCl and then treated with 300 mL anhydrous Et2O.  After filtering off
the white crystals, washing with a IPA/Et2O (2:1) mixture, with Et2O
and air drying, the final 3,4-methylenedioxy-N-ethylamphetamine
hydrochloride (MDE) weighed 37.4 g.

(from 3,4-methylenedioxyphenylacetone with NaBH3CN) To a well stirred
solution of 31.0 g ethylamine hydrochloride in 110 mL MeOH there was
added 6.6 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its
preparation) followed by 3.0 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.  About 2 days
were required for the reduction to be complete as determined by the
final stabilization of the pH.  The reaction mixture was added to 1 L
H2O and made strongly acidic with an excess of HCl.  After washing
with 2x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH,
and extracted with 3x100 mL CH2Cl2.  Removal of the solvent under
vacuum yielded 8.3 g of a pale amber oil that was distilled at 85-100
!C at 0.2 mm/Hg.  There was obtained 6.0 g of a water-white oil that
was dissolved in 65 mL IPA and neutralized with 75 drops of
concentrated HCl which produced crystals spontaneously.  These were
diluted with some 20 mL of anhydrous Et2O removed by filtration,
washed first with IPA/Et2O (2:1), and then with Et2O.  After air
drying there was obtained 6.1 g of
3,4-methylenedioxy-N-ethylamphetamine hydrochloride (MDE) with a mp of
201-202 !C.  Anal. (C12H18ClNO2) N.

DOSAGE: 100 - 200 mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 100 mg) There was a warm light all about
me.  And a gentle, almost alcohol-like, intoxication.  The drug seems
to change my state of awareness, but it does nothing else.  The world
is as intense or as dull as I choose to make it.  At the 1.5 hour
point I was clearly dropping, and an hour later yet, completely
without residue.

(with 160 mg) The first effects were felt in forty minutes and I
seemed to be completely there by the end of that first hour.  There
was an initial slightly dizzy intoxication, and then I felt very nice.
A good intoxication, with maybe a little motor incoordination.  There
was absolutely no appetite at all.  The next morning there was still
some feeling of elation but I was still very relaxed.  High marks for
the quality of the experience.

(with 160 mg) Overall this was a wonderful experience.  I felt that
the effect was stronger and smoother than MDMA, but perhaps the group
enhancement may be partly responsible.  I felt definitely fewer
physiological side-effects than with MDMA, particularly the urinating
problem; although there was dehydration, there was less burning
annoyance.

(with 160 mg) I was hard hit, to the extent that there was difficulty
in verbalizing and following other people's thoughts.  I entered the
experience with some cold symptoms, and my sore throat disappeared.  I
felt quite intoxicated and tranquilized.

(with 200 mg) Very stoned.  There was some nausea in the beginning of
the experience.  As it developed I found it very difficult to
concentrate on what I was thinking or saying simply due to the
extraordinary nature of coming on to this material.  There is
noticeable jaw-clenching and rice crispies in the ears.  This is a
meditative material not unlike MDMA except there are more difficulties
in forming words.  And there is a problem in focusing the eyes, what I
want to call Teye-romp.U My anorexia was extremely long-lived Q
perhaps a total of 72 hours.  This may have been too high a dosage.

EXTENSIONS AND COMMENTARY: This immediate homologue of MDMA has a very
similar chronology but requires a slightly larger dose.  Another
similarity is the occasional report of teeth clenching, especially
following the use of supplemental dosages intended to extend the
effects of the drug.  These supplements have been explored in the 50
to 75 milligram range, usually at the two hour point.  In one
unpublished clinical experiment with MDMA, an extension was attempted
at the 1 hour 45 minute point with MDE rather than with MDMA, to see
if there was any change in the qualitative character of the
experience.  The effective time of intoxication was extended, but the
group fell surprisingly quiet, with a drop in the usual urge to
converse and interact.

The effects of MDE are similar in many ways to those of MDMA, but
there are believable differences.  The particular magic, and affective
transference, does not appear to be there.  There is a stoning
intoxication, as there is with MDA, and there is a seemingly
unrewarding aspect to the upping of the dosages, again similar to MDA,
and the properties of unusually easy communication and positive
self-viewing of MDMA seem to be absent.  Maybe the RSS isomer would
have these properties, and they are lost in the racemate due to
something coming from a more potent RintoxicatingS RRS isomer.  The
optical isomers have never been evaluated separately in man.

There are only two ways in which two drugs can interact to produce a
result that is not obvious from the summing of their individual
actions.  One is the process of synergism, where two active materials
are allowed to interact within a single individual and at one time,
and the consequence of this interaction is different than that which
would have been expected.  The other is the process of potentiation,
where only one drug is active, but the presence of the second (and
inactive) drug enhances the observed action of the first.  MDE seems
to fall in the first category.

The Rpiggy-backS or Rwindow exploitationS studes were first discovered
and explored with MDE, and have subsequently been extended most
successfully with MDMA.  The earliest procedure used was to assay
modest quantities of active materials at the drop-off period of MDE,
to exploit the open and benign state that was present.  Usually, only
a fraction of the standard dosage of the following drug was necessary
to evoke a full experience.  In psychotherapy applications, this
sequence has been frequently used with MDMA followed by a second
material that has been chosen to modify and expand the opening that
the MDMA produced.

With the placement of MDMA under legal control in 1985, MDE
occasionally appeared in the illicit street trade.  It had been called
EVE, which carries some perverse logic in light of the nickname used
occasionally for MDMA, which was ADAM.  The term INTELLECT has been
used for it as well, but there has been no apparent reason advanced
for this.  And a final note on nomenclature.  An old literature use of
the code MDE was for the compound 3,4-methylenedioxyethanol-amine.
See the discussion on this under the recipe for DME.

I have been told of an analogue of MDE that has been synthesized, and
explored by the researcher who synthesized it.  It contains the
N-trifluoroethyl group common to several pharmaceuticals such as
Quazepam.  The analogue is
3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)amphetamine hydrochloride
(mp 207-209 !C) which was made from 2,2,2-trifluoroethylamine and
3,4-methylenedioxyphenylacetone and sodium cyanoborohydride in
methanol.  The best final line for this compound is that it is
Rpossibly active.S The most heroic dosage schedule mentioned was a
total of 500 milligrams, taken in three approximately equal portions
over the course of five or six hours, with only a very mild
intoxication and little or no sympathomimetic effects.  And what
little there might have been was quickly gone.  A collection of
totally unexplored N-substituted homologues and analogues of MDE is
gathered at the end of the recipe for MDBZ.

Another direction that has been used to homologate the MDMA and MDE
structure is with the length of the aliphatic chain that carries the
phenyl ring and the amine function.  RHS shows the two-carbon chain,
RIS shows the amphetamine chain length, and MDE can be called ETHYL-I.
The four-carbon chain is the RJS group, and this entire Muni-Metro
concept is explained under METHYL-J.

 

 

 



#107 MDHOET; HYDROXYETHYL-MDA;
3,4-METHYLENEDIOXY-N-(2-HYDROXYETHYL)AMPHETAMINE

SYNTHESIS: To a well stirred solution of 25 g ethanolamine
hydrochloride in 75 mL MeOH 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, over the next few days, to maintain the pH at
about 6 as determined with external, dampened universal pH paper.  The
reaction mixture was added to 300 mL H2O and made strongly acidic with
an excess of HCl.  After washing with 3x100 mL CH2Cl2 the aqueous
phase was made basic with 25% NaOH, and extracted with 4x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded 3.5 g of a
viscous off-white oil that was distilled at 160 !C at 1.3 mm/Hg to
give 2.0 g of a white viscous oil.  The pot residue remained fluid,
but was discarded.  This distillate was dissolved in 8.0 mL IPA to
give, eventually, a clear solution.  This was neutralized with
concentrated HCl and diluted with 100 mL anhydrous Et2O.  The loose
white crystals of 3,4-methylenedioxy-N-(2-hydroxy-ethyl)amphetamine
hydrochloride (MDHOET) that formed were removed by filtration, washed
with Et2O, and air dried.  These weighed 2.3 g, and had a mp of
147-148 !C.  Anal. (C12H18ClNO3) N.

