Hoffer 1962
Hoffer 1962
By A . Hoffer
I . Introduction . . . . . . . . . . . . . . . . 307
I1. Biochemistry of Adrenochrome . . . . . . . . . . 311
I11. Action of Adrenochrome on Cells . . . . . . . . . .
314
IV . Effect of Adrenochrome on Fish . . . . . . . . . .
315
V. Effect of Adrenochrome on Spiders . . . . . . . . .
316
VI . Effect of Adrenochrome on Pigeons . . . . . . . . .
316
VII . Effect of Adrenochrome on Mammals . . . . . . . . 320
A. Mice . . . . . . . . . . . . . . . . . 320
B.Rats . . . . . . . . . . . . . . . . . 320
C. Rabbits . . . . . . . . . . . . . . . . 324
D . Cats . . . . . . . . . . . . . . . . . 325
E . Dogs . . . . . . . . . . . . . . . . . 333
F. Monkeys . . . . . . . . . . . . . . . . 334
VIII . Effect of Adrenochrome on Electrograms . . . . . . . 335
IX . Effect of Adrenochrome and Adrenolutin on Humans . . . . 337
A. Adrenolutin Double Blind Experiments . . . . . . . 337
B. Prolonged Reactions to Adrenochrome and Adrenolutin . . 348
C . Effect of Adrenochrome on Humans as Reported by Other
Laboratories . . . . . . . . . . . . . . . 353
D . Adrenochrome Given Sublingually . . . . . . . . 357
E . Potentiation of the Action of Adrenochrome . . . . . . 359
F. Discussion . . . . . . . . . . . . . . . 360
X . Mode of Action of Adrenochrome . . . . . . . . . . 361
XI . Conclusions . . . . . . . . . . . . . . . . 365
References . . . . . . . . . . . . . . . . 365
.
I Introduction
Experimental psychiatry has been handicapped because the
diseases of man most characteristically psychiatric cannot be re-
produced in animals. The inner experience of the mentally ill patient
307
308 A. HOFFER
berg et al. (1950), Green et al. (1956), Hoffer and Kenyon (1957),
Hoffer and Payza (1958), Jantz (1956), Kaufman and Koch
(1959a, b), Lecomte and Fischer ( 1951), Maslova (1959), Nova1
et al. (1959a), Osinskaya (1957), Payza and Mahon (1959), Pick-
worth (1952), Rigdon ( 1940), Senoh and Witkop ( 1959), Sohler
et al. (1961), Sulkowitch and Altschule (1959), Sulkowitch et al.
( 1957), Utevsky and Osinskaya ( 1957), Veech et d. (1960).
The kind of scheme suggested by Gerard (1960) will be fol-
lowed in describing the activity of adrenochrome and some of its
derived compounds. The effect of adrenochrome upon simple sys-
tems will be considered first, then upon the more complex systems,
upon simple animals, and finally, upon the most complex animal,
man. The animals that have been given adrenochrome range from
spiders, fish, and pigeons to the mammals-rats, cats, dogs, monkeys,
and man. The sections on cats and on man will include much
original data.
Activity in animals has been reported so frequently and con-
sistently that it can no longer be doubted that adrenochrome is
indeed active when given to animals. Activity in man has received
less corroboration but all the published accounts (as against refer-
ences to unpublished works) are corroborative. It would be re-
markable for a compound so active in lower animals and mammals
to be inactive in man.
11. Biochemistry of Adrenochrome
The structural formulas of adrenochrome and some of its deriva-
tives are shown in Fig. 1.
The instability of adrenochrome, adrenolutin, and 5,6-di-
hydroxy-N-methylindole in aqueous solution leads to great difficul-
ties in working with these substances. Biochemists, unaware of this
difficulty, have consistently failed to demonstrate the presence of
adrenochrome in body fluids. Since adrenochrome is decomposed by
many solvents used in paper chromatography, e.g., propanol-
ammonia-water and n-butanol-acetic acid-water, this is not surpris-
ing. Distilled water and 2% acetic acid are suitable solvents (Hea-
cock, 1959b).
Reducing agents discharge the red color of adrenochrome solu-
tions and cause an internal rearrangement of the molecule, forming
quantities of 5,6-dihydroxy-N-methylindole and adrenolutin. The
312 A. HOFFER
H: f - - - J J +o /
0
I
CH,
5,6-Dihydroxy- N -
Adrenochrome
me thylindole
o+J-J---:H
Adrenolutin
/
0
I
,k
H,C H CH,
A
H,C H CH,
N-Isopropyinor- 5,B-Dihydroxy-N-
adrenochrome isopropylindole
FIG. 1. Formula of some adrenochrome derivatives.
