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Lucid
LSD
EXTASY
MESKALIN
KOKAIN
HEROIN
OPIUM
LSD-25
ACID; LYSERGIDE; D-LYSERGIC ACID DIETHYLAMIDE; METH-LAD; D-LYSERGAMIDE, N,N-DIETHYL;
N,N-DIETHYL-D-LYSERGAMIDE; 9,10-DIDEHYDRO-N,N-DIETHYL-6-METHYLERGOLINE-8b-CARBOXAMIDE
SYNTHESIS: A solution of 6.7 g KOH in 100 mL H2O, under
an inert atmosphere and magnetically stirred, was brought to 75 °C, and 10 g
ergotamine tartrate (ET) added. The reaction mixture turned yellow as the ergotamine
went into solution over the course of 1 h. The stirring was continued for an
additional 3 h. The reaction mixture was cooled to about 10 °C with an external
ice bath, and acidified to a pH of about 3.0 by the dropwise addition of 2.5
N H2SO4. White solids started to appear early in the neutralization; approximately
60 mL of sulfuric acid was required. The reaction mixture was cooled overnight,
the solids removed by filtration, and the filter cake washed with 10 mL Et2O.
The dry solids were transferred to a beaker, suspended in 50 mL 15 % ammonia
in anhydrous ethanol, stirred for 1 h, and separated by decantation. This extraction
was repeated, and the original decantation and the second extract combined and
filtered to remove a few hundred milligrams of unwanted solids. The clear filtrate
was stripped of solvent under vacuum, the residual solids dissolved in 50 mL
of 1% aqueous ammonia, and this solution was acidified as before with 2.5 N
H2SO4. The precipitated solids were removed by filtration and washed with Et2O
until free of color. After drying under vacuum to a constant weight, there was
obtained 3.5 g of d-lysergic acid hydrate, which should be stored in a dark,
sealed container.A suspension of 3.15 g d-lysergic acid hydrate and 7.1 g of
diethylamine in 150 mL CHCl3 was brought to reflux with stirring. With the external
heating removed, there was added 3.4 g POCl3 over the course of 2 min, at a
rate sufficient to maintain refluxing conditions. The mixture was held at reflux
for an additional 5 min, at which point everything had gone into solution. After
returning to room temperature, the solution was added to 200 mL of 1 N NH4OH.
The phases were separated, the organic phase dried over anhydrous MgSO4, filtered,
and the solvent removed under vacuum. The residue was chromatographed over alumina
with elution employing a 3:1 C6H6/CHCl3 mixture, and the collected fraction
stripped of solvent under hard vacuum to a constant weight. This free-base solid
can be recrystallized from benzene to give white crystals with a melting point
of 87-92 °C. IR (in cm-1): 750, 776, 850, 937 and 996, with the carbonyl at
1631. The mass spectrum of the free base has a strong parent peak at mass 323,
with sizable fragments at masses of 181, 196, 207 and 221.
This base was dissolved in warm, dry MeOH, using 4 mL per g of product. There
was then added dry d-tartaric acid (0.232 g per g of LSD base), and the clear
warm solution treated with Et2O dropwise until the cloudiness did not dispel
on continued stirring. This opaqueness set to a fine crystalline suspension
(this is achieved more quickly with seeding) and the solution allowed to crystallize
overnight in the refrigerator. Ambient light should be severely restricted during
these procedures. The product was removed by filtration, washed sparingly with
cold methanol, with a cold 1:1 MeOH/Et2O mixture, and then dried to constant
weight. The white crystalline product was lysergic acid diethylamide tartrate
with two molecules of methanol of crystallization, with a mp of about 200 °C
with decomposition, and weighed 3.11 g (66%). Repeated recrystallizations from
methanol produced a product that became progressively less soluble, and eventually
virtually insoluble, as the purity increased. A totally pure salt, when dry
and when shaken in the dark, will emit small flashes of white light.
DOSAGE: 60 to 200 micrograms, orally
DURATION: 8 - 12 hrs
QUALITATIVE COMMENTS: In the case of LSD, it seems presumptuous
to attempt to select typical comments for quotation. Literally thousands of
reports are in the literature, from early exploratory research, to clinical
applications for treatment of autism, of alcoholism, or mental illness, to assisting
in psychotherapy and in the dying process, to the adventures of the military
in both intelligence and chemical warfare, to innumerable anecdotal tales of
pleasure and pain. Dozens of books have been devoted to these topics.
EXTENSIONS AND COMMENTARY: LSD is an unusually fragile molecule and some comments
are in order as to its stability and storage. As a salt, in water, cold, and
free from air and light exposure, it is stable indefinitely. There are two sensitive
aspects of its structure. The position of the carboxamide attachment, the 8-position,
is affected by basic, or high pH, conditions. Through a process called epimerization,
this position can scramble, producing isolysergic acid diethylamide, or iso-LSD.
This product is biologically inactive, and represents a loss of a proportionate
amount of active product. A second and separate point of instability is the
double bond that lies between this 8-position and the aromatic ring. Water or
alcohol can add to this site, especially in the presence of light (sunlight
with its ultraviolet energy is notoriously bad) to form a product that has been
called lumi-LSD, which is totally inactive in man. Oh yes, and often overlooked,
there may be only an infinitesimal amount of chlorine in treated tap water,
but then there is only an infinitesimal amount of LSD in a typical LSD solution.
And since chlorine will destroy LSD on contact, the dissolving of LSD in tap
water is not appropriate.
There are many synthetic methods developed and reported for the preparation
of LSD. All of them start with lysergic acid, and for that reason it has been
listed as a Schedule III controlled drug, as a depressant, under Federal law.
