(ESTIMATED PUB DATE) CROSS TOLERANCE BETWEEN MESCALINE AND LSD-25 WITH A COMPARISON OF THE MESCALINE AND LSD REACTIONS

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00151800
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 14
• Document Creation Date: January 21, 2025
• Document Release Date: September 8, 1976
• Publication Date: January 1, 1962

Psycliopharmacillogia 3, 1-14 (1902)
From the National In.stitute of Mental Health Addiction Research renter
U.S. Public Health ;'..'erviec Hospital Lexington, Kentucky, U.S.A.
Cross Tolerance between Mescaline and LSD-25
With 3 Comparison of the Mescaline and LSD Reaytions
By
A. U. WoLamm Mums TsumA, and E. J. MINER
With 2 Figures in the Text
(Receired .Vorrtnber S. 1961)
Although some differences have.been reported. the reactions produced
in Man by the diethylamide of lYsergic acid (LSD-25) and mescaline
seem very similar. Both drugs cause autonomic stimulation manifested
by increased papillary size, increase in pulse rate and blood pressure, and
elevation of body temperature (B,tr-EsTmEni and FONTANARI ; BUCHA-
NAN ; HOCH ei al.; IsBELL et at., 1956; STOCKINGS ; STOLL). Both create
anxiety, difficulty in concentration and thinking, flight of ideas, fluc-
tuations in mood, perceptual distortion in all sensory modalities, true-
and pseudo-hallucinations usually of visual nature, and depersonali-
zation (ABRAmsos et at.; BERING ER; BUCHANAN ; a-mi.-Ls and Mac--
LAY; Hoox et al.; ISBELL et at., 1956; iNfavEn�Guoss; RLNKEL et at..;
STOCKINGS; STOLL). Some authors have referred to the mental state
induced by either agents as "experimental schizophrenia" (RIslux, et
at.; STOCKIN GS).
The clinical resemblance of the syndromes caused by mescaline and
LSD-25 suggest that these drugs, despite differences in chemical struc-
ture, either share a common mechanism of action or act on final common
pathway. This hypothesis is strengthened by reports of cross tolerance
between the two drugs (BALEsTRIERL 1957, 19(30; BALESTREERI and
FONTANARI) .
The purposes of this paper are: (1) to present a quantitative compari-
son of the effects of LSD-25 and mescaline in the same subjects; and
(2) to show, in confirmation of BALESTRIERI (1957 und 1960) and BALE-
STRIERI and FONTANARI, that direct tolerance develops to mescaline.
and that subjects tolerant to mescaline are cross tolerant to LSD awl
vice versa.
Methods
Experiments. Two experiments were performed, Experiment I was
a comparison of the effects and a determination of the equivalent dosages
of LSD, mescaline, and psilocin in 10 subjects. The data on psiloein will
3
jerk were calculated by subtracting the average of the two pre-drug
observations from the values obtained at the various hours after the
drug. The areas under the time-action curves for each of the above
measurements composed of these figures were calculated by the method
;'Of WmEn and FLA.TAKER, thus converting all the data on a particular
drug, a particular measurement, and, a particular day to one figure
termed "degree-hours" (temperature), "rate hours" (pulse rate), etc.
"Positive" answers on the questionnaire were scored by counting all
positive responses that were not scored positively before the drugs were
given. Means, and standard errors of the means were calculated accord-
ing to standard statistiCal techniques (Enw.utns). Callculations of the
relative potency of LSD and mescaline were performed on each of
these parameters, using a method (Gannt-m) for four-point assays.
In order to obtain time-action cuives, changes in temperature, pulse
rate, systolic blood pressure, pupillary size, and threshold for the
kneejerk were tabulated and averaged for each observation time after
the drugs. The number of positive responses on the questionnaire were
also averaged at each observation time. In addition to providing data
on the time-action course, these tabulations identified the time at which
the greatest (peak) responses occurred. Additional calculations of re-
lative potency (Gannum) were made using these peak values.
In order to compare the patterns of subjective response the 57 ques-
tions were classified into nine categoriesl. The questionnaires were then
scored by counting the. number of patients responding positively to
a given question, after which the scores for all the questions constituting
.the particular category were summed.
Experiment II
Experimental design.. A "crOss-over" design using each patient as
his own control was employed in this experiment and is summarized
in table 1. The design was similar to that used in testing cross-tolerance
between LSD and psilocybin (Isamu, et at., 1961).