TABLE I
OF PROPERTIES
COMPARISON OF CERULWLASMIN
(p-PHENYLENE
DIAMINEOXIDASE)AND EPINEPHRINE
OXIDASE"
0 From Payaa and Zaleschuk (1959) and Payza and Hoffer (1959).
PIGEON
B. FEMALE A
October 23, 1957, this bird was given 5 mg adrenochrome intraperitoneally
at 4:13 PM. There was no observable change in behavior. The next morning,
318 A. HOFFER
C. MALE PIGEONB
Pair B were nesting two eggs. The nest was in one wrner of the cage and
built of grass. This male was dominated by male A but was normally aggressive
and fond of female B. He was devoted to her and dutifully did his share of
brooding on the eggs. On October 24, male B was given 10 mg adrenochrome
at 2:07 PM. Twenty-three minutes later, he vomited and had a tremor during
which he stood and rocked back and forth. He blinked his eyes slowly and
appeared sleepy, Three minutes later, his fighting behavior was normal but he
had a slight tremor of his wing. Forty minutes after injection, his vocal ability
was diminished and his voice became feminine, sad, and dull. Male pigeons
lose their voices only when moulting. He did not court with enthusiasm and
could hardly coo. One hour later, female A was placed in his cage. Normally
male B would have driven her out but this time he ignored her. The next
morning, he was normal.
Male B was then given 20 nig adrenochrome together with 100 mg ascorbic
acid. One hour later, there was a slight and fleeting change; a few minutes
later, he was normal. One day later, he was still normal, but 2 days later he
was found dead.
D. FEMALE B
PIGEON
Female B was brooding two eggs and was very motherly and protective.
She fiercely drove off a hand reaching toward the nest. This bird was injected
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 319
with 10 mg of adrenolutin. Five minutes later, she stood over her eggs but did
not set on them. She then walked away from her eggs. Ten minutes after the
injection she retched, then sat beside her eggs and blinked her eyes. Five
minutes later, she was sick and her feathers drooped. She no longer retreated
from the hand. Twenty minutes after the injection, H.W. placed her on his
hand and walked from the office down a long corridor and back. She made no
attempt to fly away but clung to his hand. This test we termed the Baruk test
because he often demonstrated the effect of schizophrenic bile on pigeons in
this way (Baruk, 1957). This pigeon was able to fly when she was released
but was apparently not interested in flying. One hour later she had not returned
to her nest.
The next day, the bird was studied again. At 9:OO AM she appeared dis-
interested and did not set on her eggs. By 2:OO PM she was much more alert
and responsive. She fought against the hand vigorously and was better groomed.
Four days later, she appeared normal. She had again started to set on the dead
eggs in the normal way. At 1:57 PM, she was given 20 mg adrenochrome.
Three minutes later she was ill, rocked, and once more refused to set her eggs.
Four minutes after injection she vomited. One and a half hours later she had
apparently recovered. She was now very alert and vicious when the hand was
placed near her. She came toward the hand to attack. Late that night she was
dead.
E. DISCUSSION
It is not possible to draw firm conclusions from this study on
only four birds, but each bird had several injections and the results
were definite. A larger series would be required in order to complete
this kind of study. The following tentative conclusions may be
made: ( 1 ) Male pigeons are apparently more susceptible to death
from adrenochrome than female pigeons. ( 2 ) Adrenochrome in
nonlethal doses (10 mg) alters behavior, including courting, protect-
ing the nest, and brooding. ( 3 ) Adrenolutin is more effective in
altering pigeon behavior than adrenochrome. In one case, catatonia
was produced.
Lehrman (1956a, b, 1958, 1959) and Lehrman and Wortis
( 1960) have examined the factors which influence cyclical breeding
behavior in ring doves (Streptopelia risoria). This does not nor-
mally occur in birds kept in isolation from each other, According to
these workers the presence of one bird stimulates the pituitary
gland of the other; the pituitary hormones change courting behavior
to nest-building, then to incubation. When birds were placed in
cages with eggs they would normally begin to nest in 4 to 10 days.
When progesterone was injected the birds nested almost immedi-
ately. Birds treated with estrogens sat after 1-3 days or after a
320 A. HOFFER
A. MICE
Not much has been written about the effect of adrenochrome on
mice. Laborit et al. (1957a, b) found that both adrenochrome and
adrenochrome semicarbazide increased the tendency of mice for
convulsions. LSD had no effect. Serotonin protected the mice
against convulsions. Glutamic acid gave some protection. Eade
(1954) found that adrenochrome produced sedation in mice, and
before death the sedation quickly passed off and was replaced by
progressive spasmodic clonic convulsions beginning in the hind
limbs. Walking was uncoordinated. When disturbed, the mice
hopped about, often leaping in the air and falling over backward.