The amide lysergamide, a component of several varieties of morning glory seed,
is also a controlled drug and, by law, a depressant. The earliest syntheses
of LSD involved the used of an azide intermediate (the original Hofmann process,
1955), mixed anhydrides with trifluoroacetic anhydride (1956) or sulfuric anhydride
(SO3-DMF on the lithium salt, 1959), with the peptide condensation agent N,N'-carbonyldiimidazole
(1960), or with the acid chloride as the active intermediate with POCl3, PCl5
or thionyl chloride (1963) or just phosphorus oxychloride (1973). Most methods
are faulted due to excessive moisture sensitivity, generation of side-products,
or epimerization or inversion at the 8-position carbon to form d-iso-LSD. The
POCl3 procedure is clean and fast, and is the preferred process today for the
synthesis of a wide variety of substituted lysergamides.
The term LSD comes from the initials of the German for lysergic acid diethylamide,
or Lysersäure Diethylamid. The number "25" following it has many myths
attached to it, such as it was the 25th form of LSD that Hofmann tried, or it
was his 25th attempt to make LSD. From my own experience with chemical companies
that are allied with pharmaceutical houses, I had assumed that the chemical
name (which might be a mouthful for the pharmacologist) was simply replaced
with a pronounceable code number equivalent. But the answer here is yet simpler.
Hofmann, in his LSD, My Problem Child wrote: "In 1938, I produced the twenty
fifth substance in a series of lysergic acid derivatives: lysergic acid diethylamide,
abbreviated LSD-25 ... for laboratory usage."
Within a few years of the discovery of the extraordinary potency of LSD, a large
number of close analogues were synthesized by Hofmann and his allies at Sandoz.
Over the following decade many were tested in humans, both in patients and healthy
subjects, with the qualitative descriptions and dosages published in the medical
literature.
A number of analogues of LSD have maintained the diethylamide group unchanged, but additions or changes have been made in the pyrrole ring.
--indole-ring substituent--
at N-1
at C-2
Code
-H
-COCH3
-CH3
-CH2OH
-CH2N(CH3)2
-H
-H
-CH3
-CH3
-H
-H
-H
-H
-H
-B
-I
-Br
-I
LSD-25
ALD-52
MLD-41
BOL-148
MBL-61
MIL
ALD-52. 1-Acetyl-N,N-diethyllysergamide.This material has been explored in the
50-175 microgram range and there are a number of human trials reported, with
varying conclusions. One found that there was less visual distortion than with
LSD and it seems to produce less anxiety and was somewhat less potent than LSD.
Another report claimed it was more effective in increasing blood pressure. Yet
another could not tell them apart. ALD-52 just may have been the drug that was
sold as "Orange Sunshine" during the "Summer of Love" in
the late '60's. Or "Orange Sunshine" may have been, really, LSD. This
was the focus of a fascinating trial where two defendants were accused of distributing
LSD, whereas they claimed that it was ALD-52 which was not an illegal drug.
The prosecution claimed that as it hydrolyses readily to LSD, for all intents
and purposes it was LSD, and anyway, you had to go through the illegal LSD to
get to ALD-52 by any of the known chemical syntheses. The defendants were found
guilty. And yet, I do not know who has actually measured the speed or ease of
that reaction. If ALD-52 hydrolyses so easily to LSD, and the body is indeed
a hydrolytic instrument, then these two drugs should be absolutely equivalent
in every particular, This is the ergot equivalent of the psilocybin to psilocin
argument, except this is an acetamide rather than a phosphate ester. MLD-41.
1-Methyl-N,N-diethyllysergamide.The 1-methyl homologue of LSD is has more of
somatic than sensory effect, has fewer visuals and is less well accepted than
LSD, with the range of dosages being from 100 to 300 micrograms. This indicates
that it is perhaps a third the potency of LSD which is in accord with both pupilary
dilation and reflex action. However, the cardiovascular responses are actually
increased. Besides being less potent than LSD, it appears to have a slower onset
but it is equally long lived. There is cross-tolerance between MLD-41 and LSD.
BOL-148. 2-Bromo-N,N-diethyllysergamide.This synthetic ergot derivative, along
with its 1-methyl homologue MBL-61 (mentioned below) should be used as powerful
tools for studying the mechanism of action of LSD in the human animal. It does
not have LSD-like effects in man. At 6 to 10 milligrams orally, there are some
mental changes noted. But in another study, 20 milligrams was administered a
day to a subject for 7 days, and there were no reported effects. And yet it
is as potent a serotonin agonist as is LSD. How can serotonin be argued as a
neurotransmitter that is a major player in explaining the action of psychedelic
drugs, when this compound is nearly without activity.
There are some suggestions that an intervenous route may be more effective.
I have heard of effects being noted at maybe a milligram and a short (2-3 hour)
intoxicaion following 20 milligrams administered over a 20 minute period. I
was involved many years ago in a study of radio-labelled BOL-148 which was made
by the bromination of LSD. I was quite sure that the only radioactive material
present was BOL-148, but there could well have been some unreacted LSD still
present which would, of course, still be psychoactive. The synthesis is not
clean -- I was tempted to make an entry for this compound if only to reproduce
Albert Hofmann's original published experimental procedure. He reacted 13.2
grams of N-bromosuccinimide (in 400 mL dioxane, with 1.2 liters of dioxane containing
25 grams of LSD. This gave 11 grams of crude produce which had to be recrystallized.
The radioactive syntheses uses effectively elemental bromine, and gave yields
of from 5 to 15%. Visualize that reaction! A warm flask containing over a quart
of warm solvent in which there was maybe half a million doses of LSD.
1-Hydroxymethyl-LSD, 1-dimethylaminomethyl-LSD and 2-iodo-LSD.These three additional
compounds are shown here because they were described in a synthetic flurry that
followed the discovery the activity of LSD. But at the moment I know neither
their internal Sandoz codes nor if they had ever been explored in man. This
is a kind of frustrating catch-all entry, in that the long index will send you
here, and once here you realize that nothing is known. Well, at least the compounds
are known, and perhaps there is something in the Sandoz vaults that might be
interesting. I do not have access to them.