Subjects. The same 10 subjects were employed who were used in
Experiment I.
General conditions. Subjects were housed in the same special research
ward mentioned in Experiment I. Temperature, respiratory rate, and
blood pressure were measured three times daily after the patients had
rested quietly in bed during days on which special measurements were
The nine categories are shown in Table .5 and are the same that were used in
comparing LSD and psilocybin 1959). As previously explained, a large
number of other categories could be devised and many questions could be classified
in various categories. The classification therefore is completely arbitrary.
1*
ef�
4
Table 1. Summary of experimental design. Experiment II
� �
Period
Number
�I dal'
Mims and imses
�
-
Remarks �
-
Subjects X,
Subjert.41.,
1. 1st control
7-21
LSD 3 1.5,
esc.3 5.0
Mese. 5.0,
LSD 1.5
To obtain basal data.
Order Of tests ran-
domized. Minimum
.. of 3 days between
LSD and mescaline
2. 1st chronic admini-
14
LSD
31esc.
To develop tolerance
stration ,,: '
increasing
to 1.5
increasing
t03.()
3. let test of tolerance
and..cross-tolerance .
2
LSD 1.5,
3fesc. 3.0
3fese. 5.0,
LSD 1.3
Test of tolerance and
cross tolerance '
4. Withdrawal period
14
- none
none
To lose tolerance
5. 2nd control
10-24
'Mese. 5.0,
LSD 1.3
LSD 1.5,
3Iesc. 5.0
To replicate control
data and test loss of
tolerance
6. 2nd chronic admini-
14
Mese.
LSD
"Cross-over" to (level-
stration
increasing
to 5.0
increasing
to 1.5
op tolerance
7. 2nd test of tolerance
and cross-tolerance
2
3Iesc. 3.0,
LSD 1.5
LSD 1.5,
3Iese. 3.0
Test of tolerance and
cross-tolerance
'Subjects "X" rece'ved LSD chronically, first.
. . 2 Subjects "Y" received mescaline chronically, first.
LSD = diet hylarnide of lysergic acid; Mese.. = mescaline. The order of
administration of the drug in each period is indicated by the order in which they
appear in the section of table for that period. Figures after symbols for drugs indi-
cate the dose in mcg/kg for LSD and mg/kg for mescaline.
not being made. All measurements were made by the same aides as in
Experiment I.
Drugs and doses. .LSD and mescaline were administered intramuscu-
larly at 8 a.m. (during the control period and on test days) or at 6 a..m.
(during the periods of chronic intoxication). No placebos were employed
in this study because of the negligible subjective response of our sub-
jects; because placebos have no real value in assessing tolerance and
doss tolerance, and because the addition of placebo trials would have
prolonged the experiment unnecessarily. In the first and second control
periods the patients received LSD 1.5 meg,'1.-g, and mescaline 5.0 ingkg
in randomized order before chronic administration of the drugs was
begun. Detailed observations were made on these test days. These
control experiments were conducted at intervals of at least five days
in order to prevent development of tolerance during the control period.
During the first and second periods of chronic administration, the
patients received intramuscularly 0.30 mcgkg of LSD or 1 ing; kg of
5
mescaline on the first day. These doses were increased by 0.30 meglkg
(LSD) or 1 mg/kg (mescaline) daily until the patients were receiving
.L5 mcg/kg of LSD or 5.0 ingkg of mescaline on the fifth day. These
doses were maintained through the 14th (lay after beginning Chronic
intoxication. On the 15th day the patients were "challenged" with the
dose of drug they had been receiving (test of "direct" tolerance). On.
the. 16th day they were "challenged" with the test dose of ,the alternate
drug (test of "cross" tolerance). On both of these days detailed measure-
ments were made.
The patients then,received no medication for 14 days in order to lose
tolerance:
� FollOialing this withdrawal period. "second control" measurements
were obtained after the patients: had received in randomized order
mescaline 5.0 mg'kg, and LSD 1.5 Meg:kg, with at least five days inter-
vening between administration of either drug.
The patients then again received the drugs chronically; those patients
who had received LSD in the first period of chronic administration were
given mescaline according to the schedules described above and vice
versa. They were then "challenged" with LSD and mescaline in the
same manner as previously described.
