THE EFFECTS OF D-LYSERGIC ACID DIETHYLAMIDE ON CEREBRAL CIRCULATION AND OVER-ALL METABOLISM By Louis Sokoloff, Seymour Perlin, Conan Kornetsky, and Seymour S. Kety Reprinted from ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Volume 66, Article 3, Pages 468-477 March 14, 1957 THE EFFECTS OF D-LYSERGIC ACID DIETHYLAMIDE ON CEREBRAL CIRCULATION AND OVER-ALL METABOLISM By Louis Sokoloff, Seymour Perlin, Conan Kornetsky, and Seymour S. Kety National Institute of Mental Health, National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare, Bethesda, Md. d-Lysergic acid diethylamide (LSD-25), a partially synthesized derivative of ergot, has recently been found to produce in minute doses marked aberra- tions in psychological and mental functions.!:?:* Because these disturbances simulate to some degree those observed in naturally occurring psychoses, there has been considerable interest in its mode of action. It has been suggested that the psychotomimetic action of lysergic acid is related to its reported antagonism to 5-hydroxytryptamine (serotonin), °° a compound normally present in the brain.” Since serotonin is known to have powerful vasocon- sttictor properties, it is conceivable that the antagonistic action of lysergic acid might be reflected in changes in the cerebral circulation. Furthermore, since the normal functions of the brain are completely dependent on a con- tinuously obligatory consumption of oxygen and glucose, it might be supposed that disorders in the biochemical processes underlying the functions so grossly disturbed by LSD-25 would be reflected in alterations in the oxygen and glu- cose utilization by the brain. Mayer-Gross, McAdam, and Walker®: * have found both in vitro and in vivo evidence for disturbances in carbohydrate metabolism produced by LSD-25. An increase in circulating hexosemono- phosphate and glucose in vivo and a decreased breakdown of hexosephosphate in brain and liver in viiro have led these investigators to postulate that LSD-25 causes an increased metabolism of glycogen coupled with a block in the break- down of hexosemonophosphate. Studies of the effects of lysergic acid on cere- bral oxygen consumption have previously been done only in vitro, and these have led to contradictory results.” In order to determine the effects of LSD-25 on the cerebral circulation and oxygen and glucose metabolism of individuals actively demonstrating the be- havioral changes produced by the drug, measurements of these and related functions were undertaken in normal or nonpsychotic, conscious human sub- jects. Also, in consideration of the remote possibility that schizophrenic patients might react differently to the drug, similar studies were performed in a group of such patients. Method Cerebral blood flow (CBF) was measured by means of the nitrous oxide method® in 13 normal or nonpsychotic subjects and 9 chronic schizophrenic patients during a resting or control period and again during the height of action of intravenously administered LSD-25.* Eleven of the normal subjects were conscientious objectors or members of a religious sect who had volunteered to be experimental subjects in medical research. Of the remaining 2, both of * LSD-25 supplied in 1 cc, ampules containing 0.1 mg. per cc. by Sandoz Chemical Works, Inc., Hanover, N. J. 468 Sokoloff et al: LSD-25 on Cerebral Circulation 469 whom had volunteered for this specific procedure, one (Rb. M.) was a normal working employee and the other (J. K.) a patient whose diagnosis was “anxiety neurosis.”” The schizophrenic patients