SYNTHESIS: (from indole) To a well stirred solution of 10 g
indole in 150 mL anhydrous Et2O there was added, dropwise over the
course of 30 min, a solution of 11 g oxalyl chloride in 150 mL
anhydrous Et2O. Stirring was continued for an additional 15 min during
which time there was the separation of indol-3-ylglyoxyl
chloride. This intermediate was removed by filtration and used
directly in the following step. This was added to 20 mL anhydrous
diethylamine. There was then added an excess of 2N HCl, the mixture
cooled, and the resulting solids removed by filtration. These were
recrystallized from MeOH to give, after air drying, 19.4 g indol-3-yl
N,N-diethylglyoxylamide with a mp of 175-177 °C.
A solution of 19 g indol-3-yl N,N-diethylglyoxylamide in 350 mL
anhydrous dioxane was added, slowly, to 19 g LAH in 350 mL dioxane
which was well stirred and held at reflux temperature under an inert
atmosphere. After the addition was complete, reflux was maintained for
an additional 16 h, the reaction mixture cooled, and the excess
hydride destroyed by the cautious addition of wet dioxane. The formed
solids were removed by filtration, washed with hot dioxane, the
filtrate and washings combined, dried over anhydrous MgSO4, and the
solvent removed under vacuum. The residue was dissolved in anhydrous
Et2O and saturated with anhydrous hydrogen chloride. There were formed
crystals which were recrystallized from benzene/methanol to give a
yield of 14.7 g (75%) of N,N-diethyltryptamine hydrochloride (DET)
with mp of 170-171 °C.
(from tryptamine) To a solution of 1.6 g tryptamine base in 20 mL
isopropanol, there was added 5.5 mL diisopropylethylamine and 2.3 mL
ethyl bromide. After stirring at room temperature for 36 h the
volatiles were removed under vacuum on the rotary evaporator and the
light brown residue (5.17 g) was treated with 5 mL of acetic anhydride
and heated in the steam bath for 5 min. After coming to room
temperature, 3.5 mL ammonium hydroxide was added, and the exothermic
reaction was allowed to return to room temperature. The reaction
mixture was suspended in 150 mL 0.5 N H2SO4, and washed with 3x40 mL
CH2Cl2. The pooled washes were again extracted with 150 mL 0.5 N H2SO4
and the aqueous phases again washed with CH2Cl2. The aqueous phases
were combined, made basic with 6 N NaOH, and then extracted with 3x40
mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum,
and the residue (1.49 g of a dark oil with a sharp smell) was
distilled at the KugelRohr. The product, N,N-diethyltryptamine,
distilled at 175-185 °C at 0.05 mm/Hg to yield a white oil weighing
1.02 g, which spontaneously crystallized. This product was dissolved
in 20 mL boiling hexane, cooled to room temperature, and seeded. There
was thus obtained 0.72 g of a white waxy crystalline material melting
at 84-87 °C. IR (in cm-1): 741, 804, 970, 1018, 1067, 1090 and
1120. MS (in m/z): C5H12N+ 86 (100%); indolemethylene+ 130 (6%);
parent ion 206 (1%). The hydrochloride salt (crystallizing
spontaneously from an IPA solution of the base treated with a few
drops of concentrated HCl) had a mp 169-171 °C, and the following
fingerprint: IR (in cm-1): 717 (br.), 759, 847, 968, 1017, 1110. This
salt appears to be unstable, darkening with time.
DOSAGE : 50-100 mg, orally
DURATION : 2 - 4 hrs
QUALITATIVE COMMENTS : (with 44 mg, orally) "I was in a public
place, and might have had to interact with someone at any moment,
which probably accounted for a grim paranoia and wish to retreat. I
had my full effect in just over an hour, with almost no visual or
physical properties, but a crashing fear of interacting. I had to
retreat to a private place to read and appear deeply involved, but in
another hour I found it an increasingly easy task to pretend to be
normal. I carried it off, OK. Good sleep, no residues."
(with 75 mg, orally) "Onset seemed to be at 40 minutes, which were
mostly physical symptoms, which seemed to fade away at 1.25 hours. All
in all, an absolutely profound, enriching experience with both Brahms
(G-minor piano quartet) and Verdi (requiem) contributing mightily. All
over in 3.5 - 4.5 hours and a delightful afterglow."
(with 150 mg, orally) "There was a slow onset. It was more than an
hour before something started, which I didn't believe at first but
which became completely undeniable. I was heading toward an
appointment, and walked right past the meeting place. I was unable to
concentrate on just where I was and where I was hoping to go. With
enormous effort I located my appointment coordinates but the sidewalk
was doing funny things and I again managed to miss my target. I sat
down to try to manage things, but I couldn't."