Observations. On test days all observations were performed in identical
fashion to those described in Experiment I.
Analysis of data. The areas under the time-action curves were
obtained for each subject and each test condition (including first and
second controls and all "challenging" tests) in the manner described in
Experiment L In addition, mean peak response values were obtained
(as in Experiment I) for each parameter except "clinical grade," since
the latter consisted of only a single figure.
� The difference in the various area measurements after. 1.5 meg'kg
of LSD on the first and second controls were evaluated by a t-test for
paired observations (Enwanns). Data on the two sets of controls after
5.0 mg/kg of mescaline were treated similarly. Increase in blood pressure
was significantly greater after LSD. There were no significant differ-
ences on other parameters (Table 2). In addition, the differences between
the two controls were evaluated by a non-parametric rank order test for
paired observations (Wmcoxos). Since the significances of the differ-
ences by this latter statistical technique agreed well with those obtained
by the t-test on the time-action (area) figures, only the latter are herein
presented.
In order to test for equivalence of the doses of LSD and mescaline
in Experiment II. the average peak values obtained on the two controls
with 1.5 meglkg of LSD were compared with the average values obtained
o �
S
���1/4
1
11
to LSD (fourth column of figures), significant degrees of change occurred
in four parameters. The measures which reflected "direct" tolerance
and "cross" .tolerance most clearly were pupillary diameter, responses
on questionnaire, and the clinical grades.
Table 7. Tolerance and cross tolerana
Atter LSD chronically (14 days)
Atter mescaline chronically (14 days)
Measure
test with LSD
.claallensce with Ines-
test with mescaline
challenge with L'A)
"direct" tolerance
caline ''crass" tole-
"direct" tolerance
'.:CrO�5 ' rt.lerance
to LSD
ranee to mescaline
to mescaline
to LSD
Temperature
0.275 .- 0,139
-- 0.503� 0.564
- 1.14� 0.59
- 0.231 0.493
Pulse rate
Blood
.7
'-- 26.90 �12.33
i .
-43.10 �13.033
-33.00�16.15
-24.20 �12.95
pressure
7-46.25 �i4.103
1- 42.05 -:- 16.50'
- 32.60-1- 14.98
-62.90 -t- 11.303
Pupillary,
change
-12.20 -4- 1.293
_
- 9.11 =- 1.223
- 8.40� 1.283
- 6.88 -L 0.763
Kneejerk
-40.25 �16.251
-53.S5 �18.792
- 8.73 -- 11.71
-19.58 �13.37
Responses to
questionnaire
-40.85 J- 3.903
-69.30 -4-15.633
- 47.35 -L- 7.613
-56.40 -�-� 9.703
Clinical grade
- 1.20 -1- 0.203
- 1.40 -1- 0.323
- 1.45� 0.243
- 1.30 -L 0.30'
Figures represent the mean differences -L the standard errors of the differences
between responses to first control doses of LSD-25 (1.5 mczikg) or mescaline
(5.0 mg/kg) and identical "test" and "challenging" doses of these drugs after
a first period of chronic intoxication with either drug; and, second control doses of
LSD-23 (1.5 meg/ kg) or mescaline (5.0 mg/kg) and identical "test" and. "challenz-
ing" doses of these drugs after a second period of chronic intoxication with the
other drug.
Indicates increase in response after chronic intoxication.
- Indicates a decrease in response after chronic intoxication.
" Indicates significance (P < 0.05).
2 Indicates significance (P < 0.02).
3 Indicates significance (P < 0.01).
Discussion
As expected from the descriptions in the literature, the reactions
induced by LSD and mescaline proved remarkably similar, differing
chiefly in rate of onset and duration of action. Both drugs caused similar
changes in autonomic functions which were nearly identical in degree at
doses inducing equivalent grades of mental aberration. The subjective
symptoms reported after the two drugs were very similar in kind and
incidence. It is, of course, possible that the similarity in the subjective
response was partly caused by the methods of measurement and the
experimental situation. All of our subjects had received LSD on other
occasions and might have expected similar symptoms from any drug
given in this particular testing situation. In addition, the use of the
questionnaire may suggest certain symptoms. However there are cogent
10
be noted that mescaline is more potent in dilating pupils relative to its
potenc� in inducing subjective responses than is LSD.
Experiment II. Cross tolerance between LSD and mescaline. Controls.