DOSAGE: greater than 50 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Most compounds with bare, exposed polar
groups like hydroxyls are not centrally active, as they simply do not
have any way of getting into the brain.  MDHOET is certainly not very
active, if it is active at all.

There was one report that at very high doses some central effects were
indeed observed.  With quantities in the several hundreds of
milligrams a picture emerged of changes in perceived color and depth
perception, but without euphoria.  It was said to resemble a mild dose
of ketamine.  This is an interesting comment, in that ketamine has
found its major medical use as an anesthetic, and MDHOET is among the
most effective of all the N-substituted MDA derivatives assayed in
several animal analgesia models.

 

 

 



#108 MDIP; N-ISOPROPYL-MDA;
(3,4-METHYLENEDIOXY-N-ISOPROPYLAMPHETAMINE)

SYNTHESIS: To a well stirred and cooled solution of 14.75 g
isopropylamine in 100 mL MeOH there was added 4.45 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by a 1:1 mixture of concentrated HCL and MeOH, sufficient to
bring the pH to about 4.  This was followed with 1.1 g sodium
cyanoborohydride, and stirring was continued overnight.  When the pH
increased to over 6 there was added an additional 0.5 g of the
borohydride, and additional methanolic HCl was added as needed to
maintain the pH there.  When the pH became stable, the reaction
mixture was brought soundly acid with the addition of yet additional
HCl, and all solvents were removed under vacuum.  The residues were
added to 500 mL H2O and washed with 3x100 mL CH2Cl2.  The aqueous
phase was made basic with 25% NaOH, and extracted with 4x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded 2.8 g of an amber
liquid that was distilled at 95-110 !C at 0.3 mm/Hg.  There was
obtained about 2 mL of a white oil that was dissolved in 10 mL of IPA,
neutralized with about 20 drops of concentrated HCl producing
spontaneous crystals.  These were diluted with some 40 mL of anhydrous
Et2O, removed by filtration, washed with Et2O, and then air dried.
There was obtained 1.6 g of 3,4-methylenedioxy-N-isopropylamphetamine
hydrochloride (MDIP) with a mp of 186-186.5 !C with prior sintering at
185 !C.  Anal. (C13H20ClNO2) N.

DOSAGE: greater than 250 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 250 mg) At 35 minutes there was an
extremely slight head disturbance which increased over the next few
minutes.  I would have missed it if there had been any sensory input
at all.  At the one hour point there was a slight physical malaise,
but no 'open window' of any kind, either like MDMA or like LSD.  At
the most, this was a threshold, and in another half hour, I was
completely baseline.

EXTENSIONS AND COMMENTARY: The structure of MDIP can be looked at as
exactly that of MDE but with an additional methyl group (one carbon)
hanging off the ethyl that is on the nitrogen.  And with that slight
additional weight, the activity has disappeared.  On those occasions
where research has shown a compound to be inactive, there has been
some study made that could be called a RprimerS experiment.  Why not
take advantage of the fact that an RinactiveS compound might well be
sitting in some receptor site in the brain without doing anything?
Might its presence, wherever it might be, have some effect if only a
person were to explore it in the correct way?  Might it augment or
interfere with the action of another compound?  Many experiments of
this kind have been performed, geared to milk additional information
out of a new trial of a new material.

Here is an example of a primer experiment that involved MDIP.  Some
five hours following an inactive trial with 120 milligrams of MDIP
(maybe a slight disturbance at one hour, nothing at two hours) a
calibration dose of 80 milligrams of MDMA was taken.  The effects of
the MDMA were noted at the 33 minute point, and an honest plus one was
achieved at one hour.  At this point a second 80 milligrams was added
to the inventory that was already on board, and the general
intoxication and the eye effects that followed were completely
explained by the MDMA alone.  It was obvious that the two drugs did
not see one-another.

Sometimes an experiment can involve the assay of an unknown material
at the supplement time of an active drug.  This has been called
Rpiggybacking.S Here is an example.  At the five hour point of an
experiment with 140 milligrams of MDE (this had been a light
experience, a plus one which had not laster more than two hours) a
dosage of 200 milligrams of MDIP rekindled a +1 experience, a pleasant
intoxication of the MDE sort, but one that was quite invested with
tremor and some feelings of eye-popping.  It was almost as if the
physical toxic effects outweighed the mental virtues.  Imagine an
iceberg, with the bulk of its mass underwater.  The MDE had had its
own modest effects, and had submerged into invisibility, and the
response to a little bit of an otherwise inactive MDIP was to refloat
a bit of the otherwise unseeable MDE.

 

 

 



#109 MDMA; MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE

SYNTHESIS: (from MDA) A solution of 6.55 g of
3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic
acid in 150 mL benzene was held at reflux under a Dean Stark trap
until no further H2O was generated (about 20 h was sufficient, and 1.4
mL H2O was collected).  Removal of the solvent gave an 8.8 g of an
amber oil which was dissolved in 100 mL CH2Cl2, washed first with
dilute HCl, then with dilute NaOH, and finally once again with dilute
acid.  The solvent was removed under vacuum giving 7.7 g of an amber
oil that, on standing, formed crystals of
N-formyl-3,4-methylenedioxyamphetamine.  An alternate process for the
synthesis of this amide involved holding at reflux for 16 h a solution
of 10 g of MDA as the free base in 20 mL fresh ethyl formate.  Removal
of the volatiles yielded an oil that set up to white crystals,
weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL
anhydrous THF was added dropwise to a well stirred and refluxing
solution of 7.4 g LAH in 600 mL anhydrous THF under an inert
atmosphere.  The reaction mixture was held at reflux for 4 days.
After being brought to room temperature, the excess hydride was
destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4
mL of 15% NaOH and then another 22 mL H2O.  The solids were removed by
filtration, and the filter cake washed with additional THF.  The
combined filtrate and washes were stripped of solvent under vacuum,
and the residue dissolved in 200 mL CH2Cl2.  This solution was
extracted with 3x100 mL dilute HCl, and these extracts pooled and made
basic with 25% NaOH.  Extraction with 3x75 mL CH2Cl2 removed the
product, and the pooled extracts were stripped of solvent under
vacuum.  There was obtained 6.5 g of a nearly white residue which was
distilled at 100-110 !C at 0.4 mm/Hg to give 5.0 g of a colorless oil.
This was dissolved in 25 mL IPA, neutralized with concentrated HCl,
followed by the addition of sufficient anhydrous Et2O to produce a
lasting turbidity.  On continued stirring, there was the deposition of
fine white crystals of 3,4-methylenedioxy-N-methylamphetamine
hydrochloride (MDMA) which were removed by filtration, washed with
Et2O, and air dried, giving a final weight of 4.8 g.