(with 150 mg, orally) "The effects were manifestly notable in 50-60
minutes, quite intense from hour one to hour three. Then there is an
hour when trailing is still perceptible. By hour five it is all
over. There appeared to be 'vegetative effects' as they used to say. I
definitely noted sweating of hands and feet. There was a hollowness in
the chest. There was an insignificant presser response, but pronounced
tachycardia, with my normal resting pulse in the 60's going up above
100 for a while. I think that 150 milligrams is a little too much."
(with 400 mg, orally) "Too much."
(with 40 mg, smoking) "I have found that ten milligrams of DET is the
size of a match head, so I smoked four of them. The taste of the stuff
is terrible -- it smells like burning plastic -- but I don't care. The
onset was gentle, in about five minutes, euphoric and empathogenic,
and there was an immediate camaraderie with the group I was with (they
were using between twenty and forty milligrams apiece). I found myself
stroking a calico cat, and asked a friend, 'Do people purr?' and was
told, 'Sure, if you know how to listen.' We began scratching one
anothers backs, and made vaguely purring noises."
(with 90 mg, smoking) "This was with 3x30 milligrams, at ten minute
intervals. It took almost too much concentration for the last
toke. Too stoned. Some emotional insights, but I can't remember them
to write them. Fine muscular tremor. Some hangover the next day,
lassitude, fine edge of thought was blunted."
(with 40 mg, subcutaneously) "There was a slight burning and a
numbness of both the hands and feet some twenty minutes. A few minutes
later I felt an alcohol-like intoxication and a slight drifting of
thoughts. Music was slightly enhanced and eyes-closed patterning was
noted, with a predominance of greens and oranges. No music, no
patterns. The effects peaked at 30 minutes, but the numbness I felt
lasted up to three hours. Overall, this was somewhat disappointing."
(with 60 mg, intramuscularly) "The yellow walls with many windows in
them, massing over one another, appeared in increased intensity, had
an air of medieval mood about them. The ornaments, painted white, on
the roof and eaves had a particularly strong decorative effect. A test
subject, without a painter's fantasy, must certainly be greatly
impressed by this depth and colorfulness. I felt as I did when I began
to learn painting, when I tried to look at things consciously with a
painter's eye. I felt that the drug acted on fantasy, in the first
place, increasing its dynamism. On a subject with normal mind, this
experience will certainly have an astonishing and marvelous effect. An
artist with creative mind and fantasy will be less impressed."
(with 60 mg, intramuscularly) "About 15 minutes after the injection
came the same vegetative symptoms seen with DMT. The illusions and
hallucinations were the same. But the alteration of the surrounding
world and the emotional reaction to them were strong and
impressive. The mask-like faces of the persons, the dream-like
mysteriousness of the objects in the room gave me the feeling that I
had arrived in another world, entirely different and queer and full of
secrecy and mystery. The wonderful but strange world attracted me at
one moment, but the next moment I did not want to accept it. I became
perplexed; I did not know what I ought to do. I began to walk
anxiously up and down, and said, 'I ought to do something, I must!'
There was a peculiar double orientation in space and time: I knew
where I was, but I was inclined to accept this strange world as a
reality, too. The dusk of the room was lightened for some minutes, and
again the light was switched off, and that seemed to me as if this
period might be an entire epoch, filled with events and happenings,
but at the same time I knew that only several minutes had passed."
(with 60 mg, intramuscularly) "The vertigo is gone -- now comes the
attraction. I have the honor of seeing the elements of the universe in
this moment. As if I saw algae, flagellates under the microscope, in
black and white. Now I see some colours, too. As if I saw a shell, the
rainbow colours are disintegrating rapidly. One's consciousness
becomes air-like. From the neck upward I am feeling a shapeless
lightness. If we could inoculate this into all men, human
inter-relations would undoubtedly improve greatly."
(with 60 mg, intravenously) "I was looking out of the window. I was
seeing the leaves of a tree, the color of the grass, people walking to
and fro utterly without thinking, like a small child staring at
things. I felt as if I were discovering the world anew."
(with 60 mg, intravenously) "The objects opened up their essence to
me, I was feeling as if I knew them as they really are, I live in them
and was in direct contact with them. I felt an enormous drive to
write, to put down the marvelous feelings. The associations came
spontaneously, but I was unable to concentrate in a way required for
working. Anyway, I did not want to miss one moment of the visions."
