Studies on LSD-25: Tolerance in Former Morphine Addicts

The striking mental changes induced by the diethylamide of lysergic acid (hereafter referred to as LSD) have been studied ex- tensively in Europe,* Great Britain,+ and the United States.t In minute doses (20y to 120y) LSD induces a peculiar mental state characterized by anxiety, signs of au- tonomic dysfunction, perceptual distortion (chietly visual), alterations in mood and affect, synesthesias, feelings of depersonali- zation, and hallucinations. The drug is ap- parently the most effective and safest agent for inducing an experimental, but reversible, psychosis in nonpsychotic subjects.

Various interpretations have been placed on the mental state produced by LSD. Some European authors refer to it as a "toxic psychosis of the exogenous reaction type" or a "diencephalosis,'§ presumably because the autonomic signs suggest effects on the hypothalamus. The resemblance of some of the psychic manifestations which follow LSD to symptoms of the major psychoses has been stressed by others.|| The LSD re-

Received for publication May 24, 1956.

From the National Institute of Mental Health, Addiction Research Center, U. S. Public Health Hospital.

• References 1-5.

+ References 6-9.

t References 10-20.

§ References 1, 21. || References 4, 12, 14.

'

action has been referred to as schizophrenia" or "experimental psychia- try." Because some of the symptoms in-

'experimental

duced by LSD also occur in schizophrenia, it has been suggested that schizophrenia may be due to a toxin,?! to a deficiency of some metabolite necessary for brain function, or to some metabolic tissue disturbance.+ A defect in the degradation of epinephrine involving either adrenochrome* or ad- renoxine ® has been postulated. Another hypothesis, based on competitive actions of serotonin and LSD in excised smooth muscle preparations, postulates either a de- ficiency or an excess of serotonin in the brain.* Recently it has been shown that both reserpine and serotonin prolong the sleeping time of mice treated with hexo- barbital.27 LSD abolishes the prolongation of sleeping time induced by either sub- stance.* Since reserpine causes depletion of serotonin stores in the brain,} some re- lationship between serotonin and mental function is inferred. Further, LSD is pre- sumed to cause mental symptoms by "competing with" serotonin for neuronal receptor sites.

All of these theories are based on re- semblances between the LSD reaction and the major psychoses. The effects of LSD last only a few hours, and practically all experiments with the drug have been "acute"; i. e., single doses of LSD were given at intervals of days or weeks. The

{| References 22, 23.

References 5, 24.

• References 27, 28. + References 28, 29.

: :

chronic experiments that have been done involved administration of the drug to psy- chotic patients in whom the LSD response was difficult to assess. It, therefore, seemed desirable to determine whether resemblance of the LSD reaction to the major psychoses, which are chronic diseases, would become more or less prominent when the drug was administered chronically to nonpsychotic persons. It is the purpose of this paper to describe the reaction induced by LSD in former morphine addicts, to show that the intensity of the reaction is measurable, and to report the rapid development of tolerance (loss of effect) to LSD when the drug was administered daily for 3 to 85 days.

Characteristics of the LSD Reactions in Former Opiate Addicts

The patients who volunteered for the experi- ments were male drug addicts who had been absti- nent from opiates for three months or more when the studies were carried out. None of these patients was psychotic; all had either character disorders or inadequate personalities, and the majority were Negroes. Because of the great differences in economic and ethnic backgrounds and personality types, and, possibly, physiological differences resulting from antecedent opiate addic- tion, it was necessary to determine whether the LSD reaction in these subjects was similar to the reactions observed by other investigators in other kinds of people in different environments. Prelimi- nary experiments were, therefore, carried out using 12 white and 12 Negro male subjects.