(from 3,4-methylenedioxyphenylacetone) This key intermediate to all of
the MD-series can be made from either isosafrole, or from piperonal
via 1-(3,4-methylenedioxyphenyl)-2-nitropropene.  To a well stirred
solution of 34 g of 30% hydrogen peroxide in 150 g 80% formic acid
there was added, dropwise, a solution of 32.4 g isosafrole in 120 mL
acetone at a rate that kept the reaction mixture from exceeding 40 !C.
This required a bit over 1 h, and external cooling was used as
necessary.  Stirring was continued for 16 h, and care was taken that
the slow exothermic reaction did not cause excess heating.  An
external bath with running water worked well.  During this time the
solution progressed from an orange color to a deep red.  All volatile
components were removed under vacuum which yielded some 60 g of a very
deep red residue.  This was dissolved in 60 mL of MeOH, treated with
360 mL of 15% H2SO4, and heated for 3 h on the steam bath.  After
cooling, the reaction mixture was extracted with 3x75 mL Et2O, the
pooled extracts washed first with H2O and then with dilute NaOH, and
the solvent removed under vacuum The residue was distilled (at 2.0
mm/108-112 !C, or at about 160 !C at the water pump) to provide 20.6 g
of 3,4-methylenedioxyphenylacetone as a pale yellow oil.  The oxime
(from hydroxylamine) had a mp of 85-88 !C.  The semicarbazone had a mp
of 162-163 !C.

An alternate synthesis of 3,4-methylenedioxyphenylacetone starts
originally from piperonal.  A suspension of 32 g electrolytic iron in
140 mL glacial acetic acid was gradually warmed on the steam bath.
When quite hot but not yet with any white salts apparent, there was
added, a bit at a time, a solution of 10.0 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see
the synthesis of MDA for the preparation of this nitrostyrene
intermediate from piperonal and nitroethane).  This addition was
conducted at a rate that permitted a vigorous reaction free from
excessive frothing.  The orange color of the reaction mixture became
very reddish with the formation of white salts and a dark crust.
After the addition was complete, the heating was continued for an
additional 1.5 h during which time the body of the reaction mixture
became quite white with the product appeared as a black oil climbing
the sides of the beaker.  This mixture was added to 2 L H2O, extracted
with 3x100 mL CH2Cl2, and the pooled extracts washed with several
portions of dilute NaOH.  After the removal of the solvent under
vacuum, the residue was distilled at reduced pressure (see above) to
provide 8.0 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil.

To 40 g of thin aluminum foil cut in 1 inch squares (in a 2 L wide
mouth Erlenmeyer flask) there was added 1400 mL H2O containing 1 g
mercuric chloride.  Amalgamation was allowed to proceed until there
was the evolution of fine bubbles, the formation of a light grey
precipitate, and the appearance of occasional silvery spots on the
surface of the aluminum. This takes between 15 and 30 min depending on
the freshness of the surfaces, the temperature of the H2O, and the
thickness of the aluminum foil.  (Aluminum foil thickness varies from
country to country.)  The H2O was removed by decantation, and the
aluminum was washed with 2x1400 mL of fresh H2O.  The residual H2O
from the final washing was removed as thoroughly as possible by
shaking, and there was added, in succession and with swirling, 60 g
methylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145
mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL
IPA.  If the available form of methylamine is the aqueous solution of
the free base, the following sequence can be substituted: add, in
succession, 76 mL 40% aqueous methylamine, 180 mL IPA, a suspension of
50 g NaCl in 140 mL H2O that contains 25 mL 25% NaOH, 53 g
3,4-methylenedioxyphenylacetone, and finally 350 mL IPA.  The
exothermic reaction was kept below 60 !C with occasional immersion
into cold water and, when it was thermally stable, it was allowed to
stand until it had returned to room temperature with all the
insolubles settled to the bottom as a grey sludge.  The clear yellow
overhead was decanted and the sludge removed by filtration and washed
with MeOH.  The combined decantation, mother liquors and washes, were
stripped of solvent under vacuum, the residue suspended in 2400 ml of
H2O, and sufficient HCl added to make the phase distinctly acidic.
This was then washed with 3x75 mL CH2Cl2, made basic with 25% NaOH,
and extracted with 3x100 mL of CH2Cl2.  After removal of the solvent
from the combined extracts, there remained 55 g of an amber oil which
was distilled at 100-110 !C at 0.4 mm/Hg producing 41 g of an
off-white liquid.  This was dissolved in 200 mL IPA, neutralized with
about 17 mL of concentrated HCl, and then treated with 400 mL
anhydrous Et2O.  After filtering off the white crystals, washing with
an IPA/Et2O mixture, (2:1), with Et2O, and final air drying, there was
obtained 42.0 g of 3,4-methylenedioxy-N-methylamphetamine (MDMA) as a
fine white crystal.  The actual form that the final salt takes depends
upon the temperature and concentration at the moment of the initial
crystallization.  It can be anhydrous, or it can be any of several
hydrated forms.  Only the anhydrous form has a sharp mp; the published
reports describe all possible one degree melting point values over the
range from 148-153 !C.  The variously hydrated polymorphs have
distinct infrared spectra, but have broad mps that depend on the rate
of heating.

DOSAGE: 80 - 150 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 100 mg) MDMA intrigued me because
everyone I asked, who had used it, answered the question, 'What's it
like?' in the same way: 'I donUt know.'  'What happened?'  'Nothing.'
And now I understand those answers.  I too think nothing happened.
But something seemed changed.  Before the 'window' opened completely,
I had some somatic effects, a tingling sensation in the fingers and
temples Q a pleasant sensation, not distracting.  However, just after
that there was a slight nausea and dizziness similar to a little too
much alcohol.  All these details disappeared as I walked outside.  My
mood was light, happy, but with an underlying conviction that
something significant was about to happen.  There was a change in
perspective both in the near visual field and in the distance.  My
usually poor vision was sharpened.  I saw details in the distance that
I could not normally see.  After the peak experience had passed, my
major state was one of deep relaxation.  I felt that I could talk
about deep or personal subjects with special clarity, and I
experienced some of the feeling one has after the second martini, that
one is discoursing brilliantly and with particularly acute analytical
powers.

(with 100 mg) Beforehand, I was aware of a dull, uncaring tiredness
that might have reflected too little sleep, and I took a modest level
of MDMA to see if it might serve me as a stimulant.  I napped for a
half hour or so, and woke up definitely not improved.  The feeling of
insufficient energy and lack of spark that IUd felt before had become
something quite strong, and might be characterized as a firm feeling
of negativity about everything that had to be done and everything I
had been looking forward to.  So I set about my several tasks with no
pleasure or enjoyment and I hummed a little tune to myself during
these activities which had words that went: 'I shouldnUt have done
that, oh yes, I shouldnUt have done that, oh no, I shouldnUt have done
that; it was a mistake.'  Then I would start over again from the
beginning.  I was stuck in a gray space for quite a while, and there
was nothing to do but keep doing what I had to do.  After about 6
hours, I could see the whole mental state disintegrating and my
pleasant feelings were coming back.  But so was my plain, ornery
tiredness.  MDMA does not work like Dexedrine.

(with 120 mg) I feel absolutely clean inside, and there is nothing
but pure euphoria.  I have never felt so great, or believed this to be
possible.  The cleanliness, clarity, and marvelous feeling of solid
inner strength continued throughout the rest of the day, and evening,
and through the next day.  I am overcome by the profundity of the
experience, and how much more powerful it was than previous
experiences, for no apparent reason, other than a continually
improving state of being.  All the next day I felt like 'a citizen of
the universe' rather than a citizen of the planet, completely
disconnecting time and flowing easily from one activity to the next.

(with 120 mg) As the material came on I felt that I was being
enveloped, and my attention had to be directed to it.  I became quite
fearful, and my face felt cold and ashen.  I felt that I wanted to go
back, but I knew there was no turning back.  Then the fear started to
leave me, and I could try taking little baby steps, like taking first
steps after being reborn.  The woodpile is so beautiful, about all the
joy and beauty that I can stand.  I am afraid to turn around and face
the mountains, for fear they will overpower me.  But I did look, and I
am astounded.  Everyone must get to experience a profound state like
this.  I feel totally peaceful.  I have lived all my life to get here,
and I feel I have come home.  I am complete.