B. RATS
1. Review of Literature
Eade (1954) gave adrenochrome to some rats in order to
measure the lethal dose. Cause of death was respiratory paralysis
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 321
10, 10, 10, 10, 11, 10, 13, and 20. Chi-square for a median of 115
was 5.00 (0.05 < P < 0.01). Adrenochrome significantly accelerated
extinction of CAR. In most of the adrenochrome rats, it was extin-
guished at once, but of the animals given saline 3 rats required
more than 100 responses.
d. Eflect on Driue. When trained rats were used and the intensity
of the electric shock was varied, there was a slight trend for saline
rats to escape at a lower intensity of current, i.e., at 0.22 vs. 0.25
ma, but the difference was statistically insignificant. However, when
untrained rats were used and observed for startle responses (includ-
ing jumps) the saline threshold was 0.14 and adrenochrome 0.19
(0.05 < P < 0.01). The threshold for naive animals was lower than
for sophisticated animals. The intensity of current was set at 1.25
ma for one group and 2.50 for the other. Animals with adrenochrome
at a higher drive level performed slightly less well. It was concluded
that level of drive (or arousal) was not involved in the way
adrenochrome affected CAR.
e. Eflect on Bar-Pressing. The rats were tested in a Skinner box
with food and water as the reward. They had to run to one end,
press the bar, and return to the other end for their reward. After
a constant rate of bar-pressing was obtained, they were injected and
tested for 13 minutes. Adrenochrome significantly ( P < 0.01) re-
duced the rate of bar-pressing. The difference was greater when the
rats were less well-trained, i.e., received adrenochrome first,
f. Conclusion. Adrenochrome decreased the acquisition of the
conditioned avoidance response and markedly accelerated extinc-
tion. The prolongation of acquisition was related in a linear way to
the logarithm of the dose. In a Skinner box, the rate of bar-pressing
for food or water was markedly reduced.
C. RABBITS
Krupp and Monnier (1960) studied the effect of adrenochrome
on 12 rabbits. They observed these animals for changes in behavior,
for changes in frequency of respiration and pulse, and for brain
electrical activity. They injected 3.5 to 6 mg/kg of adrenochrome
by vein. Behavior was influenced slightly, The animals reacted more
strongly when stimulated by light or noise. There were slight
changes in spontaneous motility of the free animals and a transient
but slight decrease in pulse rate.
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 325
D. CATS
1. Literature Review
Schwarz et al. (1956b) made the first study of the effect of
adrenochrome and adrenolutin on cats. (Their paper should be
consulted for more detailed description of the behavioral effects. )
Pure adrenochrome (freshly prepared solution, pH 7.7), in doses
ranging from 0.125 to 1 mg, was placed in the lateral ventricles,
using permanent indwelling canulae. Adrenolutin (also freshly
prepared solution, pH 7.6) was similarly injected, using doses of
300-650 pg. “Stupor and catatonia, as described by de Jong, were
observed after the administration of adrenochrome and adrenolutin.
After an initial gradual reduction in motor activity, the cats would
finally sit in odd positions with their eyes wide open for long periods
and howl. Although, for various reasons, the term ‘waxy flexibility’
326 A. HOFFER
'1 wish to express to Dr. McColl my gratitude for his helpfulness in this
phase of our work. This kind of cooperation compensates for the many frustra-
tions one encounters in the normal course of research.
328 A. HOFFER
I I
CHI CH?
II
CH,
Adrenochrome .V-Ethylnoradrenochrorne
methyl ether
Itubcseririe 3,4-Methylenedioxy-a-
aminomethylbenzyl alcohol
oxalate
Adrenochrome, Less hostile Indifferent Much decreased Much decreased Awkward, unsteady No
>6 mg
Heparin, 1 mg Hostile Hostile Normal Normal Normal NO
Rubeserine, 1 mg Less hostile Less hostile Decreased Much decreased Normal No 2=i
&Epinephrine, 1 mg Hostile Hostile Decreased Much decreased Weak, unsteady Retched, vomited Z
Metanephrine, 1 mg Hostile Less hostile Slight decrease Slight decrease Normal No
wco
TABLE I11 8
0
RESPONSE
OF CAT “BIG” TO ADRENOCHROME
A N D SOMESIMILARCOMPOUNDS
Personality reaction
Motor L4utonomic
Compound To observer To other cat Alertness activity Gait changes
examination showed the canula placed inside the lateral ventricle and there
were no visible areas of destruction or hemorrhage. The canula had not been
displaced. Histological examination by Dr. R. Altschul, Professor of Anatomy,
University of Saskatchewan, revealed no evidence of any injury. The cause of
death remains unknown.
“Dracula” was a nervous, hostile, and suspicious cat. He never came to the
cage door to be released and resisted being removed from the cage. When
released into the room, he would immediately leap from the floor back into his
cage if the door was left open and would crouch in it. August 25, 1W0, he was
given 1 mg adrenochrome in 0.5 ml saline. At 17 minutes, he became unsteady.
He tried to jump back into his cage but was not able to leave the floor. He
was placed on a stool in front of his cage and had only to walk across a small
gap. But in doing so, he fell off the stool. At 31 minutes, he could hardly walk.
He defecated. At 67 minutes, his hind limbs were still very weak. He was the
same at 2 hours. During this experiment, he was able to defend himself well
against attack from the other cat. One week later, he was given 1 mg adreno-
chrome with 1 mg heparin. For the next 2 hours, no change at all was seen. He
remained normally active, had no difficulty jumping into his cage and eventu-
ally he became mildly affectionate to the observers.