The differences in responses to the same drug in first and second controls
after LSD and mescaline are shown in Table. 2. The only change that
was statistically significant (p z 0.05) was an increased elevation of
blood pressure after the second control dose of LSD. This could indicate
simple variability of response to LSD on this particular parameter.. The
table shows that no significant degree of residual tolerance was present
at the time the second controls were done.
�Rguivalence of dosage. The differences in the mean peak responses
to the two different active drugs (LSD and znesealine) are presented in
Table.3. It will be noted that although four of the six comparisons indi-
cate'that LSD may have produced a somewhat stronger response than
-mescaline, the only statistically significant difference between the two
drugs is in elevation of blood pressure. The magnitude of the difference
is small and probably reflects the variability of response on blood
pressure after LSD when administered on separate occasions to the
same subjects (see above). Since the majority of differences are posi-
tive, there is some indication that, on the average, the peak effects of
LSD may have been somewhat stronger than those of mescaline. Simi-
lar calculations using area measurements instead of peak values gave
_identical results with one exception. Total papillary dilatation after
mescaline was significantly greater than that after LSD. This difference
from the results with the peak data reflects the more sustained action
of mescaline on the pupil.
Tolerance and cross tolerance. The differences in responses to LSD
and mescaline after chronic administration of either drug and their
respective first and second controls are shown in Table 7. In this table
the first column of figures shows the difference in response to LSD as
compared with the corresponding first or second control after chronic
administration of LSD, and reflects "direct" tolerance to LSD. The
second column of figures shows the difference in response to mescaline
-43 compared with the appropriate control after chronic administration
of LSD, and reflects "cross" tolerance to mescaline. Similarly, the third
column of figures presents measures of "direct" tolerance to mescaline,
and the fourth column of figures, "cross" tolerance to LSD.
Inspection of Table 7 shows that all the signs are negative, indicating
an average decrease in response on all measures. In the case of "direct"
tolerance to LSD (first column of figures), the differences were statisti-
cally significant in six of the seven measures. In the case of "direct"
tolerance to mescaline (third column of figures), statistically significant
change occurred in three measures, and in the case of "cross" tolerance
" _Table 3. Equiralence of dosage of LSD
and mescaline, Experiment II PT = 10
Measure
Mean Difference in
response (RLSD'Illfese)
Temperature
Pulse rate . . .
Blood pressure .
Pupillary change
ICneejerk . . .
Responses to
questionnaire .
Clinical grade. .
- 0.0055 =0.05
+2.80 = 1.85
+4.15 =1.441
-0.212 �0.171
+1.94 �2.10
+1.45 �1.92
-0.35 �0.24
Figures respresent mean differences
S:E. of differences between mean peak
control responses to LSD-25 (1.5 mcgikg)
and mescaline (5.0 mg/kg).
+ Indicates LSD.25 stronger in effect
than mescaline.
- Indicates mescaline stronger in
effect than LSD-25.
1 Indicates significance (P < 0.02).
6
Table 2. Reproducibility of responses to LSD and mescaline in, first and secoml con-
.
Isola(N=10)
Measure
� LSD-25
-Mescaline
Temperature
Pulse rate
Blood pressure
+ 0.282� 0.372
+ 14.95 =13.68
+ 33.35 =14.031
- 0.516 = 0.480
+18.65 �14.12
-10.30 = 9.71
Pnpillary change
+ 0.325� 1.75
- 0.263� 1.27
Kneejerk
- 6.24 =12.95
+ 2.75 = 21.63
Responses to questionnaire.
+ 10.35 = 9.68
_- 4.60 = 8.56
Clinical grade
+ 0.150 0.211
+ 0.100= 0.221
Figures represent the mean differences = the standard errors of the differences
bet)veen responses to LSD-25 (1.5 mcgikg) and mescaline (3.0 mg/kg) in the first
and-second controls.
+ Indicates an increased response on the second control.
- Indicates a decreased response in the second control.
1 Indicates siznificance (P < 0.05).
on the two controls with 5.0 mglirg of mescaline (Table 3), ,using the
t-test for paired data. Similar calculations were made using the area
measurements.
The differences in the response after chronic administration of both
LSD and mescaline were evaluated by comparing the responses after
first and second chronic admini-
strations of LSD and:or mescaline
with their respective first and.
second controls using the t-test
for replicated data (Enw.IRDs).