were of most major types and had been selected from a hospitalized population on the basis of their anticipated co- operativeness during the procedure. Some of the patients, as well as the nor- mal subjects, had been given trial tests with LSD-25 no less than 1 week pre- viously in order to determine their responsiveness and the nature of their response to the drug. This screening was done to favor the occurrence of a definite reaction, but one not too violent to interfere with the procedure during the cerebral blood flow studies. The duration of the disease in the schizo- phrenic patients ranged from 5 to 22 years, and all exhibited mild to moderate deterioration. In addition to psychotherapy, almost all of the patients had re- ceived some form of shock or drug therapy, but in no case during the year preceding the time of these studies. Each study consisted of two determinations of cerebral blood flow and asso- ciated functions, a control measurement followed by an experimental deter- mination during the drug action. Immediately following the control measure- ments, the symptom questionnaire designed by Abramson and his co-workers!4 was administered to all the normal! subjects and to those schizophrenic patients who were communicative. Following the completion of the questionnaire, 120 ug. of LSD-25 were injected intravenously in all but one normal subject (M. G. L.) and one schizophrenic patient (V. S.), in whom the dose injected was 100 ug. Administration of the symptom questionnaire was repeated at approximately 15, 40, 105, and 165 minutes following the drug injection. Because the mean number of symptoms appeared to be maximum at the 40-minute point, the experimental measurements of cerebral blood flow and associated functions were made at that time. Mean arterial blood pressure (MABP) was measured with an air-damped mercury manometer connected by plastic tubing to the femoral arterial needle. Mean internal jugular venous pressure (MJVP) was determined by means of a Statham P23B strain gauge connected to the internal jugular venous needle and used in conjunction with a Brush Universal amplifier and oscillograph, the former modified to permit electrical integration of the venous pulse for the de- termination of mean pressure. Blood oxygen and carbon dioxide contents were determined by the manometric method of Van Slyke and Neill. Arterial hemoglobin concentration was measured photometrically by a modification of the method of Evelyn and Malloy.'* Blood glucose concentrations were de- termined as the mean of triplicate determinations by the Nelson method.” Blood pH was measured anaerobically at ambient temperature by means of the MacInnes-Belcher glass electrode and Cambridge Model R Potentiometer and was corrected to 37° C. by means of the factors of Rosenthal. Blood oxygen saturation was determined spectrophotometrically by means of a modi- fication of the method of Wyeth, Ecker, and Polis.!®° Blood carbon dioxide tension (pCO) was computed by means of the nomograms of Peters and Van Slyke Calculations of cerebral blood flow (CBF), oxygen consumption (CMRo,), glucose utilization (CMRg), vascular resistance (CVR), and _ res- piratory quotient (R.Q.) were made as previously described.” 