Methods.—The experiments were conducted in a closed ward devoted to research. The subjects were observed in individual rooms but were free to leave between observations and to mingle with other patients in a common dayroom. The drug was always given orally, and the subjects were fasting. Doses of LSD varied from 20y to 300y (total dose), or approximately 0.25y to 5y per kilogram of body weight. Results were con- trolled by using placebos and a randomized order of administration of LSD and placebos in all experiments. Pulse rate, systolic and diastolic blood pressures, respiratory rate, and rectal temperature were determined at hourly intervals, after 10 min- utes' rest in bed, and 2 hours before and 8 hours after administration of either placebo or LSD. Brief psychiatric examinations were carried out

clinical

approximately two, four, and six hours after ad- ministration of the drug. Pupillary diameter was determined once hourly, as follows: The patient

into a dark room, seated in a chair under constant light, and asked to look at a white spot on a wall 10 ft. (3 meters) away. The size of the pupils was compared with those of black circles of known diameter on a card which was held Neurological examinations, including pupillary reactions to light and accommodation, station and gait, coordination, deep tendon and superficial skin reflexes, and tests for abnormal reflexes were carried out hourly.

Results —Response to Various Doses: Reactions to zero dosage (placebo) were generally negligible. Doses of LSD of less than ly/kg. of body weight induced only mild effects. Autonomic changes were slight. Mental effects consisted chiefly of anxiety and mood changes, primarily in the "euphoric" Perceptual distortion was rare, and no hallucinations were re- ported. Doses of ly to 2y per kilogram induced more striking effects. The auto- nomic and neurological changes became defi- nite and measurable. Mental including anxiety, mood changes, and per- ceptual distortion, occurred in all patients, and many reported "elementary" hallucina- tions (kaleidoscopic patterns of light and color with the eyes closed) and occasionally "true hallucinations" (perception of some- thing that could be described as a definite thing, animal, or person). Feelings of un- reality and symptoms of depersonalization were common.

Doses of 3y/kg. or more induced a reac- tion which was too severe to be tolerated

was taken

alongside the patient's eyes.

direction.

changes,

on more than one occasion by most patients. A dosage range of ly to 2y per kilogram was adopted for most work, and the de- scriptions below are based on doses of this order.

Time Course: The effects of ly to 2y of LSD per kilogram were apparent within 30 minutes after oral administration, became maximal in one and one-half to two hours, remained maximal to the fourth or fifth hour after administration, and thereafter gradually declined. Usually, eight hours after the drug patients had recovered except for some residual nervousness and anxiety. All symptoms disappeared completely within 16 hours.

"Nonmental" Effects: Statistical analysis of the data showed no significant change in temperature, pulse rate, or respiratory rate. Systolic and diastolic blood pressures were significantly elevated.

The only consistent neurological changes were dilatation of the pupils and accentua- tion of the deep tendon reflexes. Occasion- ally, twitching of the muscles and tremors involving muscle clonus occurred in patients Waves of goose flesh were noted in some patients.

"Mental" Effects: The effects seemed to be identical with those described in the literature in nonaddicts. Changes in mood in the direction of either euphoria or

who had severe mental reactions.

mental

depression, difficulty in concentration, feel- ings of strangeness, anxiety, nervousness, and dream-like states were reported. Motor activity varied. Some patients were con- stantly active; others became very quiet and withdrawn.

Various alterations in all sensory modali- ties were described: acute or dull hearing, "sandpaper" feel of clothes, metallic tastes, bad odors, sensations of the body being light or heavy, and a great variety of visual changes. Actually, alteration in vision was the only sensory change reported by all pa- tients. The subjective visual phenomena included blurring; changes in perception of depth and distance ; distortion in size, shape, and color of objects, persons, and the pa- tient's own body; lights and colors on clos- ing the eyes or looking at the wall, which formed kaleidoscopic patterns not suggestive of any real thing ("elementary hallucina- tions"), and, rarely, "true hallucinations" (perception of persons or things not really present). Frequently, patients saw their hands or feet transformed into animal paws or into the extremities of a dead person. Similar sensations were experienced on look- ing at other persons. Auditory hallucina- tions were infrequent. The sensorium was clear, and insight (realization that the ef- fects were due to the drug) was usually maintained. Affect, though difficult to judge, seemed appropriate.

generally During

marked reactions most patients expressed fears of dying or of becoming permanently insane.

