SYNTHESIS: This compound has been made industrially by a number of
routes, the motant being the reduction of benzyl cyanide and the
decarboxylation of phenylanaline. It is offered in the catalogs of
all the major chemical supply houses for a few pennies per gram. It
is a very strong base with a fishy smell, and rapidly forms a solid
carbonate salt upon exposure to the air. It is a natural biochemical
in both plants and animals.
DOSAGE: greater than 1600 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 200, 400, 800 and 1600 mg) No effects.
(with 500 mg) No effects.
(with 800 and 1600 mg) No effects.
(with 25 and 50 mg i.v.) RNo effects.
EXTENSIONS AND COMMENTARY: Here is the chemical that is central to
this entire book. This is the structural point of departure for every
compound that is discussed here. It is the RPS in PIHKAL. It is
without activity in man! Certainly not for the lack of trying, as
some of the dosage trials that are tucked away in the literature (as
abstracted in the "Qualitative Comments" given above) are pretty heavy
duty. Actually, I truly doubt that all of the experimenters used
exactly that phrase, "No effects," but it is patently obvious that no
effects were found. It happened to be the phrase I had used in my own
notes.
This, the simplest of all phenethylamines, has always been the darling
of the psychopharmacologists in that it is structurally clean, it is
naturally present in various human fluids and tissues, and because of
its close chemical relationship to amphetamine and to the
neurotransmitters. These facts continuously encourage theories that
involve PEA in mental illness. Its levels in urine may be decreased
in people diagnosed as being depressed. Its levels may be increased
in people diagnosed as being paranoid schizophrenics. Maybe it is
also increased in people under extreme stress. The human trials were
initially an attempt to provoke some psychological change, and indeed
some clinicians have reported intense headaches generated in
depressives following PEA administration. But then, others have seen
nothing. The studies evolved into searches for metabolic difference
that might be of some diagnostic value. And even here, the jury is
still out.
Phenethylamine is found throughout nature, in both plants and animals.
It is the end product of phenylalanine in the putrefaction of tissue.
One of its most popularized occurrences has been as a major component
of chocolate, and it has hit the Sunday Supplements as the
love-sickness chemical. Those falling out of love are compulsive
chocolate eaters, trying to replenish and repair the body's loss of
this compound--or so the myth goes. But this amine is voraciously
metabolized to the apparently inactive compound phenylacetic acid, and
to some tyramine as well. Both of these products are also normal
components in the body. And, as a wry side-comment, phenylacetic acid
is a major precursor in the illicit synthesis of amphetamine and
methamphetamine.
Phenethylamine is intrinsically a stimulant, although it doesn't last
long enough to express this property. In other words, it is rapidly
and completely destroyed in the human body. It is only when a number
of substituent groups are placed here or there on the molecule that
this metabolic fate is avoided and pharmacological activity becomes
apparent.
To a large measure, this book has emphasized the "phenyl" end
of the phenethylamine molecule, and the "what," the "where," and the
"how many" of the substituent groups involved. There is a broad
variety of chemical groups that can be attached to the benzene ring,
at one or more of the five available positions, and in an unending
number of combinations. And, in any given molecule, the greater the
number of substituents on the benzene ring, the greater the likelihood
that there will be psychedelic action rather that stimulant action.
But what can be said about the "ethylamine" end of the
phenethylamine molecule? This is the veritable backbone that holds
everything together, and simple changes here can produce new
prototypes that can serve as starting points for the substituent game
on the benzene ring. Thus, just as there is a "family" of compounds
based on the foundation of phenethylamine itself, there is an equally
varied and rich "families" of other compounds that might be based on
some phenethylamine with a small modification to its backbone.
So, for the moment, leave the aromatic ring alone, and let us
explore simple changes in the ethylamine chain itself. And the
simplest structural unit of change is a single carbon atom, called the
methyl group. Where can it be placed?
The adding of a methyl group adjacent to the amine produces
phenylisopropylamine, or amphetamine. This has been exploited already
as one of the richest families of psychedelic drugs; and over half of
the recipes in Book II are specifically for amphetamine analogues with
various substituents on the aromatic ring. The further methylation of
amphetamine with yet another methyl group, this time on the nitrogen
atom, yields methamphetamine. Here the track record with various
substituents on the aromatic ring is not nearly as good. Many have
been explored and, with one exception, the quality and potency of
human activity is down. But the one exception, the N-methyl analogue
of MDA, proved to be the most remarkable MDMA.
The placement of the methyl group between the two carbons (so to
speak) produces a cyclopropyl system. The simplest example is
2-phenylcyclopropylamine, a drug with the generic name of
tranylcypromine and the trade name Parnate. It is a mono-amine
oxidase inhibitor and has been marketed as an antidepressant, but the
compound is also a mild stimulant causing insomnia, restlessness and
photophobia. Substitutions on the benzene ring of this system have
not been too promising. The DOM analogue,
2,5-dimethoxy-4-methyltranylcypromine is active in man, and is
discussed in its own recipe under DMCPA. The inactive mescaline
analogue TMT is also mentioned there.