3. Discussion
The changes observed in these cats were due to chemical action
and not to the increase in cerebrospinal fluid pressure, since injection
of saline, of heparin, and of several of the other compounds produced
no change. This series of experiments was not extensive enough to
determine which chemicals were most active. However, certain
findings may stand. As a general rule adrenochrome and the com-
pounds which could be formed from it were more active than the
unnatural derivatives. Thus, 5,6-dihydroxy-N-methy1indole7 which
is formed in vivo from adrenochrome (Sohler et al., 1961; Fischer
and Lecomte, 1951), produced a condition characterized by in-
creased alertness, increased activity, and increased aggressivity. But
this increase in activity, which can be compared to a human hypo-
manic state, was appropriate and directed. Hostility was directed
against the other cat and merely accentuated natural antagonism.
The cats remained normally friendly or indifferent to the observers.
Adrenolutin in one cat decreased alertness and activity, and pro-
duced marked weakness and incoordination of the hind limbs. The
cat became abnormally hostile to the observer and to the other cat.
Two adrenochrome homologs very similar in structure (N-iso-
propylnoradrenochroe and N-ethylnoradrenochrome) produced
hardly any change in behavior. The integrity of a single methyl
332 A. HOFFER
tin. It might be argued that the series should have been discon-
tinued as soon as it was noticed the chemical was changing. But
this would have biased our data in favor of a positive result.
Furthermore, it was then impossible to get any more. Each sample
sent to us by various manufacturers was as dark and deteriorated
on arrival as our own stock had become.
Another way of examining the data statistically is to examine the
recorded data for certain changes. These as recorded by Hoffer
(1957c,d ) were summarized from records made by the observers
and by the subjects before the compound given was known. The
code was not broken for each subject until all the written material
which forms the raw data was complete. I have reexamined the
reports and from data published there (Hoffer, 1957c) scored each
subject for the presence or absence of definite changes. This is
shown in Table IV. In all categories but anxiety, the evidence of
TABLE I V
EFFECT
OF ADRENOLUTINA N D RIBOFLAVIN
O N MENTALSTATUS
I N A DOUBLE
OF VOLUNTEERS BLINDSTUDY^
Number of subjects showing this change
Perception 12 I
Thought 14 1
Mood 3 1
Anxiety 1 7
Personality 3 1
Carry-over, next day 8 1
Total number subjects 20 14
think it mattered if it took three or four or even five trys which I again carried
out with the same abandon as previously. The next morning I awoke and I was
quite tired, still very very apathetic, and with a rather dull headache. I was
unable to pick up any speed in my work throughout the morning and even
into the early afternoon and although I had a fairly heavy schedule of work
ahead of me, I was unable to muster the necessary energy and initiative to
carry out these various duties. The fact that I couldn’t seem to carry out these
duties didn’t really worry me too much at any time. By the following evening,
however, I felt I had considerably more energy, I was more awake and more
able and willing to carry out the necessary daily tasks. The following day I felt
completely normal in all respects. On looking back over the whole evening, I
might say that I had received a depressant drug which made me very apathetic,
rather depressed and did not seem to completely abolish my anxiety. Although
I felt anxious, I didn’t seem to be really able to do much about it because of
this tremendous sense of fatigue. Generally speaking, I felt I had done only
moderately well or rather poorly on the tests, particularly on the first few and
especially on the critical thinking test. I regarded the evening as rather un-
pleasant and one which placed a considerable strain on me. As a result, I was
not particularly looking forward to the next week‘s experiment, which I was
afraid might have a somewhat similar effect.”
One week later, Dr. L. J. was given riboflavin. At 6:30, there was no
change. At 6:45,he was able to do calculations better than the previous week.
At 7:00,he did pretty well but failing to give a correct answer to a problem
made him upset and anxious. At 7:45, he seemed more relaxed, somewhat
elated, and full of good humor. This he described as his normal personality.
The rest of the evening, there were no changes. The following day, he was
sure he had placebo the second time because he had been wide awake, more
attentive, and much more alert. The questions had been easier, there had been
no headache, no fatigue, and the memory for the evening had remained clear.
He concluded the second drug was either a placebo or an euphorient.