MBL-61. 2-Bromo-N,N-diethyl-1-methyllysergamide.This is the compound BOL-148
(mentioned above) with a methyl group attached to the 1-position of the indole
ring (LSD has a hydrogen there). This wold be an even more tantalizing challenge
to the serotonin theory for centrqal activity of the psuchedelics, in that it
is without any activity in man at an oral dose of 14 milligrams (similar to
the inactivity of the BOL-61 compound, but it is spome five times more potent
as a serotonin agonist. With it, as with the iodiniated analogue MIL, there
are many examples of the compromising of scientific integrity in the quest for
funds and recognition. Both compounds are as effective as LSD itself in displacing
labelled LSD that is bound to the post-synaptic serotonin receptor sites in
animal brains. But neither of them show any LSD-like activity. But both have
been labelled with 11-C or 122-I to give positrol emitting forms that can be
administered to man and localized in a positrom emition tomographt instrument
(a PET scanner).
I was at a meeting of a NIDA study section a few years ago, where some one presented
some findings with a group of subjects who were complaining of continuing mental
problems alledgedly due to LSD exposure. A chart was put up showing the outline
of the brain showing the locations of the EEG foci that were observed in one
of these subjects. Along side it was a PET scan showing the distribution of
radioactive LSD in a subject. The purpose was to discuss the similarities and
differences of the coordinates of electrical activity and radio-isotope concentration.
I innocently asked what positron isotope had been used, as I did not know of
any successful positron labelling of LSD. Carbon 11, I was told. Where in the
molecule was the label incorporated, I asked. In the 1-position methyl group.
It was finally acknowledged that the compound that had actually been used was
2-iodo-1-methyl-LSD, our MIL compound, which is quite a different world. A pharmacologist
might say that they are similar in action (looking at serotonin, not psychedelic
action), and achemist might say they are of similar structure (looking at the
upper 80% of the moledule. But they are different compounds. This is a most
subtle form of deceit. It is, in fact, out and out dishonest, but it looks good
up there on the screen at a lecture.
Let me mention in passing, that there are three stereoisomers possible for d-LSD.
There are d-iso-LSD, l-LSD, and l-iso-LSD. The inversion of the stereochemistry
of the attached diethylcarboxyamido group of d-LSD gives the diastereoisomer
(d-iso-LSD) which is a frequent synthetic impurity of d-LSD itself. The corresponding
optical antipodes l-LSD and l-iso-LSD are also known and have been tasted. All
three are completely inactive: d-iso-LSD shows no psychological changes at an
oral dose of 4 milligrams; l-LSD none at up to 10 milligrams orally; and l-iso-LSD
none at 500 micrograms orally. These dramatic decreases in potency show both
the stereoselectivity of the native LSD molecule in producing its central effects,
and the LSD-free purity of these isomers.
The second major location of variations in the structure
of LSD has been in the nature of the alkyl groups on the amide nitrogen atom.
Some of these are Sandoz syntheses, some are from other research groups, and
a few of them are found in nature. Some of these have been studied in man, and
some have not. A few of the original clutch of Sandoz compounds have both 1-substituents
and amide alkyl (R) group variations:
indole
--- amide nitrogen substituents ---
R=
R=
R=
code name
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-CH3
-CH3
-COCH3
-CH3
-H
-CH3
-CH2CH3
-(CH2)2CH3
-CH(CH3)CH2OH
-CH(CH3)CH2OH
-(CH2)CH3
-CH(CH3)CH2CH2OH
-(CH2)4CH3
-CH(CH3)CH2CH2CH3
-CH(CH2CH3)2
-(CH2)5CH3
-CH(CH3)CH2CH2CH2CH3
-(CH2)6CH3
-CH(CH3)CH2CH2CH2CH2CH3
-CH3
-CH2CH3
-(CH2)2CH3
-CH(CH3)2
-CH(CH3)CH2C6H5
-CH2CH3
-(CH2)2CH3
-(CH2)2CH3
-CH(CH3)2
-CH2CH=CH2
-(CH2)2CH3
-CH2CH2CH2CH2-
-CH2CH=CHCH2-
-CH2CH2CH2CH2CH2-
-CH2CH2OCH2CH2-
-CH2CH3
-CH(CH2CH3)CH2OH
-COCH3
-CH2CH2CH2CH2-
-H
-H
-H
-H
-H*
-H
-H*
-H*
-H
-H*
-H
-H
-H*
-H
-H*
-CH3
-CH3
-CH3
-CH3
-CH3*
-CH2CH3
-CH2CH3
-(CH2)2CH3
-CH(CH3)2
-CH2CH=CH2
-(CH2)3CH3
-H
-H*
-CH2CH3
LA-111
LAE-32
Ergonovine
Methergine
DAM-57
LAMP
LSD-25
DAL
LPD-824
LSM-775
MLA-74
UML-491
APA-10
MPD75
In the amides marked with "*" there has been the introduction of a
new asymmetric center, which of course doubles the number of isomers that is
possible. In each case the resulting two optical forms were prepared separately,
and evaluated separately as to their pharmacology.
This listing is not intended to be thorough, but it is shown to suggest the
amount of synthetic effort that has been made towards the exploring and understanding
the high potency associated with those two remarkably important ethyl groups
on the amide nitrogen of LSD. I have given the Sandoz code names, again, as
far as I know them. Although none of these really warrant a dedicated recipe,
there is sufficient animal and human pharmacology reported to justify listing
them below as separate items. Most of these reports appeared in the mid-1950's
but some studies are still being done and papers are published even today with
new ideas but, sadly, only with animal pharmacology. I have been as guilty as
the next person who has tried to mount all these compounds into a table with
a "human potency" factor that compares them directly to LSD. This
is an uncomfortable simplification. Here are the actual reported observations,
and I'll let the reader provide his own potency index.