(with 100 mg of the RRS isomer) There were the slightest of effects
noted at about an hour (a couple of paresthetic twinges) and then
nothing at all.

(with 160 mg of the RRS isomer) A disturbance of baseline at about
forty minutes and this lasts for about another hour.  Everything is
clear by the third hour.

(with 200 mg of the RRS isomer) A progression from an alert at thirty
minutes to a soft and light intoxication that did not persist.  This
was a modest +, and I was at baseline in another hour.

(with 60 mg of the RSS isomer) The effects began developing in a
smooth, friendly way at about a half-hour.  My handwriting is OK but I
am writing faster than usual.  At the one hour point, I am quite
certain that I could not drive, time is slowing down a bit, but I am
mentally very active.  My pupils are considerably dilated.  The
dropping is evident at two hours, and complete by the third hour.  All
afternoon I am peaceful and relaxed, but clear and alert, with no
trace of physical residue at all.  A very successful ++.

(with 100 mg of the RSS isomer) I feel the onset is slower than with
the racemate.  Physically, I am excited, and my pulse and blood
pressure are quite elevated.  This does not have the 'fire' of the
racemate, nor the rush of the development in getting to the plateau.

(with 120 mg of the RSS isomer) A rapid development, and both writing
and typing are impossible before the end of the first hour.  Lying
down with eyes closed eliminates all effects; the visual process is
needed for any awareness of the drug's effects.  Some teeth clenching,
but no nystagmus.  Excellent sleep in the evening.

EXTENSIONS AND COMMENTARY: In clinical use, largely in
psychotherapeutic sessions of which there were many in the early years
of MDMA study, it became a common procedure to provide a supplemental
dosage of the drug at about the one and a half hour point of the
session.  This supplement, characteristically 40 milligrams following
an initial 120 milligrams, would extend the expected effects for about
an additional hour, with only a modest exacerbation of the usual
physical side-effects, namely, teeth clenching and eye twitching.  A
second supplement (as, for instance, a second 40 milligrams at the two
and a half hour point) was rarely felt to be warranted.  There are,
more often than not, reports of tiredness and lethargy on the day
following the use of MDMA, and this factor should be considered in the
planning of clinical sessions.

With MDMA, the usual assignments of activity to optical isomers is
reversed from all of the known psychedelic drugs.  The more potent
isomer is the RSS isomer, which is the more potent form of amphetamine
and methamphetamine.  This was one of the first clear distinctions
that was apparent between MDMA and the structurally related
psychedelics (where the RRS isomers are the more active).  Tolerance
studies also support differences in mechanisms of action.  In one
study, MDMA was consumed at 9:00 AM each day for almost a week (120
milligrams the first day and 160 milligrams each subsequent day) and
by the fifth day there were no effects from the drug except for some
mydriasis.  And even this appeared to be lost on the sixth day.  At
this point of total tolerance, there was consumed (on day #7, at 9:00
AM) 120 milligrams of MDA and the response to it was substantially
normal with proper chronology, teeth clench, and at most only a slight
decrease in mental change.  A complete holiday from any drug for
another 6 days led to the reversal of this tolerance, in that 120
milligrams of MDMA had substantially the full expected effects.  The
fact that MDMA and MDA are not cross-tolerant strengthens the argument
that they act in different ways, and at different sites in the brain.

A wide popularization of the social use of MDMA occurred in 1984-1985
and, with the reported observation of serotonin nerve changes in
animal models resulting from the administration of the structurally
similar drug MDA, an administrative move was launched to place it
under legal control.  The placement of MDMA into the most restrictive
category of the Federal Controlled Substances Act has effectively
removed it from the area of clinical experimentation and human
research.  The medical potential of this material will probably have
to be developed through studies overseas.

A word of caution is in order concerning the intermediate
3,4-methylene-dioxyphenylacetone, which has also been called
piperonylacetone.  A devilish ambiguity appeared in the commercial
market for this compound, centered about its name.  The controversy
focused on the meaning of the prefix, piperonyl, which has two
separate chemical definitions.  Let me try to explain this fascinating
chaos in non-chemical terms.  Piperonyl is a term that has been used
for a two-ring system (the methylenedioxyphenyl group) either without,
or with, an extra carbon atom sticking off of the side of it.  Thus,
piperonylacetone can be piperonyl (the two-ring thing without the
extra carbon atom attached) plus acetone (a three carbon chain thing);
the total number of carbons sticking out, three.  Or, piperonylacetone
can be piperonyl (the two-ring thing but with the extra carbon atom
attached) plus acetone (a three carbon chain thing); the total number
of carbons sticking out, four.

Does this make sense?

The three carbon sticking out job gives rise to MDA and to MDMA and to
many homologues that are interesting materials discussed at length in
these Book II comments.  This is the usual item of commerce, available
from both domestic and foreign suppliers.  But the four-carbon
sticking out job will produce totally weird stuff without any apparent
relationship to psychedelics, psychoactives or psychotropics
whatsoever.  I know of one chemical supply house which supplied the
weird compound, and they never did acknowledge their unusual use of
the term piperonyl.  There is a simple difference of properties which
might be of value.  The three carbon (correct) ketone is an oil with a
sassafras smell that is always yellow colored.  The four carbon
(incorrect) ketone has a weak terpene smell and is white and
crystalline.  There should be no difficulties in distinguishing these
two compounds.  But unprincipled charlatans can always add mineral oil
and butter yellow to otherwise white solids to make them into yellow
oils.  Caveat emptor.

 

 

 



#110 MDMC; EDMA; 3,4-ETHYLENEDIOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 27.6 g protocatechualdehyde
(3,4-dihydroxybenzaldehyde) in 250 mL acetone there was added 57 g
finely powdered anhydrous K2CO3 and 43 g 1,2-dibromoethane.  The
mixture was held at reflux for 16 h, and then the acetone removed by
evaporation.  The remaining tar-like goo was distributed between equal
volumes of H2O and CH2Cl2, and the phases separated by centrifugation.
The organic phase was washed with 2x50 mL 5% NaOH, and the solvent
removed under vacuum.  The residue (22.0 g with the smell of the
starting halide) was distilled to give a fraction that boiled at 110
!C at 0.25 mm/Hg to yield 3,4-ethylenedioxybenzaldehyde
(1,4-benzodioxane-6-carboxaldehyde) as a white oil weighing 6.88 g.
This spontaneously crystallized to give white solids that melted at
50-51 !C.

A solution of 6.64 g 3,4-ethylenedioxybenzaldehyde in 40 mL
nitroethane was treated with 0.26 g anhydrous ammonium acetate and
held at reflux for 3 days.  TLC analysis showed that there was much
aldehyde remaining unreacted, so an additional 0.7 g ammonium acetate
was added, and the mixture held at reflux for an additional 6 h.  The
excess nitroethane was removed under vacuum.  The residue was
dissolved in 30 mL hot MeOH which, with patience and slow cooling,
finally deposited a heavy yellow-gold powder.  This product
1-(3,4-ethylenedioxyphenyl)-2-nitro-propene melted at 95-96 !C and
weighed 6.03 g when air dried to constant weight.  Recrystallization
from either MeOH or EtOAc gave the product as a yellow solid, but
without any improvement in mp.

A solution of 4.0 g of 1-(3,4-ethylenedioxyphenyl)-2-nitropropene was
made in 30 mL warm acetic acid.  This was added to a suspension of 16
g elemental electrolytic iron in 75 mL acetic acid.  The mixture was
heated on the steam bath, and an exothermic reaction set in at about
70 !C.  Heating was continued and the reaction allowed to proceed
until the mass was a thick gray color and a dirty scum had been formed
on the surface.  After about 2 h, the entire mix was poured into 2 L
H2O and filtered free of a little residual unreacted iron which was
washed with CH2Cl2.  The filtrate and washes were extracted with 3x100
mL CH2Cl2 and the pooled organic extracts washed with 2x50 mL 5% NaOH.
Removal of the solvent gave 3.38 g of an amber oil which was
distilled.  The product 1-(3,4-ethylenedioxyphenyl)-2-propanone
distilled as a white oil, at 105-110 !C at 0.2 mm/Hg.  It weighed 2.74
g.