Symptoms which might be classed as "depersonalization" included the changes in the appearance of the extremities described above, "feelings" of being outside one's own body, and difficulty in recognizing oneself in a mirror. Patients also mentioned diffi- culties in deciding whether a thought re- ferred to a real event or object or was merely a thought. Such experiences, while puzzling, did not form a part of an organ- ized delusional system. Patients usually stated that such phenomena had not really occurred and were due to the drug.

Marked quantitative variations in the de- gree of reaction of different subjects to the drug were noted. A dose of 2y/kg. might induce only nervousness in one subject, while another subject might experience per- ceptual distortion and true hallucinations with loss of insight on the same dose. The same subject, however, responded each time to the same degree and in the same way as long as the testing situation was held constant.

Psychological Tests: In a preliminary ex- ploratory experiment, six Negro males were given a_ battery of psychological tests ( Wechsler-Bellevue Intelligence Scale, Gold- stein-Scheerer Cube and Color-Form Sort- ing Test, the test, and the Minnesota Multiphasic Personality Inven- tory [MMPI]) while receiving no drug and again at the height of the LSD reaction, after receiving a dose of ly to 2y/kg. of LSD.

Comparison of

Rorschach

the Wechsler-Bellevue

subtest scores and the intelligence quotients obtained

control conditions (no drugs) with those following LSD showed a decrease in all verbal subtest scores. Scores

under

on all performance tests, except the digit symbol, increased slightly, but the increases were less than those expected from the prac- tice effects. When corrected for the ex- pected practice effects, all subtest scores

When

showed some decrease after LSD.

= be ad | :

the intelligence quotients after LSD were corrected for the expected practice effect, the verbal I. Q. decreased 8.63 points, the performance I. Q. 6.07 points, and the full- scale I. Q. 7.43 points. Although the num- ber of subjects is small, these decreases probably represent a substantial impairment of intellectual function.

No loss of conceptual or abstract ability was found on repetition of the Goldstein- Scheerer Cube and Color-lForm tests during LSD intoxication. ap- parent that patients exerted a great deal of effort in order to complete the tasks. Much of the effort took the form of acquiring a "set," i. e., making bodily adjustments in-

However, it was

dicating an attitude of attention. Possibly, this effort was related to difficulty in con- centrating.

When responses on the Rorschach test before and after LSD administration were compared, some variation in several of the scoring categories was observed in each pa- tient. However, the basic pattern of the test responses remained the same. When the Rorschach tests of all six patients were an- alyzed as a group, changes were noted in several factors under LSD: There was a decrease in total number of responses (R), in F+ per cent, and in Z (organizational activity), and a trend toward a D approach at the expense of W. Perhaps the most sig- nificant effect was a decrease in the use of form and an increase in the use of factors other than form. In every subject, either Sum C or Sum Y was increased. Although the changes can be considered only as trends because of the small number of subjects, they seem to indicate increased emotionality and a breakdown or loosening of intellectual control in patients who characteristically maintained rigid control.

Such striking changes were observed in the MMPI profiles after LSD in the orig- inal six subjects that it appeared the MMPI might be more sensitive than other psy- chological measuring the LSD response. A separate study, which is being

tests in

reported in detail elsewhere,{ was therefore undertaken. Briefly, 24 subjects were tested in random balanced order under no drug, placebo, and LSD (50y-130y) conditions. The MMPI was given one and one-half hours after administration of placebo or LSD. Statistically significant elevations were found in the Psychasthenia (P<0.01), Schiz- ophrenia (P<0.01), Paranoia (P<0.05), and Taylor Anxiety Scales (P<0.05).