470 Annals New York Academy of Sciences 20 SYMPTOMS N N . OF ‘ Co eae CRF STUDY ome awe DATA FROM ABRAMSON ET AL CORAL ADMINISTRATION) NUMBER MEAN So PRET 15 30 40 90 105 150165 210 ‘se TIME AFTER DRUG IN MINUTES Ficure 1. Graphic illustration of responses to symptom questionnaire of Abramson et al.44 following oral and intravenous administration of LSD-25. Results In FIGURE 1 are graphically represented the results obtained in norma] sub- jects with the symptom questionnaire when administered before and at various times subsequent to the intravenous injection of LSD-25. The results obtained by Abramson and his co-workers following oral administration of the drug are similarly plotted for comparison. It is clear from FIGURE 1 that in normal subjects intravenous administration of LSD-25 does not result in any greater symptom formation than does oral administration, but the peak mean number of symptoms occurring at approximately 40 minutes following injection of the drug precedes the peak achieved with oral administration by nearly an hour. For this reason, the intravenous route of administration was chosen in these studies, and experimental data on cerebral circulation and metabolism and re- lated functions were collected at approximately the 40-minute point. Since the symptom questionnaire could not be satisfactorily administered to schizo- phrenic patients, it was assumed that the timing of the LSD-25 effect was similar in this group, and the same schedule of experimental measurements was followed as in the normal subjects. In TABLES 1, 2, and 3 are presented the data on the cerebral circulation and metabolism and related functions obtained in both the normal subjects and the schizophrenic patients. In both groups LSD-25 failed to produce any statisti- cally significant change in pulse rate, respiratory rate, or oral temperature, al- though the change in pulse rate in the normal subjects from a mean control value of 78 to a mean experimental value of 91 beats per minute was only barely short of statistical significance (p < 0.1 > 0.05). In both normal subjects and schizophrenic patients slight but statistically significant in- Sokoloff et al: LSD-25 on Cerebral Circulation TABLE 1 Errects or Lysrrcic Acip DIETHYLAMIDE ON PULSE, RESPIRATION, AND Bopy TEMPERATURE 471 Pulse Respiratory Oral temp. °C. . Interval Dose per min. rate per min. . Subject Sex Age interval in pg. I II I | II I It Thirteen Norma! Subjects M.G.L. M 19 91 100 68 78 18 20 | 36.2 _ WwW. W. M 28 127 120 74 | 110 15 18 36.8 37.3 Rb. M. M 30 100 120 82 80 21 24 | 36.6 | 36.6 ALR. M 19 110 120 58 56 18 21 36.9 36.8 J. K. F 46 120 120 83 80 19 16; 36.6] 36.2 D. B. M 24 107 120 80 82 16 17 36.9 36.7 M.L. F 22 150 120 90 85 20 17 36.8 36.7 L.N. F 24 138 120 99 | 114 18 21 37.4 | 37.2 H. H. M 25 116 120 76 | 166 10 14 | 37.4] 37.5 C.S. F 18 111 120 val 80 18 20} 37.1 36.8 Rn. M. M 19 127 120 77 84 14 16 36.7 37.2 D. H. M 19 100 120 72 78 22 20 | 36.6] 36.9 M.G. F 18 129 120 88 | 94 16 10 | 37.5 36.7 Mean.......... _— 24 117 78 91 17 18 | 36.9 36.9 Standard error...) — | +2 | +5 — | 43] 47} 41] 41) +0.1 | 40.1 Pe — —_ — |!<01>0.05 >0.4 >0.6 Nine Schizophrenic Patients V.S F 41 108 100 76 96 20 | 22 36.9 —_ T.H M 36 95 120 92 92 22 20 | 36.3 36.9 R. T M 22 82 120 60 84 16 12 36.6 — P.L M 33 82 120 104 | 105 14 15 37.0 | 37.0 J. W M 33 128 120 92 82 8 14 37.0 | 37.0 W.H M 27 113 120 76 78 19 26 | 36.8 37.3 W.C M 34 76 120 101 87 27 23 37.0 | 36.9 B.G M 31 112 120 102 | 119 32 24 | 36.6} 38.2 D.L M 27 80 120 94 | 102 20 | 21 37.01 37.3 Mean.......... —_ 32 97 89 94 20 20 | 36.8] 37.2 Standard error..| — +2 +6 _— ~5 | &5 | 42! 