LA-111, ergine, d-lysergamide.This is an active compound and has been established
as a major component in morning glory seeds. It was assayed for human activity,
by Albert Hofmann in self-trials back in 1947, well before this was known to
be a natural compound. An i.m. administration of a 500 microgram dose led to
a tired, dreamy state with an inability to maintain clear thoughts. After a
short period of sleep, the effects were gone and normal baseline was recovered
within five hours. Other observers have confirmed this clouding of consciousness
leading to sleep. The epimer, inverted at C-8, is isoergine or d-isolysergamide,
and is also a component of morning glory seeds. Hofmann tried a 2 milligram
dose of this amide, and as with ergine, he experienced nothing but tiredness,
apathy, and a feeling of emptiness. Both compounds are probably correctly dismissed
as not being a contributor to the action of these seeds. It is important to
note that ergine, as well as lysergic acid itself, is listed as a Schedule III
drug in the Controlled Substances Act, as a depressant. This is, in all probability,
a stratagem to control them as logical precursors to LSD.
LAE-32, N-ethyllysergamide.Different people have observed and reported different
effects, with different routes of administration. Subcutaneous administrations
of from 500 to 750 micrograms have been said to produce a state of apathy and
sedation. Clinical studies with dosages of 500 micrograms i.m. were felt to
be less effective than the control use of 100 micrograms of LSD. And yet, oral
doses of twice this amount, 1.6 milligrams, have been said to produce a short-lived
LSD-like effect with none of these negatives.
LPD-824, N-Pyrrolidyllysergamide.Five trials at a dosage of 800 micrograms orally
led to the reporting of a fleeting effect that was similar to one tenth this
amount of LSD.
LSM-775, N-Morpholinyllysergamide.There are conflicting reports; one states
that 75 micrograms is an effective dose, comparable to a similar dose of LSD,
and the other stated that between 350 and 700 micrograms was needed to elicit
this response, and that there were fewer signs of cardiovascular stimulation
and peripheral toxicity.
DAM-57, N,N-Dimethyllysergamide.This compound did induce autonomic disturbances
at oral levels of some ten times the dosage required for LSD, presumably in
the high hundreds of micrograms. There is some disagreement as to whether there
were psychic changes observed.
DAL, N,N-Diallyllysergamide.As the tartrate salt, there is at best a touch of
sparkle seen at 600 micrograms orally, but there is a sedation also reported.
It is certainly an order of magnitude less potent than LSD itself.
UML-491, Methysergide, Sansert.This is the synthetic homologue of methergine
(1-methyl) and is employed clinically as a treatment for migraine headaches.
When the usual therapeutic dosage of two milligrams is scaled up by a factor
of ten, there is a profound LSD-like response described by most subjects. A
number of these ergot analogues from nature can be considered as potential precursors
for the preparation of LSD. But here, there is a 1-methyl group that is effectively
permanently attached, so it cannot play this role.
The third location of structural modification of the LSD molecule has been at the 6-position in ring D. This is the LAD series with any of several alkyl groups attached to the nitrogen atom. The methyl group is found with LSD itself, and is reason for using METH-LAD in the title as a synonym. The ethyl, allyl and propyl substitutions provide ETH-LAD, AL-LAD, and PRO-LAD, and each of these commands a separate entry.
The most frequently encountered precursor for the manufacture
of LSD is ergotamine, a major alkaloid of the ergot world. It is totally unknown
in the morning glories. The usual commercial form is the tartrate salt, and
is often referred to under the code abbreviation of ET, for ergotamine tartrate.
It has found medical use in the treatment of migraine headaches, and as an oxytocic
(an agent that is used in childbirth to stimulate uterine contractions. Care
with the ET terminology must be taken, in that in the drug world it has two
additional associations; a-ET for alpha-ethyltryptamine and NET for N-monoethyltryptamine.
Ergonovine is a naturally occurring, water-soluble ergot alkaloid, found in
both ergot preparations and in many species of morning glory seeds, and there
are several reports of LSD-like action at oral levels of between two and ten
milligrams. It has an important use in obstetrics, again as an oxytocic, at
about a tenth of this dose. This pharmacological potential must be respected
in psychopharmacological trials. The one-carbon homologue (the butanolamide
rather than the propanolamide) is called methergine or methylergonovine. It
is a synthetic ally and is orally effective as an oxytocic at a dosage of 200
micrograms. It also has an LSD-like action at ten times this level.
Although there are many other chemical treasures in the ergot fungal world,
I would like to wrap this commentary up with a return to the topic of morning
glory seeds. Four additional alkaloids of the ergot world must be acknowledged
as being potentially participating factors in the MGS story. With each of these,
the primary ergoline ring system is largely intact but the amide function is
completely gone. The carboxyl group has been reduced to the alcohol to give
elymoclavine. There is the related molecule present which is the isomer with
the double bond moved to be conjugated with the aromatic ring; it is called
lysergol. There is the same molecule but with a hydroxy group attached to the
8-position carbon atom (an ethyleneglycol!) ; it is called penniclavine. And
lastly, that D-ring can actually be opened between the 5 and 6 positions, to
give us a secondary amine tryptamine derivative, chanoclavine. To be completely
anally retentive in this Ipomoea inventory, mention must be made of five alkaloids
that are present in truly trace amounts, all of which have no oxygen atoms present
whatsoever on that substitution on the ergoline 8-position. These are the 8-methyl
isomers agroclavine, setoclavine, festuclavine and cycloclavine, and the methylene
analogue lysergene. Thesestructures in effect define absolute obscurity, and
most probably do not contribute to the morning glory intoxication state. But
the others, some present is sizable amounts, may someday help explain why the
pharmacology of these seeds is so different than that of the major isolates,
the ergines.
MDMA; 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 don't 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--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 I'd 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 shouldn't have done that, oh yes, I shouldn't have done that, oh no, I shouldn't 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 "R" 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 "R" 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 "R" 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 "S" 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 "S" 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 "S" 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 "S" 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 "R" 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.