Four different comparisons were
made: (1) response to LSD after
chronic administration of LSD
("direct" tolerance to LSD), (2)
response to mescaline after chronic
administration of LSD ("cross"
tolerance to mescaline), (3) re-
sponse to mescaline after chronic
administration of mescaline
("direct" tolerance to mesca-
line), and (4) response to LSD
after chronic administration of
mescaline ("crosss" tolerance to
LSD). The signs of the diffe-
rences were so arranged that
a minus (-) sign indicated a decrease in the measurements after chronic
administration as compared with control, and a. plus sign indicated
an increase.
.0 �
8
Table 5. Comparison of pattern of subjective response on questionnaire after mesealine
and LSD-25
�
Category I
�
Number of
questions*
Ti/e31
re-.4ponses
possible
Number of rrspon;es in catt.-4 ,rY
placebo'
LSD
mesa aline
0.75
1.5
2.5 5.0
General
7 .
70
0
18
30
19,
26
Difficulty in thinking ..
4
40
0
0
14
3
4
Alteration in mood . .
3
30
0
14
15
6
9
Alteration in touch . .
4
40
0
13
20
1.5
26
Alteration in heariiig .
4
36
0
16
20
11
18
Visnal distortion . . .
10
40
0
10
39
12
23
"Elementar,y" halluci-
nations
5
45
0
3
20
8
20
"True" hallucinations. �
4
40
0
2
6
1
5
Depersonalization. . .
13-
130
0
26
44
23
34
1 Refers to type of question, e.g., "feeling strange" (general)- "feet look old"
(depersonalization); am happy" (mood); -things look small" (visual distortion);
"is difficult to concentrate" (thinking), etc.
2 Number of subjects times number of questions in category.
3 Based on responses of 10 different subjects in another experiment.
the changes in the various measures were far greater than those that
occurred in a different group of subjects after placebo. The magnitude of
.these changes was about the same after 0.75 mcg,-kg of LSD and 2.3 mg kg
of mescaline, crafter 1.5 incg kg
of LSD and 5.0 mg, kg of
mescaline. Both drugs induced
Measure anxiety, alterations in mood
(generally "euphoric"), diffi-
culty in thinking and concen-
tration, sensory perceptual
distortion particularly visual,
and both caused true- and
pseudo-hallucinations. The
subjective symptoms reported
after mescaline were very
similar to those described in
the literature. Table 5 illu-
1 Meg mescaline hcl strates the similarity of the
patterns of the subjective
response after LSD and
mescaline.
Table 6. Relative potencies of mescaline and
LSD calculated from various measurements
Relative
potency'
Ilnuts
95% confidence
Areas
Temperature .
3270
2666-3731
Blood pressure .
3034
9275-4000
PttpiLs2 . . .
9392
1779-3274
Total answers .
3355
2437-5065
Peak values
Temperature .
3280
3165� 3401
Blood pressure.
3344
1698� 7313
Pupils . . . .
2970
2008� 4201
Answers . . .
4373
2332-10000
Clinical grade .
3460
2194-- 5430
Meg LSD-25 tartrate at equal effect
2 Did not meet criterion for equivalence
of dosage.
LSD and mescaline diffe'red in time-action course. In general the
action of mescaline persisted longer than that of LSD :with peak effect
being reached later and/or being longer sustained (Fig. I and 2). These
9
curves show that pupillary dilatation after both mescaline and LSD lasts.
much longer than do the subjective effects. They also show that the ;
peak subjective effects of mescaline, as measured by the responses on
the questionnaire, were less than those after LSD. The subjective effects
of mescaline subsided more slowly than did those of LSD.
Mescaline
LSO Soma/4
ts-m.cg119
412 ZSrr.grAi
c4.
a
7 47 23S 6 7 8
hrs after drug
Fig. I. Time course of pupiltary dilatation after LSD and me5caline
6 7
hr s after drug
Fig. 2. Time course of subjective respcnase after LSD and mescaline
Calculations of relative potency are summarized in Table 6. Signifi-
cant dose-effect slopes were not obtained for pulse rate and threshold
for the kneejerk for either area or ,peak data, so these measures are
omitted from the table. Significant slopes were obtained on all other
measures and, with the exception of area measurement for pupillary
change which did not meet the criterion for equivalence of effects at
the doses used, the regression lines for all these measures met the re-
quirements for equivalence of dosage and parallelism. These calculations
show that LSD tartrate is about 2400 to 4900 times as potent as mesca-
line hydrochloride, depending on the measurement chosen. On a mole-
cular basis, LSD is 4500 to 9275 times as potent as mescaline. It should
2
not be presented in this paper but will be reported separately: Experi-
ment II was a study of cross tolerance between LSI) and tnesealine in
10 subjects.