42 | +0.1 | 40.2 DR ee — — _— >0.2 >0.9 >0.1 T: control. II: during period of LSD-25 effect. * Determined by the method of paired comparison. creases in mean arterial blood pressure (MABP) were produced by the drug rising from 86 to 91 mm. Hg (p < 0.05) in the former and from 90 to 97 mm. Hg (p ~ 0.02) in the latter. Mean internal jugular venous pressure (MJVP) was unaffected in the normal subjects but in the schizophrenic patients was raised significantly from 7 to 9 mm. Hg (p ~ 0.02) by the drug. The effects of LSD-25 on the various cerebral circulatory and metabolic functions studied, for example, cerebral blood flow (CBF), vascular resistance (CVR), oxygen consumption (CMRo,), glucose utilization (CMR), arteriovenous oxygen and glucose differences [(A-V)o, and (A-V)g, respectively], and R.Q. were re- markable only for the absence of any statistically significant changes. 472 Annals New York Academy of Sciences - MOO AMON AM AN OO com wow N ° a AAARSSAARAADMA | AS SASSSSESS | SS w a SSOSesnscssocHs oF SrAscddon lic = = Ho g RANNMAMVSOFWARON | HAS S a ADARWDAKRAOHAOWAAlLASA SHSSASTLSS | Maa £ al esccococseeseonsosse loo 2 PLAN NAN | NO & + eSonsnescss oF SiH SwWH Oo ww an 1 as! 4 J] | peeeesarsy, | [od le tlaee See AG 4 Hee WO het | sus oe mos Ox ——s i HA 3a Tee Se Lee ACMA non = Se a | | [ [meena | 6S | Se 4 tod lias eaF ei SS Raat at an nae ai Ss 4 [| | [atewse 4 “cs | nie ead of. a An wince alee “gs Wa ea : o.5 —— ° ese AAO Cpe A ma S35 | Ff ft ,, y 2 OO HOO Ink | ain a ba -_ | | [ PmmiaEo | olne | oe Bo Os 4 Sass bu | wos [I HY s HEM SHA wei ans See eee 28 mon 4 = I] [| teeezesy | | ae | lesa | oe Bs> : 7 > HI MOMOS A SAR = eS To NMASO HHA | RawA < al I] ppessesdes ajeg | | = z S Be Nba aon “¢ Oo _—_ = 7 7 is a AMAAMMINAM Doo aa con < On a pH NAN HHH [ot | iS ee |e ae PB Be 2 ye oo — So eS a ok Rmeasoanm+ malRAA ou A oO 3S m Swat fad lsd conwcomans | aa as + hoot th un aten en oF Hy} - < PWOOANWASCAT SMe | aw a % a a gl] ABWMONSAVAANMG | He 7 ZESISSGAG Ae a 7 3 MONO OOAtIANN HN | Ine 5 Pee ee ess a are 3 4 Bl comnunatnied fs . mn |S a ee & J-_| Bj te |] He 2 WARM MANNE DAO ~ ~ a —_ Fs Nn oO =o Al FRSSRSLHSSISS BAA 5 Ne Vw Bes © aon A fore ee ee co nS Z u a mw a} SSHS TK Sw Su |S By TES pies ic) z, — £ + Oo A HO 8 80 tH mo WO a +H FQ 5 a +e o et ¥ Oo NOMA HO Qo | ms oS Q ~ o 4 2 IAA tS on S| tameeae, o | 2B B be a | [adntdendspscfac Bp tae _ a aie col 5 Z|) acHtHseenta ao] Arig. o He a “35. a2] % o/s |-—| 2} -———__—_ a | HS r 5 Z —_ i oa PEE a | Nt NOM aS aSA a wo ed ayOErs Hw |G] 64 | aénedsn peal ss | WAeUsawaen | so q 9 ¥ 7 | Addn Sots] as & ff —_-___ 4H g ~ . am ~~ a od fav gersestens|eeler AD og a BOOMS SoD | ao | SH msinsnen le | int a oe | a SELARES Sj Lf AS —_— =s m s os o Be reed eet ie BOO OR QO OO HH yt ~ a Ss al RReESSRESAS LON Sh GY GG | ° E eo ool NA] [eeronmanmns |uis as 4 x bd Fis SEM OWDOSH A | OSA, a & : Heo a : -_ >A 2 — - — — : ~ Se [SA 105 NO ] Homo iinin pins 7 4 ze al l H IS IOI CATO ig fu ee i ° ooo : Ao mt moonmmmraononr loa | 5 Gi ea} _ WASH AADCACOM > Hin OM OWmBDADMH PNA nm ee = SS ot [es aAao 2 =| S& o ensweeunsucene lm =) ie en DOMmI~DAAWWOA ~ oO 4 mM OO OInin aA on a RABDWAWDMARRHR oy | i t: . | po: 2 4. . : Lee s.. ; : : : 2 OE inte mm ke Soe set eg yf oF 3 7 ee ete: mee MOR | 8 | a : ae mn: tt — m wt soe ye tet ee : a aeedsAsimumed | 6: PouMAseemeg | oS z: ZB: a: a: sv: sz: t ae) ac: o 3 oa \ | =e S34. | AN ASI * Determined by the method of paired comparison. Il: during period of LSD-25 effect. I: control. £LP TABLE 3 Errrects or Lysercic Acti) DIETHYLAMIDE ON BLoop CONSTITUENTS Blood Oz content in Blood CO: content in Blood glucose concen- Blood pH | Blood CO: tension in |Blood OQ saturation in Art. hemo- volumes % volumes “} tration in mgs. [% p | mm. Hg percentage globin con- | b centration ' ~ a Subject | in grams % . : . . i . . } mgrams vo) Arterial Int. Jugular| Arterial Int. Jugular Arterial Jundiar Arterial | Int. Jugular Arterial Juediar Arterial juntlar ! i ' : oo ee _ : | I | Il I | II I | II I | ir: I | ll | I | IL I | II I | HW I | iH I II I IE T | IL I | i i : I | __ Thirteen Normal Subjects M.G.L 16.49) 16. 