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, beta-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 beta-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 beta-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 beta-D.
DOSAGE: 200-400 mg (as the sulfate salt), 178-356 mg (as the hydrochloride salt) [Erowid Note: The original text read "178-256" but this was an error. The error was found by Bo and verified with Shulgin. See the Erowid Mescaline Dosage page for a more complete discussion of the forms of mescaline].
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, wasn't. 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--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--to commit an overt harmful or painful act on anyone or anything is beyond one's capabilities. One cannot pluck a flower--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 "qualitative comments" are given as if measured as the sulfate, although the actual form used was usually the hydrochloride salt. The conversion factor is given under "dosage" 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 "twice the potency of mescaline" or "twice as long-lived as mescaline." This simple drug is truly the central prototype against which everything else is measured. The earliest studies with the "psychotomimetic amphetamines" had quantitative psychological numbers attached that read as "mescaline units." 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 "dosage," but a full page given to "qualitative 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.
The basic formula for cocaine starts by purchasing or making tropinone, converting the tropinone into 2-carbomethoxytropinone (also known as methyl-tropan-3-one-2-carboxylate), reducing this to ecgonine, and changing that to cocaine. Sounds easy? It really is not very simple, but with Reagan's new drug policies, cracking down on all of the drug smuggling at the borders, this synthetic cocaine may be the source of the future. This synthesis is certainly worth performing with the high prices that cocaine is now commanding. As usual, I will start with the precursors and intermediates leading up to the product.
Succindialdehyde. This can be purchased, too. 23.2 g of succinaldoxime powder in 410 ml of 1 N sulfuric acid and add dropwise with stirring at 0! a solution of 27.6 g of sodium nitrite in 250 ml of water over 3 hours. After the addition, stir and let the mixture rise to room temp for about 2 hours, taking care not to let outside air into the reaction. Stir in 5 g of Ba carbonate and filter. Extract the filtrate with ether and dry, evaporate in vacuo to get the succindialdehyde. This was taken from JOC, 22, 1390 (1957). To make succinaldoxime, see JOC, 21, 644 (1956).
Complete Synthesis of Succindialdehyde. JACS, 68, 1608 (1946). In a 2 liter 3 necked flask equipped with a stirrer, reflux condenser, and an addition funnel, is mixed 1 liter of ethanol, 67 g of freshly distilled pyrrole, and 141 g of hydroxylamine hydrochloride. Heat to reflux until dissolved, add 106 g of anhydrous sodium carbonate in small portions as fast as reaction will allow. Reflux for 24 hours and filter the mixture. Evaporate the filtrate to dryness under vacuo. Take up the residue in the minimum amount of boiling water, decolorize with carbon, filter and allow to recrystallize in refrigerator. Filter to get product and concentrate to get additional crop. Yield of succinaldoxime powder is a little over 40 g, mp is 171-172!.
5.8 g of the above powder is placed in a beaker of 250 ml capacity and 54 ml of 10% sulfuric acid is added. Cool to 0! and add in small portions of 7 g of sodium nitrite (if you add the nitrite too fast, nitrogen dioxide fumes will evolve). After the dioxime is completely dissolved, allow the solution to warm to 20! and effervescence to go to completion. Neutralize the yellow solution to litmus by adding small portions of barium carbonate. Filter off the barium sulfate that precipitates. The filtrate is 90% pure succindialdehyde and is not purified further for the reaction to create tropinone. Do this procedure 3 more times to get the proper amount for the next step, or multiply the amounts given by four and proceed as described above.
Take the total amount of succinaldehyde (obtained from 4 of the above syntheses combined) and without further treatment or purification (this had better be 15.5 g of succindialdehyde) put into an Erlenmeyer flask of 4-5 liters capacity. Add 21.6 g of methylamine hydrochloride, 46.7 g of acetonedicarboxylic acid, and enough water to make a total volume of 2 liters. Adjust the pH to 8-10 by slowly adding a saturated solution of disodium phosphate. The condensate of this reaction (allow to set for about 6 days) is extracted with ether, the ethereal solution is dried over sodium sulphate and distilled, the product coming over at 113! at 25 mm of pressure is collected. Upon cooling, 14 g of tropinone crystallizes in the pure state. Tropinone can also be obtained by oxidation of tropine with potassium dichromate, but I could not find the specifics for this operation.
2-Carbomethoxytropinone. A mixture of 1.35 g of sodium methoxide (this is sodium in a minimum amount of methanol), 3.5 g of tropinone, 4 ml of dimethylcarbonate and 10 ml of toluene is refluxed for 30 min. Coo] to 0! and add 15 ml of water that contains 2.5 g of ammonium chloride. Extract the solution after shaking with four 50 ml portions of chloroform, dry, evaporate the chloroform in vacuo. Dissolve the oil residue in 100 ml of ether, wash twice with a mixture of 6 ml of saturated potassium carbonate and three ml of 3 N KOH. Dry and evaporate in vacuo to recover the unreacted tropinone. Take up the oil in a solution of aqueous ammonium chloride and extract with chloroform, dry, and evaporate in vacuo to get an oil. The oil is dissolved in hot acetone, cool, and scratch inside of flask with glass rod to precipitate 2- carbomethoxytropinone. Recrystallize 16 g of this product in 30 ml of hot methyl acetate and add 4 ml of cold water and 4 ml of acetone. Put in freezer for 2l/2 to 3 hours. Filter and wash the precipitate with cold methyl acetate to get pure product.