The dropping of one carbon from the phenethylamine chain gives a
benzyl amine, basically an inactive nucleus. Two families deserve
mention, however. The phencylidine area, phenylcyclohexylpiperidine
or PCP, is represented by a number of benzyl amines. Ketamine is also
a benzyl amine. These are all analgesics and anesthetics with central
properties far removed from the stimulant area, and are not really
part of this book. There is a benzyl amine that is a pure stimulant,
which has been closely compared to amphetamine in its action This is
benzylpiperazine, a base that is active in the 20 to 100 milligram
range, but which has an acceptability similar to amphetamine. If this
is a valid stimulant, I think that much magic might be found in and
around compounds such as (1) the MDMA analogue,
N-(3,4-methylenedioxybenzyl)piperazine (or its N-methyl-counterpart
N-(3,4-methylenedioxybenzyl)-N'-methylpiperazine) or (2) the DOM
analogue, 2,5-dimethoxy-4-methylbenzylpiperazine. The benzyl amine
that results by the relocation of the amine group of MDA from the
beta-carbon atom to the alpha-carbon atom is known, and is active.
It, and its N-methyl homologue, are described and discussed in the
commentary under MDA. Dropping another carbon atom gives a yet
shorter chain (no carbons at all!) and this is to be found in the
phenylpiperazine analogue 3-trifluoromethylphenylpiperazine. I have
been told that this base is an active hallucinogen as the
dihydrobromide salt at 50 milligrams sublingually, or at 15 milligrams
intravenously in man. The corresponding 3-chloro analogue at 20 to 40
milligrams orally in man or at 8 milligrams intravenously, led to
panic attacks in some 10% of the experimental subjects, but not to any
observed psychedelic or stimulant responses.
What happens if you extend the chain to a third carbon? The parent
system is called the phenyl-(n)-propylamine, and the parent chain
structure, either as the primary amine or as its alpha-methyl
counterpart, represents compounds that are inactive as stimulants.
The DOM-analogues have been made and are, at least in the rabbit
rectal hyperthermia assay, uninteresting. A commercially available
fine chemical known as piperonylacetone has been offered as either of
two materials. One, correctly called 3,4-methylenedioxyphenylacetone
or 3,4-methylenedioxybenzyl methyl ketone, gives rise upon reductive
amination to MDA (using ammonia) or MDMA (using methylamine). This is
an aromatic compound with a three-carbon side-chain and the
amine-nitrogen on the beta-carbon. The other so-called
piperonylacetone is really 3,4-methylenedioxybenzylacetone, an
aromatic compound with a four-carbon side-chain. It produces, on
reductive amination with ammonia or methylamine, the corresponding
alpha-methyl-(n)-propylamines, with a four-carbon side-chain and the
amine-nitrogen on the gamma-carbon. They are completely unexplored in
man and so it is not known whether they are or are not psychedelic.
As possible mis-synthesized products, they may appear quite
unintentionally and must be evaluated as totally new materials. The
gamma-amine analogue of MDA, a methylenedioxy substituted three carbon
side-chain with the amine-nitrogen on the gamma carbon, has indeed
been made and evaluated, and is discussed under MDA. The extension of
the chain of mescaline to three atoms, by the inclusion of an oxygen
atom, has produced two compounds that have also been assayed. They
are mentioned in the recipe for mescaline.
The chain that reaches out to the amine group can be tied back in
again to the ring, with a second chain. There are 2-aminobenzoindanes
which are phenethylamines with a one-carbon link tying the
alpha-position of the chain back to the aromatic ring. And there are
2-aminotetralines which are phenethylamines which have a two-carbon
link tying the alpha-position of the chain back to the aromatic ring.
Both unsubstituted ring systems are known and both are fair
stimulants. Both systems have been modified with the DOM substituent
patterns (called DOM-AI and DOM-AT respectively), but neither of these
has been tried in man. And the analogues with the MDA substitution
pattern are discussed elsewhere in this book.
And there is one more obvious remaining methylation pattern. What
about phenethylamine or amphetamine compounds with two methyl groups
on the nitrogen? The parent amphetamine example,
N,N-dimethylamphetamine, has received much notoriety lately in that it
has become a scheduled drug in the United States. Ephedrine is a
major precursor in the illicit synthesis of methamphetamine, and with
the increased law-enforcement attention being paid to this process,
there has been increasing promotion of the unrestricted homologue,
N-methylephedrine, to the methamphetamine chemist. This starting
material gives rise to N,N-dimethylamphetamine which is a material of
dubious stimulant properties. A number of N,N-dimethylamphetamine
derivatives, with "psychedelic" ring substituents, have been explored
as iodinated brain-flow indicators, and they are explicitly named
within the appropriate recipes. But none of them have shown any
psychedelic action.
This is as good a place as any to discuss two or three simple
compounds, phenethylamines, with only one substituent on the benzene
ring. The 2-carbon analog of 4-MA, is 4-methoxyphenethylamine, or
MPEA. This is a kissing cousin to DMPEA, of such fame in the search
for a urine factor that could be related to schizophrenia. And the
end results of the search for this compound in the urine of mentally
ill patients are as controversial as they were for DMPEA. There has
been no confirmed relationship to the diagnosis. And efforts to see
if it is centrally active were failures--at dosages of up to 400
milligrams in man, there was no activity. The 4-chloro-analogue is
4-chlorophenethylamine (4-Cl-PEA) and it has actually been pushed up
to even higher levels (to 500 milligrams dosage, orally) and it is
also without activity. A passing bit of charming trivia. A
positional isomer of MPEA is 3-methoxyphenethylamine (3-MPEA) and,
although there are no reported human trials with this, it has been
graced with an Edgewood Arsenal code number, vis., EA-1302.
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