EXTENSIONS AND COMMENTARY: I have to bear the responsibility
for much of the mythology that maintains that DET is only active by
some parenteral route. All of the published human studies that
explicitly mentioned dose and dosage, involved intramuscular
administrations. Most of the people with whom I had private
conversations about this material had evaluated it through the smoking
route. It was only recently that I began to hear of oral trials. I had
assumed that it was inactive orally, and ha said so in a number of
reviews that I had published over the years. As they say in Latin, mea
culpa. There was one mention of oral activity that had been made, in
one table written by Steve Szara, in 1969, presented at a meeting that
we both participated in, at Irvine, California. I gave the opening
overview, and deferred tryptamine questions to Steve, later, in his
talk. And in this talk, he presented a Table that referred to DET as
being active at a dose of 60 mg, i.m. or p.o. This is the Latin for
per os, and means that it was orally active, but he had never
mentioned it explicitly to me, and I had never asked. Some 25 years
later, we met again and rehashed old times, and at this meeting I gave
yet another review paper with the parenteral restriction on DET
activity, and he never mentioned anything. And yet, the damned thing
is indeed orally active, and since I have said otherwise in
publications, I accept the responsibility for the error. Apparently
the MAO systems do not chomp up the dialkylamines higher than
methyl. Certainly the dipropyl and the diisopropyl are active by
mouth, and so is the diethyl.
Several clinical studies were conducted in the late 1950's and early
1960's. They employed the oppresive research environment that was
considered scientific at that time, and there were variable
results. One study involved ten physically normal subjects, who were
unemployed men from a depressed mining area. The DET was administered
in i.m. injections and trials were conducted in a partially
soundproofed experimental clinic equipped with a one-way mirror and
microphones. The subjects were subjected to a battery of psychological
tests and body function measurements at frequent intervals. The
consensus expressed was one of dysphoria. Neurological signs varied
from slight generalized tremors to gross athetoid movements. Among the
bizarre somatic complaints were such as: "Air is rushing through my
body," "My chest is empty and there is a jelly ball in my spine," "My
hands aren't there, my whole body feels funny." All subjects
experienced dizziness and increased sweating. Six of the subjects
stated that the experience was an unpleasant one, three of them
markedly so. There was no enthusiasm in the group for a repetition of
the experience, and several stated that they would leave the clinical
center before submitting to it again. A similar study with ten chronic
paranoid schizophrenic patients (in the same setting and with the same
dosage) produced similar effects. Most became pale, shaky, and either
complained of feeling sick or actually vomiting. Several also
developed tremors. In general, these were pretty negative experiences,
and contribute to the negative medical and scientific opinions that
are held concerning these drugs.
Another study was carried out in an entirely different setting, with
professional colleagues, with other professionals and with
artists. These were with personal friends of the research scientists,
rather than strangers to them. The observed mood changes (produced, in
this study, by the i.m. administration of 0.70 to 0.80 mg/Kg of DET)
were described as being in the direction of euphoria; the subjects
generally enjoyed the experience and wished to repeat it. The
volunteered comments under the drug tended towards the mystical and
philosophical, and several of these experimental subjects responded to
music and art in ways that were new to them.
In the earliest research with DET and the related dialkyltryptamines,
the chemistry of metabolism was studied for any clues that could
explain the activity of these materials. It must be remembered that
this was in the heyday of the concept of psychotomimesis, the search
for drugs that would imitate the psychotic state. What an appealing
concept, that there might be a drug that could produce the syndrome of
mental illness and thus be an accepted model for designing some
treatment for it. There was a delicious search made at that time (the
1950's) for names that could be given to these remarkable substances
that would obscure any spiritual or positive aspects, so that one
could present one's findings into the orthodox medical literature. At
that time, I chose to use the name psychotomimetic in the titles of my
publications, because I knew it might deflect criticism from the
medical community for the findings that I described. But such a
variety of names were used as keywords to these studies. In my notes I
find: "delirients," "delusionogenics," "dysleptics,"
"misperceptinogens," "mysticomimetics," "phanerothymes,"
"phantasticants," "pharmakons," "psychosomimetics" (an "s" for the
"t"? why?), "psychotaraxics," "psychoticants," "psychotogens,"
"psychogens," "psychotoxins" and "schizogens." Not a very appealing
collection from which to choose a week-end trip.
In 1956, Humphry Osmond suggested, at a New York Academy of Science
meeting that it might be less pejorative to soften the prefix that was
used to relate to the mind from psychoto- or psycho-(used in medical
diagnoses that are largely negative) to a misspelled but softer
alternative, psyche- (which had not yet been tarred by the image of
medical pathology). His suggestion was "psychedelic," it was aped
in many trials with such creations as "psychephoric" (mind-moving),
"psychehormic" (mind-rousing), "psycheplastic" (mind-molding),
"psychezymic" (mind-fermenting), "psycherhexic" (mind-bursting-forth)
and "psychelytic" (mind-releasing). But, psychedelic
(mind-manifesting) has weathered all storms, and is now a fixed
component of our vocabulary. There are several recent contributions
for possible class names for some of these compounds, such as
entheogen (God-created-within), entactogen (touching-within) or
empathogen (the discovery of empathy), are creations that try to
address the integrity and warmth that can be part of the psychedelic
experience. Each uses the suffix, "-gen," that suggests genesis, or
creation. Each has its use, and each has its limitations. One must
remember that none of these terms describe what occurs within an
experience. Their value is limited to the search for a label for the
drugs that allow these experiences to happen.