To 2.0 g. of 1 inch squares of light-weight aluminum foil there was
added a solution of 50 mg mercuric chloride in 70 mL water.  After
standing at room temperature for 30 min, the H2O was drained away, and
the amalgamated aluminum washed twice with H2O, and shaken as dry as
possible.  There was then added, promptly and in immediate sequence, a
solution of 3 g methylamine hydrochloride in 3 mL H2O, 9 mL IPA, 7.25
mL 25% NaOH, 2.70 g of 1-(3,4-ethylenedioxyphenyl)-2-propanone, and 18
mL IPA.  The mixture was heated on the steam bath until an exothermic
reaction set in, and then it was continuously swirled as the reaction
proceeded.  When the aluminum was consumed, there was a colorless gray
sludge, and this was filtered and washed with 2x10 mL MeOH.  The
combined mother liquors and washes were stripped of solvent under
vacuum.  The two phase residue was suspended in 400 mL H2O containing
sufficient H2SO4 to make the resulting water solution acidic to pH
paper. This was washed with 3x50 mL CH2Cl2, made basic with 25% NaOH,
and the product extracted with 3x50 mL CH2Cl2.  The resulting 3.01 g
slightly amber residue oil was distilled at 110-120 !C at 0.25 mm/Hg
to give 2.53 g of a white oil, which did not appear to absorb carbon
dioxide.  This was dissolved in 12 mL IPA, neutralized with 1 mL
concentrated HCl and diluted with anhydrous Et2O to the point of
initial turbidity.  There separated white crystals of
3,4-ethylenedioxy-N-methylamphetamine hydrochloride (MDMC) which
weighed, when air dried to constant weight, 2.53 g.

DOSAGE: 200 or more mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 150 mg) A flood of paresthesia at the 30
minute point, and then nothing.  There was the development of a plus
one-and-a half effect over the next hour with the tendency to drift
into a dozing state with hypnogogic imagery.  There were colored
letters in the periphery of my visual field.  There was no appetite
loss nor was there any blood pressure rise.  And no eye jiggle or
teeth clenching.  I was out of the experience in 4 to 5 hours.  A
repeat of this level a few days later gave a bare possible threshold
with no other effects.

(with 200 mg) There was something unmistakable at 45 minutes, with
hints of nystagmus.  Possibly MDMA-like, with no indicators of
anything psychedelic.  Subtle return to baseline, and there were no
after-effects.

(with 250 mg) Alert at 40 minutes, and to a clear ++ at an hour.
Slight something in the eye muscles.  Dropping thirty minutes later,
and baseline at three hours.

(with 250 mg) I am at a bare threshold at best.

EXTENSIONS AND COMMENTARY: What a strange and completely
unsatisfactory compound!  In the original run-up from low levels to
increasing higher levels, there never was a dosage that was a minus,
that had no effect.  At every level, something was thought to be
there, usually at a level of a single plus or thereabouts.  But with
different people, different responses.  There is no way of guessing
what an active level might be, or how consistent that level might be
between different people, or for that matter what the responses are
that might be expected at that level.

This was yet one more effort to find an MDMA-like substitute by the
miniscule manipulation of the MDMA molecule.  Perhaps a small
molecular change might leave the particular magic of the MDMA action
alone, but eliminate the serotonin neuron problem in test animals.
Maybe the serotonin neuron change is essential for MDMA to have the
action it has.  Who can tell?

The original name that this compound got, during the several
explorations of MDMA analogues, was based on the nickname for MDMA
which was Adam.  HADUEM was mentioned with the hydroxy compound, MADAM
with the 6-methyl homologue, and FLADAM with the 6-fluoro analogue.
This compound got the sobriquet MACADAM from that horrible black gooey
mess generated at the aldehyde stage.  This was shortened to RCS and
eventually the RCS was added to the MDMA parent name.  Thus, MDMC.  It
doesnUt really make sense; EDMA is more reasonable.  But then there is
no reason why MDMC should make sense.

 

 

 



#111 MDMEO; N-METHOXY-MDA; 3,4-METHYLENEDIOXY-N-METHYOXYAMPHETAMINE

SYNTHESIS: To a solution of 20.9 g methoxyamine hydrochloride in 75 mL
MeOH (a strongly acidic solution) there was added 4.45 g
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.10 g sodium cyanoborohydride.  There was the immediate
formation of a solid phase, and the evolution of what appeared to be
hydrogen cyanide.  To this there were added about 4 mL 5% NaOH which
brought the pH to the vicinity of 3 or 4.  Another 1.0 g of sodium
cyanoborohydride was added (no gas evolution this time) and stirring
was continued at ambient temperature for 6 days.  All was added to 500
mL H2O, acidified with 10 mL HCl, and extraction with 3x100 mL CH2Cl2
removed almost all the color.  The aqueous phase was made basic with
25% NaOH, and extracted with 4x100 mL CH2Cl2.  Evaporation of the
solvent from these extracts yielded 1.8 g of a pale yellow oil which,
on distillation at 90-95 !C at 0.5 mm/Hg, gave a 1.6 g fraction of an
absolutely white, viscous, clear oil.  This was dissolved in 8 mL IPA
and neutralized with concentrated HCl.  The product was an
exceptionally weak base, and appropriate end points must be respected
on the external pH paper (yellow to red, rather than purple to
orange).  Anhydrous Et2O was added to the point of turbidity, and as
soon as crystallization had actually started, more Et2O was added with
stirring, for a net total of 200 mL.  After a couple of h standing,
the fine white crystalline 3,4-methylenedioxy-N-methoxyamphetamine
hydrochloride (MDMEO) was removed by filtration, Et2O washed, and air
dried to constant weight.  There was obtained 1.7 g of a product with
a mp of 143-146 !C.  The proton NMR was excellent with the N-methoxyl
group a sharp singlet at 4.06 ppm.  Anal. (C11H16ClNO3) N.

DOSAGE: greater than 180 mgs.

DURATION: unknown

EXTENSIONS AND COMMENTARY: Why the interest in the N-methoxy analogue
of MDA?  There are several reasons.  One, this is an isostere of MDE
and it would be interesting to see if it might serve as a primer to
the promotion of the effectiveness of other drugs (see primer
discussion under MDPR).  In one experiment, wherein a 60 microgram
dosage of LSD was used an hour and a half after a 180 milligram load
of MDMEO, there was no augmentation of effects.  Thus, it would appear
not to be a primer.  Another reason for interest was that the
material, although having an extremely similar overall structure to
most of the active MD-series compounds, is very much a weaker base.
And MDOH, which is also a very much weaker base than MDA, still shows
the action and potency of MDA.  And, as this compound appears to be
inactive, base strength is not a sole predictor of activity.

The ultimate reason for making MDMEO was, of course, that it could be
made.  That reason is totally sufficient all by itself.