His sown account follows:
“On this Monday, in spite of the fact that I had again stayed out rather
late Sunday evening, the day before the test, I was in moderately good spirits
when I embarked upon the test. I felt somewhat more confident about what
was going to happen. I knew that the test would b e somewhat similar and
therefore I had no particular apprehension. At 5:30 to 6:00,I had the usual
flicker test which I did with some enthusiasm as before, knowing that they
would be rather boring but that it could be well tolerated. From 6:OO to 7:OO
my reactions were considerably different from the previous week and I didn’t
feel nearly the anxiety that I’d had. My hands remained warm and dry, I was
attentive and relaxed. The psychiatrist fired a similar type of question at me
involving the rather simple arithmetic questions. Unlike the previous week, I
did not have a certain sense of panic and confusion but was able to make at
least an effort at working out an equation. I was making a sincere and some-
what enthusiastic effort to at least make a good stab at the question even
though I might not be able to get the answer. The fact that I couldn’t get the
answer didn’t particularly worry me as it had the week before. I seemed
344 A. HOFFER
generally able to give more answers this week in a quick and more accurate
manner. 1 did not feel the humility nor was I as apologetic when I made
mistakes on this occasion. My examiners did not arouse the antagonism and
hostility in me as they had done previously. I felt in a quite good humour from
the hours of 6:OO to 7:OO. I seemed to be able to muster the necessary energy
and initiative and enthusiasm to tackle the questions even though I probably
would not get the right answer. I was not particularly discouraged or depressed
at all and was in an exceptionally good mood when we moved on to the second
part of the experiment which again consisted of the EEG and stroboscopic ex-
amination. . . . I think I did a better job on the proverbs although there were
one or two which I seemed to have a mental block in explaining. On the ques-
tions of abstract thinking , . . my performance was better than the week
before. On the EEG and stroboscopic examination, I think the results were
markedly different from the previous week. At no time was I really aware of
geometry and symmetry to the field that I saw; there were no definite centres
of light particularly and no straight radiating lines coming off the centre of
light. . . . The critical thinking test, I noticed a very marked subjective dif-
ference. I was able to understand the instructions immediately on reading
them over. I found the questions quite difficult and still not clear today, but I
was able to make what I thought was an astute try at the questions and on the
whole, I felt much better about the test when I finished than the week before.
I felt that I was clearer in my mind, my judgment was better, and I had
definitely done the test in a more precise and much more rapid manner. I
believe that I had bettered my time by perhaps twenty minutes to half an hour.
I felt no particular sensations other than one of extremely well being. I was
much more awake at that hour than I usually am.
“. . . In retrospect, looking back over the evening, I felt the whole ex-
perience was much more pleasant the second evening and I think that I
actually enjoyed it. I was able to maintain my interest throughout it and I
seemed able to bring my powers of concentration to bear on all the questions
so that I could give them all a good try. I didn’t feel any anxiety and was in
extremely good spirits throughout the evening. I felt quite kindly towards my
psychiatrists who I felt were my colleagues and generally felt that the experi-
ment on the second evening was well worthwhile and that the tests were astute
ones. As a final conclusion therefore I think that on the first evening I was given
a depressant drug, which made a very unpleasant evening for me. On the
second evening, I was given an euphorient drug, a stimulant type of drug and
the evening was quite passable. However, the drugs are of such a subtle nature
that following the first evening, I would not be sure that I had had anything
and even following the second evening, taken by itself, I could not be s u e
that I had had anything. However, in comparing the two evenings, there was
a very very marked difference in the way I felt and therefore I must have had
contradictory types of drugs on these occasions.”
After the two sessions had been completed the subject was very concerned.
For most of the week after having had adrenolutin he was very disturbed
because of his unusual paranoid ideation during the first experimental night,
which he had not disclosed to the investigators. On the second day after the
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 345
first experience he reported to me that he had not told the two investigators
everythmg that had occurred as he had been instructed to do. What had hap-
pened was now worrying him since he was quite certain he had had placebo. I
asked him to come for an interview after he had finished the second half of
the experiment because I then did not know what he had had.
After the experiments were over, he reported what he had neglected to
tell the two observers. During the first experiment, he was asked his opinion of
socialized medicine. He immediately felt very strongly that the two observers
were both communists and were trying to draw him out. He thought he would
play along with their little game and tried to draw them out in order to obtain
evidence that they really were communists. This he proceeded to do by agreeing
with e v e r y h n g they said about socialized medicine. He watched them care-
fully for evidence. He felt B. was a very sinister person although he had known
him before, Finally he saw B. pick up a pencil marked “Government of
Saskatchewan.” This immediately confirmed his suspicions, for who but a
communist would get a pencil from the Government of Saskatchewan? He
then became preoccupied with the EEG procedure. The next morning, he
could not understand how he could have had these ridiculous ideas. He felt so
guilty over this he did not wish to tell anyone. For the next few days, he was
very quiet and subdued on the wards, quite unusual for him.
I told Dr. Hoffer I was all right. The flashing light gave me a suffocating feel-
ing and I felt like running away or telling them to stop, but couldn’t. Later, I
went to the bathroom and felt like getting away from the experiment. There
were some people in the hall. I thought they were looking at me and thinking
I was foolish.
“The next three tests seemed very foolish but I still maintained I was
interested. I did not care how I had done. Before going home I believed
nothing had happened and that I had been normal.
“At home I decided not to tell my friends anything. I slept well. The next
morning I was tired but my head was clear. I was able to figure out the math
problem in my head easily [the one she could not solve the previous night].