Back to the metabolism discussion. And to the search for the actual
drug, the magic bullet, that actually precipitated a model
schizophrenic state. If one were to find it, one could look skillfully
for the counterpart in the human animal, the one that simply appeared
on the scene from some mismanaged metabolic process, and thus could be
blamed for mental illness. It had been observed that the longer the
chains on the N,N-disubstituted tryptamine, the less the potency. And
the longer the chains, the less of the drug was excreted as the
6-hydroxyl metabolite. This focused attention on the hydroxy
metabolites of the two simplest and most potent of the
dialkyltryptamines, DMT and DET.
6-HO-DET has been observed to be a minor human metabolite of DET, with
the excretion of about 20% of the administered dose as the glucoronide
conjugate. In a study with normal and schizophrenic patients, a
positive correlation was observed between the amount of 6-HO-DET
excreted and the intensity of the experience. Also, there was a
suggestion that the schizophrenics produced greater amounts of this
metabolite. This led to a hypothesis that perhaps it was an active
factor in the generation of the intoxicated state. In principle, as
with bufotenine, that bare, exposed polar hydroxyl group should make
its entry to the brain quite difficult. But, on the other hand, if it
were generated there from DET after it had gotten into the brain,
entry would not be a concern and the lipophilic barrier could serve to
make its exit difficult. Then, if it were an effective compound, it
might well be a long acting one. There is an early report of the
self-administration intramuscularly, within a single subject, of 10
milligrasms 6-HO-DET with the description of what appeared to be
DET-like effects from about the second to fourth hour. Although this
report suggested that it was several times more potent than DET, it
has never been replicated and it does not jibe too well with the
6-HO-DMT report below.
As a challenge to the hypothesis that hydroxylation at the 6-position
of the N,N-dialkyltryptamines might play some role in the expression
of the activity, this position was metabolically blocked by the
insertion of a fluorine atom there, giving 6-F-DET. This compound,
with DET as the control, was studied in some twelve hospitalized
alcoholics at doses of about 60, 80 and 100 milligrams
intramuscularly. It "does produce autonomic effects, pupillary
changes, blood pressure changes; but it does not produce the drifting
away into a dream world and other phenomena characteristic for the
hallucinogenic activity." The experimenters considered its possible
experimental role as an "active placebo" but nothing more was done
with it.
6-HO-DMT is a minor metabolite of DMT in man,
and it was studied for the same reasons. Could this compound play a
role in explaining the activity of the parent dialkylamine? It was
explored in a series of subjects who had responded spectacularly to
DMT. The five volunteers in this study were former opium addicts who
were serving sentences for violation of United States narcotics
laws. They were administered 6-HO-DMT at either 0.75 mg/Kg (one
subject) or 1.0 mg/Kg (four subjects) and reported no differences from
the inactive placebo control. The objective measures (blood pressure,
respiration and heart rate, pupillary dilation) confirmed this absence
of activity at this level. The active control drug was DMT itself, and
it showed the expected responses in all regards.
I have always been quite skeptical, and just a little embarrassed,
that so many of these early studies used hospitalized patients,
schizophrenics, alcoholics, and prisoners as subjects. These latter
experiments were carried out at the Lexington, Kentucky Public Health
Service Hospital. This has been for years a major site for human
research in the area of addictive or psychotropic drugs. But it cannot
be forgotten that it was first, and foremost, a prison and the people
there were prisoners. A complete objectivity of reporting, from a
person who is in custody and who might wish to please his jailers, is
unlikely. The whole scene started shortly after the Harrison Narcotics
Act passed back near the time of World War I. The medical profession
held that narcotics addiction was a medical problem, and the legal
authorities held that it was a legal problem. In other words, was a
heroin user sick, or was he a criminal? The law enforcement viewpoint
prevailed, the physicians who objected went to jail, and the addicts
went to what were called "narcotics farms." They were indeed prisons,
but the name carried the suggestion of rehabilitation. And it was at
the last of these, at Lexington, that this hydroxylated DMT study was
done.
The results were negative, to the disappointment of the
researchers. It is pretty generally accepted that 6-HO-DMT is
inactive. I am not too surprised. There are so few things with open
and exposed hydroxyl groups that succeed in making it through the
lipid barriers to the brain.