Experiment I
Experimental design. . A "single-blind" cross-over design was em-
ployed in this experiment (patients did not know the drugs they were
receiving, but observers did known). Each subject received, in rando-
mized order at weekly intervals, two doses of LSD and mescaline.
Placebos were not included since experience (IsnEtt. et al., 1956. 1960
: has shown that former morphine addicts do not react markedly to
placebos. For comparison, placebo data from another experiment
- (IsnELL et al., 1959) are presented.
Subjects. The subjects who volunteered for this experiment were
former opiate addicts who were serving sentences for violation of 'United
States narcotic laws. Their ages varied between 25 to 3:1 years, all were
physically healthy males, and none presented any evidence of the major
psychoses. All had psychiatric diagnoses of character or personality
disorders and all had received LSD in previous experiments.
General conditions. The subjects entered a special ward devoted to
clinical research the night before the day on which test drug was ad- ,
ministered and remained until the following morning. Observations
were performed by specially trained aides with long experience in detect-
ing behavioral changes due to drugs. The patients were told nothing
about the nature of the drugs they were to receive or the purposes of the
experiments.
Drugs and doses. LSD tartrate and mescaline hydrochloride were
administered intram'useularly in doses of 0.75 megikg and 1.5 megikg
(LSD), and 2.5 mg/kg and 5.0 mg/kg (mescaline). The drug concen-
trations employed for LSD and mescaline were 30 meglinl and 100inmind
respectively, in distilled water. Prior to administration each dose was
diluted to a constant 5 ml volume with sterile pyrogen-frce physiological
saline solution. The following detailed observations were made at
.. hourly intervals after 10 minutes rest in bed, twice before, and eight
times after administration of drugs: rectal temperature, pulse rate.
systolic blood pressure, pupillary size, and threshold for elicitation of the
kneejerk. The methods used were those previously described by IsBELL
et al. (1956, 1961). In addition the subjects (with the help of an aide)
completed a special questionnaire at hourly intervals from 7.30 a.m.
to 3.30 p.m. At these same times general notes on behavior were written
Clinical grades of the intensity of the reaction were assigned aecomlin,
to the system of 'Isur.a.t. et al. (1956).
Analysis of data. The changes in rectal temperature, pulse ra-ti
pupillary size, blood pressure and threshold for elicitation of the knee
�
7
Since mescaline has a longer duration of action than LSD the
differences (except for "clinical grade") were also evaluated, using
values obtained at the peak of both LSD and mescaline reactions rather
than using the areas (integrated time action curves) as described above.
� In addition, the differences were evaluated by Wu-coxox's non-para-
metric rank order test for paired observations. The significance of the
differences by these statistical techniques agreed well with those obtained
by the t-test on the time-action (area) figures, so only the differences .
obtained by the area methad are shown in this paper.
� Results
. Experiment I. The objective and subjective changes induced by LSD
and mescaline were very similar. As can be seen in Table 4, both drugs
Table 4. Comparison of the total course of the LSD and mescaline reactions
Placebo,
Treatment
LSD-25
mescaline
0.733 1.5"
2.33
3.0'
Tempera-
ture
Pulse
rate 4 �
Blood
pressure a
Pupillary
change 4
+ 2.7� 0.3
+ 37.3 =14.5
+ 15.6�13.5
+ 0.2� 1.4
+ 3.5 = 0.4
�50.2 = 10..2
+ 45.5 = 12.5
+ 8.0 = 0.9
4.3 = 0.5
56.6 = 7.7
6.5.2 -- 10.1
12.9 = 1.6
+ 3.4 = 0.4
+ 33.4 = 9.3
+45.4 =13.5
+10.4 = 1.6
+ 4.6= 0.4
+ 71.1 -1- 17.7
+ 76.6 -= 12.4
+ 17.3 = 2.0
Kneejerica
Positive
answers'
Clihcai
gral4e4
- 20.7 = 11.1
0.1� 0.3
0 = 0
-54.2 =11.0
37.1 = 4.7
1.83� 0.2
-54.0 = 9.6
72.3 =11.1
2.45� 0.2
-65.5 =15.1
35.3 = 5.9
1.63� 0.