Methylecgonine. 0.4 mole of tropinone is suspended in 80 ml of ethanol in a Parr hydrogenation flask (or something that can take 100 psi and not react with the reaction, like stainless steel or glass). 10 g of Raney Nickle is added with good agitation (stirring or shaking) followed by 2- 3 ml of 20% NaOH solution. Seal vessel, introduce 50 psi of hydrogen atmosphere (after flushing vessel with hydrogen) and heat to 40-50!. After no more uptake of hydrogen (pressure gauge will hold steady after dropping to its lowest point) bleed off pressure and filter the nickle off, rinse out bottle with chloroform and use this rinse to rinse off the nickle while still on the filter paper. Make the filtrate basic with KOH after cooling to 10!. Extract with chloroform dry, and evaporate the chloroform in vacuo to get an oil. Mix the oil plus any precipitate with an equal volume of dry ether and filter. Add more dry ether to the filtrate until no more precipitate forms, filter and add to the rest of the precipitate. Recrystallize from isopropanol to get pure methylecgonine. Test for activity. If active, skip down to the step for cocaine. If not active, proceed as follows. Stir with activated carbon for 30 min, filter, evaporate in vacuo, dissolve the brown liquid in methanol, and neutralize with 10% HCI acid in dry ether. Evaporate the ether until the two layers disappear, and allow to stand for 2 hours at 0! to precipitate the title product. There are many ways to reduce 2-carbomethoxytropinone to methylecgonine. I chose to design a Raney Nickle reduction because it is cheap and not as suspicious as LAH and it is much easier than zinc or sodium amalgams.
Cocaine. 4.15 g of methylecgonine and 5.7 g of benzoic anhydride in 150 ml of dry benzene are gently refluxed for 4 hours taking precaution against H20 in the air (drying tube). Cool in an ice bath, acidify carefully with hydrochloric acid, dry, and evaporate in a vacuum to get a red oil which is treated with a little portion of isopropanoi to precipitate cocaine.
As you can see, this is quite a chore. The coca leaves give ecgonine, which as you can see, is only a Jump away from cocaine. If you can get egconine, then dissolve 8l/2 g of it in 100 ml of ethanol and pass (bubble) dry HC1 gas through this solution for 30 min. Let cool to room temp and let stand for another 11/2 hours. Gently reflux for 30 min and evaporate in vacuo. Basify the residue oil with NaOH and filter to get 8.4 g of methylecgonine, which is converted to cocaine as in the cocaine step above.
Below is given a somewhat easier method of producing tropinone by the general methods of Willstatter, who was instrumental in the first synthetic production of cocaine and several other alkaloids. After reviewing this method, I found it to be simpler than the above in many respects.
Tropinone. 10 g of pyrrolidinediethyl diacetate are heated with 10 g of cymene and 2 g of sodium powder, the reaction taking place at about 160!. During the reaction (which is complete in about 10 min) the temp should not exceed 172!. The resulting reaction product is dissolved in water, then saturated with potassium carbonate, and the oil, which separates, is boiled with dilute sulfuric acid. 2.9 g of tropinone picrate forms and is filtered.
Here are two more formulas devised by Willstatter that produce tropinone from tropine. Take note of the yield differences.
Tropinone. To a solution of 25 g tropine, dissolved in 10 times its weight of 20% sulfuric acid are added 25 g of a 4% solution of potassium permanganate in 2 or 3 g portions over 45 min while keeping the temp at 10-12!. The addition of permanganate will cause heat (keep the temp 10-12!) and precipitation of manganese dioxide. The reaction mixture is complete in I hour. A large excess of NaOH is added and the reaction is steam distilled until I liter of distillate has been collected. The tropinone is isolated as the dibenzal compound by mixing the distillate with 40 g of benzaldehyde in 500 cc of alcohol and 40 g of 10% sodium hydroxide solution. Let stand several days to get dibenzaltropinone as yellow needles. Yield: 15.5 g, 28%. Recrystallize from ethanol to purify.
Tropinone. A solution of 12 g of chromic acid in the same amount of water (12 g) and 60 g of glacial acetic acid is added dropwise with stirring over a period of 4 hours to a solution of 25 g of tropine in 500 cc of glacial acetic acid that has been warmed to 60-70! and is maintained at this temp during the addition. Heat the mixture for a short time on a steam bath until all the chromic acid has disappeared, cool and make strongly alkaline with NaOH. Extract with six 500 cc portions of ether and evaporate the ether in vacuo to get an oil that crystallizes readily. Purify by converting to the picrate or fractionally distill, collecting the fraction at 224-225! at 714 mm vacuo.
The tropinones can be used in the above formula (or in a formula that you have found elsewhere) to be converted to cocaine. Remember to recrystallize the 2-carbomethoxytropinone before converting to methylecgonine.
I. The Poppy
Illicit cultivation of the opium poppy (Papaver somniferum) has traditionally been an Asian business. More recently, production has spread to the highlands of the tropical regions of the Western Hemisphere, primarily Mexico and Colombia. The worldwide illicit opium harvest in 1995 was estimated at 4,157 metric tons, the majority accounted for by the estimated 2,561 tons produced in Southeast Asia (primarily Myanmar (Burma), with significant crops also in Laos, Thailand, China, Vietnam, and Cambodia) (1). Following Southeast Asia is Southwest Asia, primarily Afghanistan (with smaller amounts growing in Pakistan, Turkey, Iran, India, Lebanon and Khirgistan), these two regions accounting for the vast majority of opium destined for conversion to illicit heroin. Colombia was estimated to have produced 65.5 tons of opium in 1996 (2), while Mexico was estimated to have grown 53 tons in 1995 (3). Heroin originating from these Western Hemisphere sources is destined almost exclusively for the United States, while Southeast Asian product enjoys worldwide distribution. Heroin of Southwest Asian origin is mostly exported to Europe or consumed locally.