25| 20.66} 20.81 14.20! 14.84) 45.63 45.38" 51.91: 50.96, — _ _ —_ 7.35} 7.35| 7.33 | 44 $2. | Sd -1) 63.1 W.W. 14.07] 15.09) 18.75] 20.12 11.76; 13.54] 47.94] 46.58! 54.68 52.85] — — _ — 7.41] 7.39] 7. | 42 50 | 49 -9| 66.5 Rb. M. 15.18) 15.63) 19.14] 19.15] 13.47] 13.59) 48.26 46.28; 53.45° 51.27; — | —_ _ _ 7.42: 7.40 7. | 40 46 50 -2} 70.9 ALR. 14.68] 15.17] 19.50] 20.10) 12.97] 13.78] 49.74] 48.57; 55.30 54.69) — | — _ _ 7.42) 7.44 7, 1 38 49 47 -5| 69.1 J. K. 13.57; 13.98] 18.12} 17.68] 13.33] 13.46) 46.26) 45.91! 51.01 50.22; 84.5] 74.4) 79.1] 69.6) 7.43° 7.39) 7. 40 47 47 33) 72.5 D. B. 15.09; 15.63 20.65] 21.20] 13.00) 14.15! 41.34] 38.04) 48.46 45.27! 107.8] 109.7] 100.5]/101.0! 7.47: 7.46] 7. 30 41 37 -8| 67.3 M.L. 13.49; 14.35] 18.08! 18.42] 11.33] 11.43) 49.55] 47.97} 55.64 53.58! 82.3] 86.3) 76.0] 78.0) 7.38! 7.37) 7.3 1 43 Si] Sl -01 60.4 L.N. 12.381 13.49) 16.91] 17.72) 11.34] 11.42! 46.85] 44.70] 51.53 50.66; 98.7, 99.3] 66.7] 64.2; 7.43! 7.42] 7. 137 | 42 | 46 -7, 64.2 H.H. 15.63; 16.70] 20.46; 22.16 4.39) 12.17) 48.89) 30.02) S4.44. 39.94: 93.7, 129.4) 80.9/114.8) 7.45 7.54) 7. | 20 i 50 51 9) S44 Cc. S. 12.46; 13.66] 16.68) 17.72) 11.32! 12.81) 45.97] 46.13] 51.46! 50.69 96.8! 92.7; 87.0) 84.21 7.39, 7.35] 7. ; 435 48 50 5.7 70.3 Ro. M. 14.89} 15.63; 19.70) 20.49] 14.28] 15.23] 46.96] 45.28 51.67; 49.55) 89.5) 91.0; 79.5) 84.8: 7.39. 7.37) 7.3 » Al 48 49 -5! 72.2 D.H. 13.37] 13.12] 17.53) 17.47] 13.90! 14.24) 45.06) 44.56[ 49.28: 44.81) — _— _ _ 7.38. 7.38) 7. | 39 45 47 -O} 77.6 M.G. 12,91] 12.91] 17.03; 17.14! 11.66 11.63! 46.31) 45. 20) 51.43] 50.59) 101.0) 94.9) 89.1) — 7.39) 7.40) 7. | 38 48 47 -7/| 65.1 Mean qo 14.17] 14.74 a 19.25] 12.84. 13.25] 46.83 $4.2) 52.34) 49.62! 94.3) 97.2 a 85.2| 7.41] 7.40] 7.36] 7, 36 39.7) 38.1) 47.5) 48. -9) 67.4 tandar | error..... 0.35/40. 34)+0.40'+0.46 +0.34l40.35 +0.62/+1.37; pho. oe #1.12/4 3.0) 45.8 3.5) +6.7/40.01;40.01 £0.011-40.01 i£0.7'41.8)20.9'+1. 11.6 | <0.01 <0.01 >0.1 <0.1>0.05, 0.02 >0.5 ~0.5 >0.6 | >0.4 >0.3 >0.3 0.7 Nine Schizophrenic Patients V.S. 11.25] 13.37) 17.00) 18.10] 11.08] 11.56] 46.40] 44.02. _ _ | _ es 7.48| 7.48] 7.46 7.43 32 i 32 37 | 39 96.91 94.9) 66.2] 66.3 T.H. 13.66) 14.35} 18.15) 18.76) 13.42] 14.81] 47.32] 46.30 72.7) 75.8) 65.0! 69.9] 7.38) 7.37) 7.32 7.34) 42 42 51 54 97.2; 95.5] 70.0] 73.9 R.T 14.77) 16.25| 19.79: 21.50) 14.11] 15.58) 49.38] 46.38 83.7} 83.4| 78.6) 75.7; 7.36) 7.40) 7.30) 7.34: 46 41 57 51 97.4) 98.8] 67.3} 70.3 PLL. 14.77) 15.18! 19.05] 19.42) 13.73] 12.02} 43.15] 36.61 173.0] 155.0) 168.0/142.0, 7.49] 7.46) 7.34] 7.42! 32 28 44 36 98.4} 97.9] 68.8] 58.2 J. W. 14.35) 14.48: 18.29) 18.40) 11.61] 13.01] 42.70] 44.58) 101.0} 97.7} 92.0) 88.0; 7.41] 7.38] 7.33] 7.34) 36 40 49 48 98.0] 97.5] 59.6] 66.8 W.H. 13,28] 13.57| 18.01] 17.88; 12.98] 13.51] 48.27] 48.94 _ _ _ > 7.41] 7.41, 7.37) 7.37] 40 39 46 48 98.0] 97.6] 69.0) 72.6 W.c, 13.20] 13.57) 17.75] 17.20) 11.80] 11.73] 48.86] 46.67 87.7| 98.3} 79.0] 89.7 7.37) 7.37) 7.32) 7.31) 43 42 54 52 99.4) 97.2) 71.5) 71.1 B. G. 15.65; 16.49] 20.14] 21.53) 14.05; 15.24! 42.68) 36.31 96.6) 119.0) 85.9|108.9| 7.40; 7.38] 7.34! 7.33) 38 34 47 43 97.8] 98.0! 