I realized I had been uncommunicative last night but was able to talk freely
now. I realized that I had not reacted normally last night but today I’m think-
ing more clearly and critically.”
Two weeks later, she was again given 50 mg adrenolutin. She was more
relaxed this time. The first half hour, she discussed the three things which had
impressed her about the first experience. These were ( a )her feeling she must
not communicate; ( b ) her feeling of suspiciousness; ( c ) her difficulty in think-
ing. At 6:30,she again felt she must not talk, became suspicious, and felt again
that we were looking down at her. She also felt quiet. She described one
observer’s face as having cruel eyes, an accentuated mouth and eyebrows. At
6:45, she again saw words move but less than the first experiment, and they
were blurred. At 6:50,these visual changes were gone. At 7:00, she felt more
relaxed and was more sure of herself. She tried the serial seven test four times
and failed each one but it did not disturb her. On proverbs and on the
Wechsler-Bellevue test, she was somewhat better. At 8:00, there was no tension.
She felt quiet. There was less paranoid feeling about the observers this time. At
10:00, she was relaxed and felt she had done much better this evening. There
was actually very little difference on the scores.
The next day she reported:
“At 5:15 p.m. I was not apprehensive, and was looking forward to the
evening. I was curious to know what would happen. After the first test, I
took the drug. After a few minutes, we went back to the first room-repeating
the first test to which I felt I responded fairly well. After this, Dr. Hoffer gave
me a book and asked me if I saw the same thing as last week (movement in
page)-I did not. I then experienced the feeling of being looked down upon
by A. more than Dr. Hoffer. A.’s eyes appeared somewhat cruel, his eyebrows
were pronounced as was his mouth; just Dr. Hoffer’s eyes and eyebrows were
pronounced. This lasted only momentarily and was not as intense as last week.
After this we went out to do the “distance test.” At this time, I realized that my
mood was definitely calm, that I was not suspicious as on the previous test
and that I would probably be more truthful in my comments but still not too
talkative. My reaction towards the resident psychiatrist was friendly and not
critical realizing he knew his work. The test passed quickly; I was sure of my
measurement and did not feel as though I was underestimating myself. Interest
did not seem to fade during the test. I believe at this time I was somewhat
relieved to think I was not having the same reactions. Dr. Hoffer began his
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 347
math quiz again. I thought I could do better than I did, however. I did have
several different answers to the 93-7 test; felt I did better on the math but the
fact that I had made some errors did not greatly concern me. I felt that Dr.
Hoffer and A. were friendly and kindly towards me; also was not as worried
about not being able to answer questions but felt perhaps could still do better.
During the EEG, I felt very relaxed and calm-could easily have gone to sleep.
The time of the test did not annoy me, the hyperventilation part of the test-
had some headache, but not as severe as last week. I was finding the evening
more interesting even though the tests were the same-perhaps I enjoyed the
calm, relaxed feeling I was experiencing in contrast to the previous evening.
The Rorschach test also was more enjoyable-I still saw some bats and crawl-
ing animals although not as sinister or frightening; and I was able to see more
pleasant things-clouds, melting snow, rock and tree reflections in water, just
modern art painting for my imagination could not see anything but color. The
colors were softer, warmer blue.
“February 25. This morning I was still tired-somewhat more than usual.
Talked to the Director-was not the least bit annoyed with her this morning
either-a feeling which is different from the annoyance I have felt towards her
( P.s., this is a feeling that is experienced not only by myself but also my fellow
workers). I still feel relaxed and calmer I believe than what I normally am.
“February 26. I believe the calming effect lasted well into Saturday
evening. I was going out Saturday evening and had none of my usual appre-
hensive manifestations-an excessive perspiration in axilla and palms of the
hands. I am still somewhat tired this morning but I am unable to be definitely
certain that this is a result of the medication. The experience still remains
enjoyable and is beginning to repress the first evening from my mind.”
rather tired and not interested in any more problems. But on walking back to
the office, I wakened up again and felt quite normal. However, I was beginning
to get hungry. I think I did and said the same things on the tests then as I
would have without any drug. After I returned home, I felt quite normal, ate
and went to bed and to sleep right away.”
4. Summary
A summary of the fourteen subjects who received adrenolutin
and placebo is shown in Table V.
A score was derived by giving the subject one point for an ab-
normality and zero for normality under the headings shown in the
table. Thus the presence of changes in thought is scored one. I
consider it normal for the subject to have had anxiety during these
experiments. Its absence is scored as one. The mean score of 14
adrenolutin runs was 4.43, with a range of 1 to 7. For placebo, it
was 0.93 with a range of 0 to 3. In 11pairs of results the scores for
placebo were less.
The subjective accounts were then examined for the presence of
residual changes in the days following the experiments. Out of 18
subjects given adrenolutin, there were 9 prolonged reactions. Out
of 32 placebo experiments, only 4 were prolonged (Chi-square =
6.4, P < 0.01).