 

 

 



#112 MDMEOET; N-METHOXYETHYL-MDA;
3,4-METHYLENEDIOXY-N-(2-METHOXYETHYL)AMPHETAMINE

SYNTHESIS: A crude solution of methoxyethylamine hydrochloride was
prepared from 17.7 g methoxyethylamine and 20 mL concentrated HCl with
all volatiles removed under vacuum. This 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 1.3 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.  About 4.5 mL were added over the course of 5
days, at which time the pH had stabilized.  The reaction mixture was
added to 400 mL H2O and made strongly acidic with an excess of HCl.
After washing with 2x100 mL CH2Cl2 the aqueous phase was made basic
with 25% NaOH, and extracted with 4x75 mL CH2Cl2.  Removal of the
solvent under vacuum yielded 6.0 g of an amber oil that was distilled
at 110-120 !C at 0.2 mm/Hg.  There was obtained 4.7 g of a
crystal-clear white oil that was dissolved in 30 mL IPA and
neutralized with 45 drops of concentrated HCl producing a heavy mass
of spontaneous crystals that had to be further diluted with IPA just
to be stirred with a glass rod.  These were diluted with 200 mL of
anhydrous Et2O, removed by filtration, and washed with additional
Et2O.  After air drying there was obtained 4.9 g of
3,4-methylenedioxy-N-(2-methoxyethyl)amphetamine hydrochloride
(MDMEOET) with a mp of 182.5-183 !C.  Anal. (C13H20ClNO3) N.

DOSAGE: greater than 180 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This is another example of the replacement
of a neutral atom out near the end of a chain, with a more basic and a
more polar one.  MDMEOET would be called an isostere of MDBU in that
it has the same shape, with a methylene unit (the CH2) replaced by an
oxygen atom.  No activity turned up with either compound, so nothing
can be learned from this particular example of change of polarity.

 

 

 



#113 MDMP; a,a,N-TRIMETHYL-3,4-METHYLENEDIOXY-PHENETHYLAMINE;
METHYLENEDIOXYMEPHENTERMINE

SYNTHESIS: To a well stirred solution of 1.64 g of
1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane
(see under MDPH for its preparation) in 10 mL anhydrous THF there was
added a suspension of 0.38 g LAH in 25 mL THF.  All was held at reflux
for 24 h, the excess hydride was destroyed by the addition of 1.5 mL
H2O, and sufficient aqueous NaOH was added to make the reaction
mixture basic and flocculant enough to be filterable.  The inorganic
solids were removed by filtration and, following washing with THF, the
combined filtrate and washings were stripped of organic solvent under
vacuum.  The residue was dissolved in 100 mL Et2O and washed with 2x50
mL saturated aqueous NaHCO3.  After drying the organic phase with
anhydrous MgSO4, the solvent was removed under vacuum to give a yellow
oil.  This was dissolved in 50 mL absolute EtOH and neutralized with
concentrated HCl.  Removal of the solvent under vacuum yielded an
off-white solid that was recrystallized from an EtOH/EtOAc mixture to
provide 0.84 g of a,a,N-trimethyl-3,4-methylenedioxyphenethylamine
hydrochloride (MDMP) with a mp of 206-208 !C.  The NMR spectrum showed
the a,a-dimethyl pair as a singlet at 1.38 ppm.  Anal. (C12H18ClNO2)
C,H,N.

DOSAGE: above 110 mg.

DURATION: perhaps 6 hours.

QUALITATIVE COMMENTS: (with 60 mg) There was a faint, dull alerting
at just over a half hour.  The time sense was out of order, and an
absence of visuals but a generalized attentiveness to my surroundings
was suggestive of MDMA.  Nothing remained at the six hour point.

(with 110 mg) There was a light-headedness, and a complete absence of
libido.  Nothing in any way psychedelic, but there are hints of
discomfort (jaw tension) that will bear close watching at higher
dosages.  It might evolve at higher levels into something like MDMA.

EXTENSIONS AND COMMENTARY: This is one of several candidates for
clinical use as a substitute for MDMA, but there will have to be a
much broader study of its qualitative action in man.  It is clearly
not psychedelic at these modest levels, and in in vitro animal studies
it was apparently inactive as a serotonin releaser.  The warped logic
for looking at phentermine analogs was discussed in the comments that
concerned MDPH.  The initials used here have been chosen with care.
MDM should not be used as it has found some currency as an
abbreviation for MDMA (Methylene-Dioxy-Methamphetamine).  MDMP fits
neatly with Methylene-Dioxy-Me-Phentermine.

 

 

 



#114 MDOH; N-HYDROXY-MDA; 3,4-METHYLENEDIOXY-N-HYDROXYAMPHETAMINE

SYNTHESIS: To a well stirred solution of 14.8 g hydroxylamine
hydrochloride in 120 mL MeOH there was added 3.6 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.0 g sodium cyanoborohydride.  The oxime, prepared from
the ketone and hydroxylamine in MeOH with pyridine, may be substituted
for these two components.  Concentrated HCl was added over the course
of a couple of days, to keep the pH near neutrality.  When the
reaction was complete, it was added to H2O, made strongly acidic with
HCl, and washed with 3x100 mL CH2Cl2.  The aqueous phase was made
basic with 25% NaOH, and reextracted with 3x100 mL of CH2Cl2.  The
extracts were pooled, and the solvent removed under vacuum to give 1.7
g of an oily residue which, with pumping under a hard vacuum for a few
minutes, changed to a white solid.  This can be Kugelrohred if the
vacuum is sufficiently good to keep the temperature during the
distillation below 100 !C.  The extremely viscous distillate formed
crystals immediately upon wetting with IPA.  It was dissolved in 20 mL
of warm IPA and neutralized with concentrated HCl, with the titration
end-point being red rather than orange on universal pH paper.  Modest
addition of Et2O allowed the formation of
3,4-methylenedioxy-N-hydroxyamphetamine hydrochloride (MDOH) as white
crystals, which weighed 1.4 g when air dried.  If the temperature of
distillation exceeded 100 !C, there was extensive decomposition during
distillation, with the formation of 3,4-methylenedioxyamphetamine
(MDA) and the oxime of the ketone.  Under these circumstances, the
only base isolated was MDA.  The surest isolation procedure was to
obtain MDOH as the free base, as a crystalline solid which could be
recrystallized from 5 volumes of boiling IPA.  The free base had a mp
of 94-95 !C (and should not be confused with the oxime of
3,4-methylenedioxyphenylacetone which has a mp of 86-88 !C since the
mixed mp is depressed, mp 56-62 !C, or with the free base of MDA which
is an oil).  Anal. (C10H13NO3) N.  The hydrochloride salt had a mp of
149-150 !C (and should not be confused with the hydrochloride of MDA
which has a mp of 185-186 !C since the mixed mp is depressed, mp
128-138 !C).  Anal. (C10H14ClNO3) N.  Acetic anhydride can serve as a
useful tool for distinguishing these materials.  MDA gives an N-acetyl
derivative with an mp of 92-93 !C.  MDOH gives an N,O-diacetyl
derivative with a mp of 72-74 !C.  Methylenedioxyphenylacetone oxime
gives an O-acetyl derivative that is an oil.

DOSAGE: 100 - 160 mg.

DURATION: 3 - 6 h.

QUALITATIVE COMMENTS: (with 100 mg) I felt hampered the first hour by
some internal barrier, which prevented total enjoyment.  However, this
began to break through in a wonderful way just before the supplement
was offered.  Since I felt I was beginning to move through the
barrier, I declined the supplement, particularly since I was anxious
to compare the after-effects with my first experience.  I had found
the first time very remarkable, but felt unusually tired for several
days following.  I feel it is important to know whether this is a
specific drug-induced effect, or the result of psychological
phenomena.  The experience continued in a rich, meaningful way.  There
was a marvelous inner glow, the warmth from all the other participants
was wonderful to feel, nature was most beautiful.  There were no
dramatic breakthroughs, or rushes of insight or energy, but just a
wonderful contemplative space where things gently unfolded as you put
your attention on them.

(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 temperature.  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.