-70.1� 16.9
67.2 =12.1
2.1� 0.2
Data from 9 other subjects in another experiment (Isszt.r., 1959)
2 Dose in meg/kg.
'Dose in. mglicg.
'Figures are means (9 subjects on placebo; 10 on LSD and mescaline) = stan-
dard errors of areas under time-action curves (" deg.ree-hours," "beat-hours," etc.).
The signs indicate increases (+) or decreases (-) in the measurement from pre.
drug controls.
'Means -1- standard errors of number of questions scored positively in the
71/, hours after the drug which were not scored positively before the drug.
'Means 4- standard errors of intensity of mental reaction based on a scale of
caused increases over pre-dnig measurements in body temperature,
pulse rate, systolic blood pressure, and pupillary size, and both decreased
the threshold for elicitation of the kneejerk. The table also shows that
12
reasons against the similarity being due to the experimental situatlon
or to suggestion. The patterns of effect after many other drugs (am-
phetamine, scopolamine, marihuana, etc.) in the same kin& of subjects
and under the same conditions differ markedly from the pattern induced
by mescaline and LSD. In addition, the ziruilarity between the LSD and
mescaline reactions. is readily apparent in the descriptions in the litera-
ture, even though the subjects were tested under widely varying condi-
tions with different methods, and in subjects who received only mescaline
or LSD. Thus it seems likely that the similarity between the reactions
caused by LSD and mescaline is a real phenomenon and not an artifact
due to the methods of testing.
he similarity of the effects of LSD and mescaline suggests that the
two drugs act by common mechanisms or through some final common
pathWay. This hypothesis is strongly reinforced by the finding (in
agreement with BALESTRIERI, 1957) that definite cross tolerance develop-
ed between both drugs on chronic administration. Direct tolerance to
mescaline and cross tolerance to LSD could not be demonstrated on
as many measures in patients receiving mescaline chronically as could
direct tolerance to LSD and cross tolerance to mescaline in patients
receiving LSD chronically. However a high degree of direct and cross
.tolerance. occurred in both instances on the most reliable and least
variable of the measures (pupillary change, responses on the question-
naire, and clinical grade).
Since persons directly tolerant to LSD are cross tolerant to �psilo-
cybin (IsBELL, 1961) it seems likely, although not proved by direct
experiments, that persons directly tolerant to psilocybin would be cross
tolerant to mescaline. LSD, mescaline, and psilocybin appear to con-
stitute a definite group of drugs with identical.or closely related biological
effects, just as morphine, methadone and meperidine constitute a bio-
logically related group of analgesic drugs exhibitiqg high degrees of
cross tolerance. �
Since psilocybin is an indole and since LSD can be regarded as an
indole; one might hypothesize that the similarities in biological effect
and the development of tolerance and cross tolerance are related to
similarities in chemical configuration. Mescaline is, however, not an
indole, and although it has been postulated that mescaline is converted
to an indole in the body, no direct evidence of such a biotransformation
exists at present. In fact, investigators who have studied the biotrans-
formation of mescaline have reported that mescaline is excreeted largely
unchanged (Woons et al.), or partly unchanged and partly as 3.4,5-tri-
methoxyphenylacetie acid (SrEcTon). For the moment. it seems best
to attribute the similarities of action of LSD, mescaline and psilocybin
to some common biological mechanism rather than to similarities in
chemical structure.
D
14
FREEDMAN, D. X., G. K. AGIIAJANIAN, E. M. ORNrrz and B. S. ROSNER: Patii;rmi.
of,Mlerance to lysergic acid diethylamicle and mescaline in rats. Science 127,
1173-1174 (1938).
GADDr3i, J. H.: Bioassays and mathematics. Pharmacol. Rev. 5, 87-134 (1933).
GUTT3IANN, E., and W. S. MacLAY: Mescaline and depersonalization. J. Neurol.
Psychopath. 16, 193-212 (1936).
HOCII, P. H., J. P. CaTTELL and H. H. Ps: Effects of mescaline and lysergic
acid (d-LSD-25). Amer. J. Psychiat. 108, 579-584 (1952).