67.3] 67.6 D.L. 13.57] 14.15 18.50) 18.52} 13.72] 14.00; 48.02) 46.19 91.5) 94.6; 83.61 85.4 7.37} 7.37) 7.33} 7.32] 43 42 51 51 97.9| 97.7) 71.9] 72.7 rea a 13.83] 14.60) 18.52} 19.03] 12.94) 13.50] 46.31} 44.00) 51.54) 49.43/100.9 | 103.4] 93.2| 94.2; 7.41] 7. | 7.35) 7.36) 39.1] 37.8] 48.4] 46.9) 97.9) 97.2] 68.0) 68.8 tandar error..... £0.42! 0. 38/40. 33/40. 51/40. 38/+-0.51)/+0. 91/41. 50/40. 83141. 29/412. 7/4-10.0/412.9!+9, 2/-+0.02/-+0.01 0.02/40. 01/1. 7/1. 7/42.0/42. 1/0. 2140.4) 41. 2141.6 PR eee <0.0t <0.1 > 0.05 >0.1 <0.05 ~0.02 >0.6 >0.8 >0.4 | >0.3 >0.t >0.1 >0.1 >0.6 I; control. II: during period of LSD-25 effect. * Determined by the method of paired comparison. 474 Annals New York Academy of Sciences Arterial hemoglobin concentration was significantly elevated by LSD-25 in both normal subjects and schizophrenic patients, rising from mean control values of 14.17 and 13.83 gm. per cent to mean experimental values of 14.74 and 14.60 gm. per cent, respectively (p < 0.01 in both groups). As a conse- quence of the hemoconcentratiof, mean arterial oxygen content rose from 18.71 to 19.25 vol. per cent (p < 0.01) in the normal group, but in the schizophrenic patients the increase to 19.03 vol. per cent during the LSD-25 action from a control value of 18.52 vol. per cent only approached statistical significance (p < 0.1 > 0.05). The slight increases in oxygen content observed in the internal jugular venous blood were not statistically significant. Arterial carbon dioxide content was reduced in normal subjects by LSD-25 from a mean control value of 46.83 vol. per cent to 44.20 vol. per cent, a change barely lack- ing statistical significance (p < 0.1 > 0.05). Internal jugular venous carbon dioxide content was reduced significantly from 52.34 to 49.62 vol. per cent (p < 0.02). In the schizophrenic patients LSD-25 caused a fall in both arterial and cerebral venous carbon dioxide contents, the former decreasing from 46.31 to 44.00 vol. per cent (p < 0.05) and the latter from 51.54 to 49.43 vol. per cent (p ~ 0.02). It is likely that the tendency for carbon dioxide contents of the arterial and cerebral venous bloods to fall during LSD-25 action was the result of hyperventilation. The fact that the decreases in carbon dioxide tensions in the same bloods were not statistically significant probably reflects only the greater precision of the method for measuring blood carbon dioxide content as compared with that for calculating blood carbon dioxide tension. In both the arterial and internal jugular venous bloods of both the normal subjects and the schizophrenic patients, glucose concentration, pH, and the percentage of oxygen saturation of hemoglobin remained unchanged by LSD-25. Discussion Perhaps the most obvious and striking feature of the results reported here is the remarkable paucity of effects of LSD-25 on the cerebral circulatory and metabolic functions studied. Indeed, except for the minimal increases in ar- terial hemoglobin concentration and mean arterial blood pressure and a marked dilatation of the pupils, there is little in the results of these physiologica! studies to indicate any activity on the part of the drug. This is equally true for both the normal and schizophrenic groups. On the other hand, the results of the psychological and psychiatric evaluations of the drug action clearly demon- strated the characteristic responses ascribed to LSD-25. It is, therefore, neces- sary to conclude that the disturbances in psychological and mental functions produced by lysergic acid are unrelated to any changes in the cerebral circula- tion or those aspects of