P. somniferum is an annual, flowering plant, believed to have evolved, through centuries of breeding and cultivation, from a wild-growing ancestor native to the northeastern Mediterranean coast (4). It grows best in dry, temperate climates, usually at altitudes of over 800 meters (2500 ft) above sea-level. The optimal growing season is from September to July depending on the regional climate. In Southeast Asia, planting is completed by late October, in order to take advantage of the long days of the Southern Hemisphere winter. Growing plots are selected for maximum sun exposure on slopes of gradients of 20 to 40 degrees for optimal drainage. (Excessive moisture is damaging to the plant). About one pound of seed is needed to sow one acre of land. By November, when the young plant enters the cabbage or lettuce stage and has reached a height of about one foot, some of the plants are removed in order to leave room for the others to grow (about 1 to 2 feet between plants). A typical opium poppy field has 60,000 to 120,000 plants per hectare (2.46 acres) (5). The mature plant reaches a height of about 2-5 feet by late winter, beginning to flower after about 90 days of growth, 3 to 8 flowers per plant. Flowering continues for several weeks, reaching full bloom by early spring (or later, depending on the region; later development is typical in more western regions (4)). After full bloom, the petals drop to reveal a small, round grayish-green fruit which continues to develop into an oblate, elongated or globular capsule ( also called the seedpod, bulb or poppy head) about the size of a chicken egg. The skin of the pod encloses the ovary, the walls of which secrete the latex (opium) which collects in a network of vessels and tubes throughout the pod.
About two weeks after the petals have fallen, the pods are fully mature, as indicated by the aforementioned shape of the capsule, a change in color from grayish-green to dark green; the points of the pods crown now stand straight out or are curved upward. At this point the pods are ready to be scored (or tapped, incised or lanced). Harvesters make the incision with a a three- or four- bladed instrument (iron or glass blades bound tightly on a wooden handle), designed to make an incision of about one millimeter deep. (Too deep an incision may result in excessive spilling either into the center of the pod or to the ground; too shallow and the latex will not ooze as desired). The pods are scored two to three times each in the afternoon, causing the white latex to drip onto the surface of the pod. The opium oxidizes, darkens, and thickens overnight, and in the morning is scraped from the surface with a flat iron blade. This process is repeated over several days until each pod is depleted of its opium. Each pod may yield from 10 to 100 milligrams of opium, with an average of 80 milligrams, which is set aside in a container to dry in the sun. (Pods giving highest yields are marked, cut from the plant, cut open and dried in the sun, their seeds saved for the next planting). Dried, raw opium is brown to black in color; higher-quality product is brown and sticky. A typical farm will produce 3 to 9 kilograms of opium per acre (5).
II. Opium: Some vital statistics
Over 40 different alkaloids have been identified as present in opium (4,6), mostly as salts of meconic acid (4). The most important of these, of course, is morphine. Although Turkish opium (Druggists Opium) may contain up to 21% morphine (4), the average morphine content of opium tapped from P. somniferum is 9 to 14% by mass. Next most prominent is codeine (3-methoxymorphine) which constitutes 0.5 to 2.5% of the dried latex. Noscapine, comprising 4 to 8% of opium, has been used as an over-the-counter, non-psychoactive cough suppressant (6). Papaverine, present at 0.5 to 2.5%, is sold as a digestive antispasmodic. Thebaine, 0.5 to 2%, is a convulsant in high doses; it is also similar in structure to morphine is used in the licit manufacture of semisynthetic opiates such as hydrocodone and oxycodone. (Other species of poppy, notably _Papaver bracteatum_ , contain higher concentrations of thebaine and are cultivated for the extraction of this alkaloid (7)). Other alkaloids include narceine, protopine, laudanine (laudanosine), codamine, cryptopine, lanthopine, and others.
Ideally, the above alkaloids should be removed in the purification of opium for conversion to heroin. However, clandestine chemistry is rarely ideal, and some of these alkaloids are often not removed, remaining as imupurities of origin. The most notable impurity of origin results from the failure to remove codeine. The manufacture of heroin, discussed in detail below, involves the acetylation of morphine to form 3,6-diacetylmorphine. Acetylated codeine (acetylcodeine) often constitutes 10% of the narcotic content of street heroin, sometimes up to 45% of this quantity (6). Acetylcodeine is a key marker used in signature analysis of heroin, as the heroin-to-acetylmorphine ratio of seized batches has been found to vary among source countries (6,8-11). Also, acetylcodeine has been found to be two times as toxic as diacetylmorphine (heroin) in mice (6), and hence it may contribute to street heroins toxicity. Unreacted morphine and codeine are also present in some poorly processed heroin, which may bring about adverse reactions in users, especially when the drug is injected intravenously. The non-phenanthrene alkaloids (i.e, all alkaloids except morphine, codeine, and thebaine) are more rarely found, probably decomposed in the acetylation process (6). Noscapine, papaverine, laudanosine and/or cryptopine are occasionally present but in such small amounts that although toxic at higher doses, they are not thought to contribute to the pharmacological effects of street heroin. Thebaineis decomposed by acetylation, and although the decomposed product, acetylthebaol, is sometimes present, it is not thought to have any harmful effect.
III. Heroin manufacture
The complete conversion of raw opium to pure heroin hydrochloride (diacetylmorphine HCl) may be summarized as follows:
After step 4, diluents and adulterants may be added either by the manufacturer or by parties further along the distribution chain. Also, shortcuts may be taken at steps 2, 3 and 4, and steps 2 and 4 may be eliminated altogether. The process delineated in this section is that observed in Southeast Asia (5), designed to result in nearly pure diacetylmorphine HCl. A brief discussion of how the aforementioned shortcuts bear on the properties of heroin originating from other regions and comments on diluents and adulterants commonly found in seized samples will follow.
1.) Purification of opium.
Raw opium collected from the poppy as described above is placed in an open cooking pot of boiling water. This should dissolve all of the alkaloids in the opium, while solid plant material, soil, twigs, etc. remain undissolved and float to the top of the solution. Solid impurities are scooped out or filtered by straining the mixture though cheesecloth or burlap. The liquid is then re-heated over a low flame, evaporating the water to leave behind a thick, dark paste, which is then dried in the sun. The opium left behind has a putty-like consistency and is generally about 20% lighter (20% more pure) than the raw material. At this point the product may be exported for smoking or eating or consumed locally. This process may be carried out by farmers before shipping for consumption or further processing, or the raw opium may be transported to heroin manufacturing sites where the preparation is undertaken on a larger scale.