Methods of Measurement and Analysis

On the basis of the preliminary work described above, methods for measuring both the "mental" and the "nonmental" aspects of the reaction were developed. Pupillary diameter, systolic blood pres- sure, and change in patellar reflexes were chosen as objective and measurable signs of the LSD reaction. Systolic blood pressure was measured after 10 minutes' rest in bed, using the standard auscultatory method. Pupillary diameter was esti- mated as described above. Patellar reflexes were graded according to the following system: Grade 0: No response elicitable, even with rein-

forcement Grade 1:

forcement

Response elicitable only with rein-

Grade 2: Response elicitable without reinforce-

excursion after light tap less than a 6-in. arc and not repetitive

Grade 3: Response elicitable with light tap; ex- cursion greater than 6-in. arc

Grade 4: Response very quick, forceful, and repetitive; almost complete extension of leg These measurements were made at hourly inter-

vals for two hours before and eight hours after

ment ;

administration of LSD. Data obtained were plotted on graph paper and the area under each curve measured with a planimeter, thus

summarizing the data for each particular measure- ment in one figure. The average of the pre-drug measurements was used as the base line in each case.

Mental effects induced by LSD were assessed in two ways: 1, The questionnaire devised by Abramson and associates" was administered hourly for two hours before and for eight hours after LSD. The number of positive responses on the questionnaire was counted over the entire eight- hour period after administration of LSD, but answers to questions which were also. scored positive before administration of the drug were eliminated. The questionnaire includes such items

t Belleville, R. E.: MMPI Score Changes In- duced by Lysergic Reid Dithylamide (LSD-25), to be published.

confused," This ques-

as "I am trembling inside," "I am "Things seem near or far away," etc. tionnaire has several disadvantages—it may sug- gest symptoms; few positive responses are given to many of the questions, and it does not cover all the mental phenomena observed after LSD. The questionnaire, however, has the advantage that a systematic record of certain symptoms is obtained at definite intervals before and after administra- tion of the drug.

1. The degree of mental effect was also assessed by conducting a short psychiatric examination be- tween the second and fourth hour after admin- istration of the drug. In carrying out this exami- special attention was given to anxiety, nervousness, perceptual distortion, presence or absence of hallucinations, and _ insight, "grade" was assigned to the reaction according to the following scheme :

Grade 1: Anxiety and nervousness, without per- ceptual distortion or hallucinations

Grade 2: Anxiety, nervousness, and visual per- ceptual distortion without "true" hallucinations

Grade 3: Anxiety, nervousness, perceptual distor- tion, and "true" hallucinations, but with insight maintained

Grade 4: Same as Grade 3, except that insight

(realization that the effects are due to the drug)

is lost

The grading the time course and on the response to increasing dosage observed in the preliminary work. The system has

nation,

and a

system was based on

the disadvantage that the various grades may not form a continuous scale (Grade 2 may not be twice that of Grade 1). It gives no information concerning the quantitative aspect of the symptoms which go into determining the grades. Also, Grade 4 was seldom reached with doses of less than 3y/kg.

These methods were tested by determining the response to graded doses and by determining the

Patellar reflext

Pupillary diameter?

| Blood pressuret

| Questions§

Grade§

• Data on seven patients only.

+ Data on six patients only.

t Expressed as mean area under curve (square inches). § See text for method.

reproducibility of the reaction in the same sub- jects.

Response to Varying Doses.—Eight non- tolerant Negro males were used in this ex- periment. They were given, under "blind" conditions and in randomized order at weekly intervals, a placebo and 0.25y, 0.5y, 0.75y, ly, 1.5y, and 2y per kilogram of body weight of LSD. Two of the patients, who were very sensitive to LSD, did not receive the 2y dose, and one did not receive the 1.0y dose. Observations were carried out as described above. Results obtained with the various doses are shown in Table 1. Allowing for the omission of the sensi- tive patients in the 1.5y and 2y columns, the degree of change in all measurements increased with the dose. Peak effects were attained at the 1.5y/kg. dose except for blood pressure. Statistical analysis, using a t-test for paired observations *® showed that changes from placebo to LSD were significant (P<0.05) for all measurements at all doses except 0.25y/kg. Differences between doses that varied as much as ly/kg., e. g., between 1.0y/kg. and 2.0y/kg., were statistically significant, whereas differences between doses varying 0.5y/kg. or less, e. g., between 0.5y/kg. and 1.0y/kg., were not sig- nificant.