QUALITATIVE COMMENTS: (with 160 mg followed at 2 h by 60 5gs LSD) RThe
visual phenomena were extraordinary.  We were at the beach just south
of Mendocino.  In anything that had ever been living, there was an
endlessly deep microcosm of detail.  Endless, and forever more
microscopic in intricacy.  A sea urchin shell, a bit of driftwood, a
scrap of dried seaweed, each was a treasure of jewels.  I have never
had such wealth of visual eroticism and bliss before.  Later, we
visited the pygmy forest, but these living fossils were not as
magical.

(with 160 mg followed at 2 h by 60 5gs LSD) RWe both felt the first
effects at about 30 minutes, and an hour later we found ourselves in a
startling folie-a-deux, involved in reliving the origins of manUs
arrival on earth.  We were deep in a tropic environment, defending
ourselves against the nasties of nature (insects, threatening things,
blistering heat) and determining that man could indeed live here and
perhaps survive.  A shared eyes-closed fantasy that seemed to be the
same script for both of us.

(with 160 mg followed at 2 h by100 5gs LSD) RThis proved to be almost
too intoxicating, and a problem arose that had to have a solution.
The entire research group was here, and all were following this same
regimen.  Two hours into the second half of the experiment a telephone
call came that reminded me of a promise I had made to perform in a
social afternoon with the viola in a string quartet.  Why did I answer
the phone?  My entire experience was, over the course of about 20
minutes, pushed down to a fragile threshold, and I drove about 10
minutes to attend a swank afternoon event and played an early
Beethoven and a middle Mozart with an untouched glass of expensive
Merlot in front of me.  I could always blame the booze.  I declined
the magnificent food spread, split, and returned to my own party.
Safely home, and given 20 more minutes, I was back into a rolling +++
and I now know that the mind has a remarkable ability to control the
particular place the psyche is in.

(with 200 mg followed at 2 h by 60 5gs LSD) RThere was a steady climb
from the half-hour point to about 2 hours.  There was not the
slightest trace of anything sinister.  There was simply a super
tactile person-to-person window.  I had an overpowering urge to go out
and interact with other people.  To see, to talk, to be with others.
There are unending fantasies of things erotic.  Perhaps being with
others should be circumspect.  By evening the effects had largely worn
off, but this was an incredible day, beautiful and unexpectedly
relaxing.

EXTENSIONS AND COMMENTARY: There is need for more commentary.  It must
be noted that all of the above comments used rather modest dosages of
LSD.  The notes of this period, some two years of exploring
interactions of the MD series of compounds as preludes to true
psychedelics, are difficult to distill into a simple pattern.  Most of
these studies used LSD in the 60-100 microgram range which is
fundamentally a modest level.  Many trials were made where the
challenge of acid plopped right on top of an active residue of another
drug was more in keeping with the RpiggybackS argument.  An
illustration of this is a trial in which the primer was MDMA followed
at 5 hours (this is at a time of almost no effect) with a larger dose
of LSD (250 micrograms).  The LSD overwhelmed the residual numbing of
the MDMA, and the generated state was overwhelmingly erotic and out of
body.  There can be no way of analytically organizing such a gemisch
of drug-drug interactions with any logic that would allow a definitive
interpretation.  And LSD is not the only agent that can be used to
challenge the Rbody windowS such as that produced by MDPR.  2C-B,
2C-T-2 and 2C-T-7 have all been used with fine success as well.

In general, the use of an MD compound (looking at it as a stimulant
and primer) followed by a psychedelic, brings about an exaggeration
and enhancement of the latter compound.  Much work must be done in
this area to make sense of it all.



#119 ME; METAESCALINE; 3,4-DIMETHOXY-5-ETHOXYPHENETHYLAMINE

SYNTHESIS: To a vigorously stirred suspension of 18.6 g of
5-bromobourbonal in 100 mL CH2Cl2 there was added 14.2 g methyl
iodide, 1.0 g decyltriethylammonium iodide, and 120 mL 5% NaOH.  The
color was a deep amber, and within 1 min the top phase set up to a
solid.  This was largely dispersed with the addition of another 50 mL
of water.  The reaction was allowed to stir for 2 days.  The lower
phase was washed with H2O, and saved.  The upper phase was treated
with another 100 mL CH2Cl2, 50 mL of 25% NaOH, another g of
decyltriethylammonium iodide, and an additional 50 mL of methyl
iodide.  The formed solids dispersed by themselves in a few h to
produce two relatively clear layers.  Stirring was continued for an
additional 3 days.  The lower phase was separated, washed with H2O,
and combined with the earlier extract.  The solvent was removed under
vacuum to give 20.3 g of an amber oil that was distilled at 120-133 !C
at 0.4 mm/Hg to yield 15.6 g of 3-bromo-4-methoxy-5-ethoxybenzaldehyde
as a white crystalline solid with a mp of 52-53 !C.

A mixture of 15.6 g 3-bromo-4-methoxy-5-ethoxybenzaldehyde and 10 mL
cyclohexylamine was heated with an open flame until it appeared free
of H2O.  The residue was put under a vacuum (0.5 mm/Hg) and distilled
at 148-155 !C yielding 19.2 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine as an off-white
crystalline solid with a melting point 66-68.5 !C.  Recrystallization
from 100 mL boiling MeOH gave a mp of 67-68.5 !C.  The C=N stretch in
the infra-red was at 1640 cm-1.  Anal. (C16H22BrNO2) C,H.

A solution of 17 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzyl-idenimine in 200 mL
anhydrous Et2O was placed in an atmosphere of He, stirred
magnetically, and cooled with an external dry-ice acetone bath.  Then
38 mL of a 1.55 M solution of butyllithium in hexane was added over 2
min, producing a clear yellow solution.  There was then added 25 mL of
butyl borate at one time, and the stirred solution allowed to return
to room temperature.  This was followed with 100 mL of saturated
aqueous ammonium sulfate.  The Et2O layer was separated, washed with
additional saturated ammonium sulfate solution, and evaporated under
vacuum The residue was dissolved in 200 mL of 50% MeOH and treated
with 12 mL of 30% hydrogen peroxide.  This reaction was mildly
exothermic, and was allowed to stir for 15 min, then added to an
aqueous solution of 50 g ammonium sulfate.  This was extracted with
2x100 mL CH2Cl2, the pooled extracts washed once with H2O, and the
solvent removed under vacuum.  The residue was suspended in dilute
HCl, and heated on the steam bath for 0.5 h.  Stirring was continued
until the reaction was again at room temperature and then it was
extracted with 2x100 mL CH2Cl2.  These extracts were pooled and in
turn extracted with 2x100 mL dilute NaOH.  The aqueous extracts were
reacidified with HCl, and reextracted with 2x100 mL CH2Cl2.  After
pooling, the solvent was removed under vacuum to yield an oily
residue.  This was distilled at 118-130 !C at 0.2 mm/Hg to yield 7.5 g
of 3-ethoxy-5-hydroxy-4-methoxybenzaldehyde as a distillate that set
to white crystals.  Recrystallization from cyclohexane gives a product
with a mp of 77-78 !C.  Anal. (C10H12O4) C,H.

A solution of 7.3 g of 3-ethoxy-5-hydroxy-4-methoxybenzaldehyde in 100
mL acetone was treated with 5 mL methyl iodide and 8.0 g finely
powdered anhydrous K2CO3, and held at reflux on a steam bath for 6 h.
The solvent was removed under vacuum, and the residue was suspended in
H2O.  After making this strongly basic, it was extracted with 3x50 mL
CH2Cl2, the extracts were pooled, and the solvent removed under
vacuum.  The residual amber oil was distilled at 110-120 !C at 0.4
mm/Hg to yield 7.3 g of a white oil.  This spontaneously set to white
crystals of 3,4-dimethoxy-5-ethoxybenzaldehyde which had a mp of
49-49.5 !C.  Anal. (C11H14O4) C,H.  This same aldehyde can be
obtained, but in a less satisfactory yield, by the ethylation of
3,4-dimethoxy-5-hydroxybenzaldehyde described under the preparation of
metaproscaline (MP).