2.) Extraction of morphine.
Processed opium is stirred in large drum of boiling water until it has completely dissolved. Slaked lime (calium hydroxide), at about one-fifth the mass of opium (8), (or a fertilzer with a high lime content) is added to the solution. This has the effect of converting morphine, insoluble in cool water, into the soluble salt, calcium morphenate. For the most part, the other alkaloids do not react, and when the mixture is cooled, the morphenate remains in solution, while the other chemicals settle to form a brown sludge at the bottom of the container. (Codeine is somewhat soluble in water and some amount is likely to remain in solution). The calcium morphenate solution is scooped or poured from the drum and filtered and pressed through burlap rice sacks or some other makeshift filtration apparatus. The filtered solution is re-heated, but not boiled, in cooking pots to which ammonium chloride is added at about one-fourth the mass of opium processed (8). After the pH of the solution reaches 8 or 9 it is cooled. Within a few hours, morphine base and any remaining codeine precipitate out of solution and settle to the bottom of the pot. The solution is then poured off through cloth filters, leaving chunks of morphine base on the cloth, which are squeezed dry and set aside to dry further in the sun. The dried crude morphine base is a coffee-colored powder. (A more scrupulous chemist might use ether in the filtration to dissolve any residual codeine out of the base mixture, but this is not reported in accounts of illicit manufacture).
From this point, some manufacturers may proceed directly to step 3. Ideally, however, the crude morphine base is purified by dissolution in dilute hydrochloric (or sufuric) acid, forming a solution of morphine hydrochloride (or sulfate). Activated charcoal is added, and the solution is heated and filtered hot through a fine cloth. The filtration is repeated several times, removing the charcoal and colored impurities with it. The filtrate may be dried in the sun to leave behind morphine hydrochloride, a fine white powder if purification is complete, which may be pressed into 1 kg bricks and transferred for further processing at a remote site. Alternatively, ammonium hydroxide may be added to the morphine HCl solution (or re-dissolved morphine HCl), precipitating morphine base, filtered and dried to form a granular solid (8).
3.) Conversion of morphine to heroin base.
The key chemical used in the acetylation of morphine to form heroin is acetic anhydride, a colorless, highly combustible liquid with a strong pickle-like odor. Though internationally controlled as a heroin precursor, acetic anhydride also used to synthesize aspirin and chemicals for leather tanning and photography. Morphine hydrochloride or morphine base is mixed with acetic anhydride at about three-times the mass of the former in a stainless steel or enamel pot. The pot lid is tied or clamped on with a damp towel for a gasket (a makeshift reflux apparatus), and the mixture is heated at 85 degrees Celsius (185 degrees F), avoiding boiling. The cooking proceeds for about 5 hours until all the morphine has dissolved. The pot is opened, and the mixture -- now a solution of water, acetic acid, and diacetylmorphine (heroin) -- is allowed to cool. Water is added to the mixture at three-times the volume of acetic anhydride, and the mixture is stirred. (Optionally, a small amount of chloroform is added. The mixture is allowed to stand for 20 minutes. The chloroform dissolves colored impurities and settles to the bottom of the pot as a red, greasy liquid, and the water layer is carefully poured off.) Activated charcoal is added to the mixture, absorbing solid impurities, which are filtered out repeatedly until the solution is clear. Approximately 2.2 kilograms of sodium carbonate (soda ash) per kilogram of morphine are dissolved in hot water and added solwly to the mixture until effervescence stops, precipitating solid heroin base. Heroin base is filtered with a fine cloth, set aside and heated until dry. The heroin base should be a granular, white powder at this point. If still colored (beige or light brown), the base may be re-dissolved in dilute hydrochloric or citric acid (8), treated with charcoal again, re-precipitated and dried. Alternatively, in some manufacturing regions, the incompletely purified base may be packed and transported for sale (a practice probably typical in Southwest Asia). About 700 grams of heroin base will be produced from each kilogram of morphine.
Optionally, skilled heroin chemists may further purify the base by dissolving it in twice its mass of boiling ethyl alcohol, filtering the solution through a heated funnel into a heated flask. This removes traces of sodium carbonate remaining in the base. The flask is submerged in an ice bath, where it is transformed into a thick white cream. The substance is placed in a pan in a refrigerator with a fan set to blow across the pan to slowly evaporate the alcohol . The paste crystallizes after several hours and is then vacuum filtered. The product, referred to as alcohol morphine base, is re-crystallized heroin base.
4.) Conversion of heroin base to heroin hydrochloride.
For each kilogram of heroin base (or re-crystallized heroin base), 6.6 liters of of ethyl alcohol, 6.6 liters of ether, and 225 milliliters of concentrated hydrochloric acid are measured out. The base is dissolved by heating with one-third of the alcohol and one half of the acid. Another one-third of the acid is stirred in. Next, the remaining acid is added slowly, dropwise, until the product is completely converted to the hydrochloride salt. This result may be confirmed either by observing that a drop of solution evaporates on a glass plate leaving no cloudy residue or by placing a drop of solution on Congo red paper, observing it turn the paper blue. Once the conversion is complete, the remaining alcohol is stirred in. Then half of the ether is added, and the mixture is allowed to stand for 15 minutes. As soon as crystals begin to form in the solution, the remaining ether is added at once, stirred, and the the vessel is covered. The mixture becomes nearly solid after an hour. It is then filtered, and the solids are collected on clean filter paper. Wrapped in the paper, the solid is dried on a wooden tray, usually over lime rock, and dried in the sun. The fully dried product, heroin hydrochloride, is a fine white powder, ready for packing and shipping.