IsRELL, H.: Comparison. of the reactions induced by psilocybin and LSD in'inati.
Psychopharmacologia I, 29-38 (1939).
� 'R. E. BELLEVILLE, H. F. FRasErt, A. WIRLER and C. R. LOG.: Studies on
lysergic acid diethylamide (LSD-25). I. Effects in former morphine addicts
and -developmeirt of tolerance during chronic intoxication. Arch. Neurol.
Psychiat. (Chicago) 76, 468-473 (1956).
� A. B. WOLBACH, A. WIELER and F,. J. MINER: Cross tolerance between LSD
and psilocybin. Psychopharmacolozia 2, 147-159 (1961).
MATER-GRoss, W.: Experimental :psychoses and other mental abnormalities pro-
duced by drugs. Brit. med. J. 1951 II, 317-321.
-Rolm, M., H. J. DESnoN, R. W. HYDE and. H. C. SOLomoN: Experimental
schizophrenia-like symptoms. Amer. J. Psychiat. WS. 572-577 (1932).
SPECTOR, E.: Identification of 3,4,5-trimethoxyphenylacetic acid as the major
metabolite of mescaline in the dog. Nature (Land.) 189. 751-752 (1061).
STOCEINGS, G. T.: A clinical study of the mescaline psychosis with special reference
to the mechanism of the genesis of schizophrenic and. other psychotic states.
J. merit. Sci. 86, 29-17 (1940).
STOLL, W. A.: L3.-sergsaure.dia,thylamid, em Phantasticum aus der 3lutterkorn-
gruppe. Schweiz. Arch. Neurol. Psychiat. 60, 279-324 (1947).
Wrt.coxoN, F.: Some rapid approximate statistical procedures. New York:
American Cyanamid Comp: 1949.
WINTER, C. A., and L. FLATafiER: Studies on heptazone (6-morpholino-4.4-di-
pheny1-3-heptanone hydrochloride) in comparison with other analgesic drugs.
J. Pharmacol. exp. Ther. 98, 305-317 (1930).
WOODS, L. A., J. Coc-fax, E. J. FORNEFELD, F. G. 3Ic3laRoN and M. H. SEEvERS:
The estimation of amines in biological materials with critical data for cocaine
and mescaline. J. Pharmacol. exp. Ther. 101, 183-199 (1051).
HARRIS IsRELL, M.D., Director N.I.3I.H. Addiction Research Center
U.S. Public Health Service Hospital, Lexington, Kentucky,
13
Summary �
1. The reactions caused by intramuscular administration of 0.7mcgi
kg and 1.5 mcgikg of LSD-25 have been compared in the same 10 sub-
jects with those induced by 2.5 mg/kg and 5.0 mg/kg of mescaline.
2. Both LSD and mescaline caused dilatation of the pupils, increase
in body temperature, elevation of pulse rate and increase in systolic
blood pressure. Both drugs decreased the threshold for elicitation of the
kneejerk.
3. After both drugs, similar abnormal mental states characterized by
anxiety, difficulty in thinking; alteration in mood (generally euphoric),
altered sensory perception. (particularly visual), elementary and true
visual hancinations and alterations of body image were reported by
the subjects.
4. The effects of mescaline appeaceci more slowly and persisted some-
what longer than did the effects of IfSD.
5. LSD tartrate is 200-1900 times as potent as mescaline hydro-
chloride. On a molecular basis, LSD is 4500 to 9275 times as potent- as
mescaline.
6. Patients receiving LSD daily developed direct tolerance to LSD;
such patients were also cross tolerant to mescaline. Likewise patients
receiving mescaline daily became tolerant to mescaline and cross tolerant
to LSD.
7. It war inferred that LSD, psilocy-bin and mescaline probably share
common mechanisms of action or some common final pathway.
Acknowledgments. We are indebted to Drs. R. BIRCHER and C. HENZE of
Sandoz Pharmaceuticals, Hanover, N.J., for supplies of diethylamide of lysergic
acid tartrate (LSD-23), and to Dr. L. A. Pim:, Hoffmann-La Roche, Inc., Nutley
Park, N.J., for supplies of mescaline hydrochloride.
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BUCHANAN, 11. N.: 3Icskalinrausch. Brit. J. med. Psycho!. 9, 67-88 (1929).
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