Although the number of patients used was small, the results showed that the degree of effect was related to the dose and _ that methods were useful in assessing the in- tensity of the LSD response.

[Tables 1–3 showing dose-response and tolerance data omitted.]

EXPERIMENT 3.—Six Negro males served as subjects for this experiment. Five of these had been diagnosed as having character disorders and one as having an inadequate personality. No evidence of psychosis was found on _ psychiatric examination of any of these patients. Intelligence quotients ranged from 84 to 125. Prior to chronic intoxication, patients were tested at weekly inter- vals and in randomized order with doses of 0, 90y to 130y, 140y to 150y, and 180y of LSD (approx- imately ly to 1.5y, 1.5y to 2y and 2y to 3y per kilogram).

no

Measurements were made as described above. Following completion of the initial testing, five patients were placed on a single daily dose of 90y to 130y of LSD once daily for seven to eight days. The dose was then increased to 150y for three days and then to 180y for three days. One of these five patients withdrew after the

AR $Q. IN.

PATELLAR REFLEX

PUPILLARY [} SIZE

SYSTOLIC BLOOD PRESSURE

DEGREE OF MENTAL EFFECT

ANSWERS ON QUESTIONNAIRE

VAI

PRIOR TO C ADMINISTRATION

Fig. 1—Tolerance to LSD in Experiment 3.

c

ninth day. The sixth patient, who had a very severe reaction to the 180y test dose, began chronic intoxication with a dose of 50y of LSD, which was gradually increased to 180y by the 22d day of chronic intoxication. Questionnaires were obtained daily, and the clinical grade was assessed daily. Pupillary size, knee jerks, and blood pressure were At

the end of the 14 days of chronic administration

measured at intervals of three to four days.

in four patients and of 22 days of chronic intoxi- cation in one patient, LSD was discontinued without the patients' knowledge, water being given in its place. Five patients were tested with a single dose of 120y to 130y two to six days after discontinua- tion of LSD.

Results —The _ results graphically in Figure 1.

are protrayed On the left, in individual blocks, are shown the mean re- sponses of the six patients to the three doses of LSD and to placebo prior to chronic intoxication. The results on patellar reflex, pupillary size, and systolic blood pressure are expressed in terms of the area under the time action curves (see 'Methods

py)

DAY OF CHRONIC ADMINISTRATION

of Measurement"). Degree of mental ef- fect and number of positive answers were assessed as described above. The mean re- sponses to LSD during chronic administra- tion are shown on the right, in the large block. In reading the Figure, it is necessary to remember that one patient withdrew after the ninth day and that the measure- ments obtained during only the first 14 days of chronic intoxication of the patient who received the drug for 22 days are included in the values shown. A rapid decline in the degree of response during chronic ad- ministration, despite the increase in the dose of LSD, is obvious. Statistical analy- sis, using a method for paired observa- tions,*" showed that the differences between the results before and after three days or more of chronic administration were highly significant statistically (P<0.01) for all measurements.

Patients did not notice the transition from LSD to water at the end of the period of chronic intoxication. The reaction was as intense three days after discontinuing LSD as prior to chronic intoxication.