The subjects were not asked regularly what they thought they
had received. But several spontaneously remarked that they had had
something active or inactive. Of 9 subjects each of whom received
both adrenolutin and a placebo, only 1 subject erred by calling
adrenolutin inactive; in all instances the placebo was termed inac-
tive. (For this distribution, with one df.,the value of chi-square is
10; therefore P < 0.001.)
This sample of series is of course biased in that people guessing
what they had may have been different, and it is possible that if all
subjects had been asked to make these predictions, the results would
have been different. The work reported by Grof d d.( 1961) makes
this suggestion quite unlikely. Their subjects were able to detect
adrenochrome very well.
B. PROLONGED TO ADRENOCHROME
REACTIONS AND ADRE”
1. Adrenochrome
Some of the changes produced by adrenochrome may persist
several days, and in some cases the effects nearly led to disastrous
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 349
a. Miss F . M . This young female, age 16, had been well until age 8. For
the next 2 years, she had unusual sensations in her chest and nose every night.
A few weeks before this investigation, she developed changes in perception (her
mother’s face seemed strange and altered as she watched; the visual field was
covered with a checkerboard pattern, her body image was different, time
moved very slowly, and houses looked like cornflake boxes). There was no
thought disorder but she was very apprehensive. For several years, she had
been given dilantin and phenobarbital for mixed petit and grand ma1 epilepsy.
At the time of investigation, she was normal. The EEG showed a very marked
left anterior temporal focus characterized by high voltage, slow waves, and an
occasional saw-tooth wave with single spikes (Szatmari et al., 1955, p. 607).
The left temporal focus increased with hyperventilation.
At the beginning of the EEG test, she was happy, cheerful and friendly.
She was given 50 mg of adrenochrome by vein. After 10 minutes, she developed
a feeling of estrangement and fear and her nose itched. The pathological activity
of the temporal focus increased and dysrhythmia became generalized. She was
now morose, quiet, and depressed. When she was urged to describe how she
felt she cried. Then she reported that the strange feelings and disturbances in
body image which had been present 2 weeks before had returned. She was
given 500 mg of nicotinic acid by vein. Within 15 minutes, the focus was less
intense, the dysrhythmia had disappeared, and she was mentally normal.
That evening at home, she was moody and quiet. One week later, she was
very disturbed and 2 weeks after the treatment required committal to a mental
hospital.
On admission, she suffered from perceptual changes (all faces were strange;
there were marked ddjd vu, feelings of estrangement and unreality, and visual
hallucinations). She had thought disorder (her present life was merely a show
and a replay of a previous period in her life; she was confused, rambling, and
almost incoherent) and referential ideas with delusions of guilt, and she was
paranoid. Her mood was flat. The staff were not aware she had received
adrenochrome. On admission, the diagnosis of schizophrenia was entertained
but with her history of epilepsy, she was finally diagnosed as having an epileptic
psychosis.
A few days after admission, her psychosis cleared and a few weeks later,
she had typical grand ma1 convulsions. These were controlled by anti-convulsant
medication. She was in the hospital about 6 months. Over the next 6%years,
she has shown no schizophrenic-like symptoms.
b. M r . D. S. This patient, age 18, was first treated June 7 to September
29, 1957. He was diagnosed as having a neurotic hysterical reaction with
marked depression. Schizophrenic features were present. He was given regular
psychotherapy and 20 ECT and was discharged much improved. Two weeks
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2. Adrenolutin
There have been many prolonged reactions to adrenolutin. Some
of these changes have already been described in the case histories
(cE. Section IX, A ) . Other reactions lasted more than 1 day after a
single administration of adrenolutin, and reactions up to 1 week
have occurred.
M r . 1. K . Mr. I. K. was given 25 mg of adrenolutin at 6:OO PM on January
27, 1955. Over the next few hours, a few visual changes were present; he was
relaxed and felt his mind was clear but his thinking was altered. He had dif-
ficulty in following conversation and felt other people about him were
unimportant to him. Between 8:30 and 1O:OO P M voices seemed unnaturally
loud. The next day he suffered from a slight headache all morning, and he was
listless and tired,
On March 3, 1955, he was given 50 mg of adrenolutin at 6:OO PM. There
was little change in him. Two hours later, he was quieter and spoke with dif-
ficulty. Later, he developed an irritating headache over his left eye. W e con-
cluded that there had been no reaction and he was allowed to go home at
1O:OO PM. His wife reported he looked drawn and tired. He was unusually
unresponsive and did not tell his wife anything about the evening. That night
he slept fitfully and he was less responsive to the fussing of his two young
children. The next morning, he was irritable and seemed disinterested in his
mail. Episodes which normally did not bother him were causes for irritation.
That night, he was angry about his car being stuck in the snow near his house.
