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

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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. 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