The development of tolerance can best be illustrated by comparing the reaction of one patient to a dose of 180y before and during chronic intoxication. When this dose was given prior to chronic intoxication, the pa- tient became extremely anxious and felt that he was being shocked with electricity. His body seemed to shrink and enlarge. His hands appeared to have extra fingers. People and objects changed size, shape, and color. The walls

shadows and colors.

were a_ flickering of He felt that he would die or would become permanently insane. Blood elevated 60 mm. of

mercury; pupils were maximally dilated;

pressure was knee jerks were very hyperactive; spon- taneous tremors of large muscle groups were observed, and ankle clonus could be elicited. After recovery from this severe reaction, the patient wished to drop out of the ex- periment but, after considerable persuasion, agreed to continue. He was started on 50y of LSD once daily, and this dose was in-

creased until he again received 180y of LSD on the 22d day. At this time he had no subjective effects, sat quietly, read, and watched His reflex, pupillary, and blood pressure changes were minor.

[Experiment 4, a 91-day tolerance trial with similar findings, omitted.]

Comment

The effects induced by LSD appear to be the same in former opiate addicts as in nonaddicts, despite great differences in ethnic backgrounds, socioeconomic status,

Fig. 2.—Tolerance to LSD in Experiment 4.

life history, personality patterns, and the environment in which testing with LSD was carried out. This fact indicates that the LSD reaction is, to some extent, independ- ent of these variables. The LSD reaction appears to be a specific toxic psychosis which is mimicked only by intoxication with mescaline. It differs in its clinical features from the toxic psychoses induced by scopo- lamine, cannabis, cocaine, or withdrawal of alcohol and barbiturates.

Under the conditions of these experi- ments, the LSD reaction, when viewed in toto, had only a superficial resemblance to the chronic forms of any of the major psychoses. Symptoms suggesting schizo- phrenia which occurred in various patients included depersonalization, derealization, confusion, withdrawal from other persons, and changes in response to psychological tests. Affect, however, usually seemed ap- propriate, and auditory hallucinations were rare, as were ideas of reference and control. Systematized delusions were never observed. The outstanding change after LSD appears to be visual perceptual distortion. The kaleidoscopic changes in size, form, and color of objects, persons, and the patient's own body are very characteristic of the

| CURVE

REFLEX size * PRESSURE ' OF MENTAL EFFECT

das so ANSWERS

Dose MCG/KG. 5 40 3 Yy Yj YA 7 4 2x 3x 4X 2 3 TOLERANT DAY OF CHRONIC EFFECT OF INCREASING DAYS OFF LSD 'ADMINISTRATION DOSE WHILE TOLERANT a

= g :

LSD psychosis and are not a common part of the symptomatology of schizophrenia. The neurological signs induced by LSD are also not found in schizophrenia.

If it had been possible to maintain the original degree of effect throughout the experiment, the resemblance of the LSD psychosis to schizophrenia might have be- come more pronounced. It is conceivable that schizophrenia is associated with some chronic perceptual disorder and that a per- son who is having peculiar sensory experi- ences may develop peculiar explanations for these experiences. Such explanations might be interpreted by a person who is not experiencing such distorted perception as delusional thinking, and hence as evidence of schizophrenia.

Summary

Summary

In former opiate addicts, the diethylamide of lysergic acid (LSD-25) induced anxiety, mood changes, feelings of unreality, visual perceptual distortion, optical hallucinations, depersonalization, and derealization. Con- comitantly, resting blood pressure was ele- vated, pupils were dilated, and the tendon reflexes accentuated. Characteristics of the LSD reaction appeared to be the

were

References 31, 32.

same in former opiate addicts and in non- addicts.

The degree of both the "mental" and the "nonmental" changes increased with the dose of LSD. The intensity of the reaction induced by LSD remained the same when the same dose was repeated after an in- terval of a week or more.

When LSD was given daily, tolerance was evident after administration for only three days. After tolerance was well de- veloped, administration of as much as four times the standard dose of LSD did not re- store the original intensity of the reaction. On discontinuation of LSD, tolerance was lost as rapidly as it was developed.

[References list omitted.]