The second morning, he seemed more normal. When he could not start his
car, he came rushing in and shouted at his wife that he could not start the car
and that it was all her fault. This degree of anger and this type of accusation
was most unusual for him. When asked how it was her fault, he stated "if she
had not wakened him yesterday, he wouldn't have been able to help her sister
get her car out and therefore she wouldn't have had to drive home again and
so get stuck in the same hole and that therefore he wouldn't have had to drive
EFFECT OF ADRENOCHROME AND ADRENOLUTIN 353
his car around to the front and leave it there to freeze on the road and ruin
the starter.”
That evening when Mrs. I. K. was feeding a young child, he suddenly
without warning shouted her name in a violent manner and then said she was
harming the child by her concern over the feeding. When Mrs. K. asked him
why he shouted instead of just quietly telling her, he glowered and muttered
something. That evening, he appeared haggard and ill. He was unreasonable
and uncommunicative. The third day, he awoke cheerful and normal until late
in the afternoon when his irritability, restlessness, and peevishness returned.
The rest of the day be was alternately normal and withdrawn and irritable.
Much has been made of placebo reactions, and they are indeed
very powerful. But the incidence of prolonged reactions was very
unusual with our placebo subjects. Most of them stated they were
normal on the day following the experiment. The records of 25
subjects were reexamined and only their subjective accounts used. In
these accounts they described how they felt the following day.
Thirty-two subjects had placebo. Four stated there was some resi-
dual effect which consisted of some dizziness in three and euphoria
in one. Most subjects received Tuinal 200 mg at bedtime. Eighteen
subjects received adrenolutin. Of these, nine had prolonged reac-
tions. Chi-square for this is about 6.4. There is less than 2%chance
that this difference is due only to chance. Furthermore, not a single
placebo subject had any residual reaction lasting more than one-half
a day. Yet many adrenolutin subjects were not normal by noon and
some were clearly abnormal for several days; there was one reaction
that lasted 2 weeks.
C. EFFECTOF ADRENOCHROME ON HUMANS AS REPORTED BY
OTHERLABORATORIES
In order that investigators can judge a report, it must include a
description of the subjects used, the nature of the chemical, and the
results which were found. Using these criteria, there have so far
been recorded corroborative results from three independent investi-
gators; there are no adverse papers, although apparently sporadic
trials by some have proven negative. Rinkel et al. (1954) showed
that adrenochrome semicarbazone did not produce changes in
human volunteers. This is the derivative of adrenochrome which is
used for hemostasis. It is not hydrolyzed in the body to adreno-
chrome; neither is it active in producing changes in spiders.
The first group of workers to corroborate our work was Schwarz
354 A. HOFFER
D. ADRENOCHROME GIVENSUBLINGUALLY
The Taubmann and Jantz method for giving adrenochrome
seems most useful. We therefore ran a few trials with crystalline
adrenochrome. Since two adrenochromes are known, made from
either d- or I-epinephrine both forms and the dl mixture were tested.
1. Adrenochrome f r o m l-Epinephrine
In several studies 6 mg of d-adrenochrome given sublingually
produced no change. In one instance, 10 mg produced a change
which was very clear and obvious for about 2 days. This case is
unusually well documented.
The usual adrenochrome changes in perception and thinking resulted. The
subject was depressed and irritable, and suffered a marked change in person-
ality. In another case, 3 mg did produce a marked change. After 30 minutes,
there was a flush. One and a half hours later, the subject developed strong
feelings of isolation. The room became unclear visually and there seemed to be
much movement about him. The rest of the day passed without having any
sensation of time. In the evening, while in bed, he momentarily hallucinated the
face of a person close to him and he became very anxious. In the morning, he
was normal.
2. Adrenochrome f r o m d-Epinephrine
This was synthesized by R. A. Heacock in 1958. Three mg was
given sublingually to two subjects.
Subject 1 observed some difficulty in reading and focusing at 7 minutes. At
10 minutes, he was light-headed. At 12 minutes, far objects seemed very far
away, At 24 minutes, he was euphoric and could not estimate time. At 35
minutes, time had seemed almost stationary. At 45 minutes, colors were very
bright and vivid. At 80 minutes, he was very active in speech and movements
and abrupt with people. At 5% hours, he felt normal. However, for the next 24
hours, people’s faces and other objects would become alternately small and
large in size. In one instance, a speaker’s face appeared to move away and
toward him. Objects moving toward him increased in size too quickly.
Subject 2 also received 3 mg. At 4 minutes, printing on a page became
blurred and he had difficulty grasping the meaning of words. At 9 minutes, he
became tired and his vision was blurred. At 30 minutes, his thinking was
fuzzy. He was apathetic and could not concentrate. The outline of his hand
seemed blurred, At 39 minutes, curtains in the room appeared to shimmer. At
52 minutes, he was withdrawn. For the next 30 hours, he was depressed, with-
drawn, and disinterested.
358 A. HOFFER
seemed like 3%hours since taking it. His headache was now gone. H e reported
that the most pleasant part of the experience was that it was wearing off. The
next hour, he was easily confused and still could not estimate time correctly.
After that he was normal.
E. POTENTIATION
OF THE ACTION OF ADRENOCHROME
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