A solution of 7.2 g 3,4-dimethoxy-5-ethoxybenzaldehyde in 100 mL
nitromethane containing 0.1 g anhydrous ammonium acetate was held at
reflux for 50 min.  The excess nitromethane was removed under vacuum
producing 6.8 g of a red oil which was decanted from some insoluble
material.  Addition of 10 mL hot MeOH to the decantings, gave a
homogeneous solution that spontaneously crystallized on cooling.  The
yellow crystals were removed by filtration, washed sparingly with MeOH
and air dried yielding 3.5 g yellow crystals of
3,4-dimethoxy-5-ethoxy-'-nitrostyrene, with a mp of 89.5-90 !C after
recrystallization from MeOH.  Anal. (C12H15NO5) C,H.

A solution of 2.0 g LAH in 100 mL anhydrous THF under He was cooled to
0 !C and vigorously stirred.  There was added, dropwise, 1.3 mL of
100% H2SO4, followed by the dropwise addition of a solution of 3.1 g
3,4-dimethoxy-5-ethoxy-'-nitrostyrene in 50 mL anhydrous THF, over the
course of 10 min.  The mixture was stirred at 0 !C for a while, and
then brought to a reflux on the steam bath for 30 min.  After cooling
again, the excess hydride was destroyed with IPA in THF, followed by
the addition of 20 mL 10% NaOH which was sufficient to convert the
solids to a white and granular form.  These were removed by
filtration, the filter cake washed with IPA, the mother liquor and
filtrates combined, and the solvents removed under vacuum.  The
residue was added to 150 mL dilute H2SO4, and the cloudy suspension
washed with 2x75 mL CH2Cl2 which removed much of the color.  The
aqueous phase was made basic with 25% NaOH, and extracted with 3x50 mL
CH2Cl2.  The solvent was removed from these pooled extracts and the
residue distilled at 103-116 !C at 0.25 mm/Hg to provide 2.3 g of a
colorless viscous liquid.  This was dissolved in 10 mL IPA,
neutralized with about 25 drops of concentrated HCl, which produced an
insoluble white solid.  This was diluted with 40 mL anhydrous Et2O
added slowly with continuous stirring.  The white crystalline
3,4-dimethoxy-5-ethoxyphenethylamine hydrochloride (ME) was isolated
by filtration, washed with Et2O, and air dried, and weighed 2.4 g.  It
had a mp of 202-203 !C which increased by one degree upon
recrystallization from boiling IPA.  Anal. (C12H20ClNO3) C,H.

DOSAGE: 200 - 350 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 200 mg) It tasted pretty strong.
However, the taste was soon gone, and an energetic feeling began to
take over me.  It continued to grow.  The feeling was one of great
camaraderie, and it was very easy to talk to people.  Everyone was
talking to everyone else.  I found it most pleasant, energetic and at
the same time relaxing, with my defenses down.  This material did not
seem to lead to introspection; however, it might if one took it
without other people around.  Heightened visual awareness was mild,
but the audio awareness was quite heightened.  The feeling of being
with everyone was intense.

(with 250 mg) Initially I took 200 milligrams of metaescaline, and
the experience developed for me very gradually at first, and very
pleasantly.  After about one half hour I became aware of a wall that
seemed to shut me in, not unpleasantly.  The wall slowly dissolved,
but I was afraid I might get into a negative experience.  I felt
immediate relief (from this isolation) upon taking the additional 50
mg (at 2:23 into the experiment) as though glad of the decision.  I
lay down outside on a blanket.  There was a marvelous feeling inside,
although no imagery.  I felt the wall dissolve completely, and I
desired to join the group.  From this point on the experience was most
enjoyable, euphoric.  Although not dramatic like some psychedelics, it
was most rewarding for me personally.  I felt a marvelous bond with
everyone present, with clear-headed, excellent thinking, and excellent
communication.  All in all, a most rewarding and enjoyable experience.
Afterwards I felt much strengthened, with good energy and good
insight.  I have a strong feeling that the group tailored the nature
of the experience, and that I and others were most desirous of group
interaction.  I feel that one could do a lot of other things with it
if one turned one's attention to it.

(with 275 mg) Onset of both physical and mental change was slow
relative to other psychochemicals.  Very gradual internal stirrings
were felt at about the hour-and-a-half point. These were mostly
feelingful rather than cognitive, and were quite pleasurable.  At
about the two-and-a-half hour point I grew quite thirsty, and drank a
pint of beer.  Almost immediately, and quite unexpectedly, I tomsoed
to a much higher level and remained there for another three hours
until the whole experience waned.  [The verb, to tomso, means a sudden
rekindling of the drug-induced altered state with a small amount of
alcohol. It is explained in the recipe for TOMSO.]  During the
experience heights, and in fact before it reached its height, talking
was easy and unimpeded.  The transference feelings so characteristic
of MDMA were basically not there.  But for purposes of psychotherapy,
there were some advantages: fluent associations, undefended positions,
and general bonaise.

(with 400 mg) Ingested 300 milligrams at about 1:30 in the afternoon.
Very quiet climb.  Occasional yawns.  Matter-of-fact view of the
world.  No rosy glow.  At the end of the second hour, I seem to be
stuck at a ++.  Take another 100 milligrams at 3:45 PM.  Still tastes
awful.  Feel a small head-rush fifteen minutes after taking the
supplement, and within a half hour I am completely +3.  For a while
this was a sterner mescaline.  Saw the eternal, continual making of
choices, all opposites continually in motion with each other.  Yin and
yang everywhere, giving life to every molecule.  The universe itself
keeps alive by the action-reaction, the yes-no, the black-white,
male-female, plus-minus.  All life is a continual making of choices on
all levels.  Then I closed my eyes, and I found myself floating up to
the very top of a temple, where there was radiant light and a sense of
homecoming.  Making love is a clear stream over and through rocks and
canyons Q the earth and sky make love, and the rocks make love to
other rocks, and the water is the teasing, fondling, living and moving
actions of loving.  To realize that, on some level, all existence
makes love to all other existence.  The Japanese Garden: a structured
way of laying out a small glimpse into cosmic love-making, so that it
can be read by other human souls.  All loving, when direct and free
and undemanding, is a touching of the Source.  The hardest lesson, of
course, is how to love yourself that same way.  And it remains both
the first lesson of Kindergarten and the Ph.D. final.  I was able to
drift into sleep at about 4:00 AM.

EXTENSIONS AND COMMENTARY: The reorientation of the single ethyl group
of escaline (E) to the meta-position produces metaescaline (ME).  In
cats, in studies of over 50 years ago, the two compounds produced
similar effects at similar dosages.  In man, ME also appears to be
similar to mescaline in potency.  However, a subtle difference is
apparent between ME and Peyote, the natural source of mescaline.  With
Peyote itself, the initial taste of the crude cactus is more than just
foul; it might better be described as unbelievably foul.  But in the
middle of a Peyote experience, the taste of the cactus is truly
friendly.  When ME was retasted in the middle of an experience, the
taste was still foul.

There are other distinctions from mescaline.  Unlike mescaline or
Peyote, there is rarely any body discomfort during the early phase of
intoxication, no nausea and only an occasional comment suggesting
hyperreflexia.  And, also unlike mescaline, most subjective reports on
ME claim that music produces little imagery, and the exaggeration of
color perception is more reserved.  Appetite is normal, the tastes and
textures of food are unusually rewarding.  No subject has ever
expressed a reluctance to repeat the experience.  Sleep is easy,
refreshing, and the following day seems free from residue.

 

 

 



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