the metabolism that are reflected in the rates of oxygen and glucose utilization by the brain as a whole. These results concerning the effects of LSD-25 on the in vivo cerebral metabo- lism are in contrast with some of those obtained in studies on cerebral tissue in vitro, For example, Mayer-Gross, McAdam, and Walker® have reported that in guinea pig brain brei, lysergic acid produced a stimulation of oxygen con- sumption associated with a decreased utilization of hexosemonophosphate. Sokoloff et al: LSD-25 on Cerebral Circulation 475 Grenell!® has observed a similar stimulation of oxygen consumption by LSD-25 in cortical homogenates but one associated with a decrease in the recoverable adenosinetriphosphate. On the other hand, Lewis and MclIlwain"™ have ob- served slight depressions in oxygen consumption produced by LSD-25 in corti- cal slices of guinea pig brain, and the inhibitory effect of the drug was en- hanced by electrical stimulation of the tissue slices. Geronimus and his co-workers” have also observed an inhibitory effect of lysergic acid on brain oxygen consumption im vitro. In view of these contradictory findings in vitro, which are in disagreement not only with our in vivo findings but also among themselves, it is difficult to evaluate their significance. Indeed, in an organ such as the brain in which the normal function of the cellular elements depends to so great an extent on the normal interaction of those elements, particularly as regards the processes affected by LSD-25, any effects observed ix viiro that are in disagreement with those im vive must be seriously questioned before attaching any great functional significance to them. It is possible that the action of lysergic acid is associated with changes in cerebral circulation or metabolism, but in areas representing so small a fraction of the total brain that the effects are obscured in measurements in the brain as a whole. Alternatively, it may be that in a heterogeneous organ like the brain, many of whose parts are functionally inversely or reciprocally related, changes in metabolic activity in some areas are balanced by inverse changes in other areas so that the net metabolic rate of the brain remains unchanged. These possibilities await further evaluation by methods that measure blood flow and metabolism in localized areas of the brain in vivo. The psychotomimetic state produced by lysergic acid must now be added to a growing list of conditions in which gross alterations in mental and psychologi- cal functions are not related to any significant changes in cerebral circulation or metabolic rate. Thus a similar lack of changes in the latter functions has been observed in schizophrenia,” during the performance of mental arithmetic,” and during the action of the tranquilizing drug, chlorpromazine.» Also, although there is a slight but significant rise in cerebral blood flow, no change in cerebral metabolic rate occurs during natural sleep.2> On the basis of the results obtained in studies such as these, it has become increasingly obvious that the cerebral processes underlying many mental and psychological functions are too subtle to reflect their changes in the over-all circulation and metabolism of the brain. The only truly positive physiological changes observed in the present study were a marked mydriasis, a slight increase in mean arterial blood pressure, and a mild hemoconcentration. Whether the hemoconcentration represents an absolute increase in circulating hemoglobin mobilized from stored pools of red cells or is the result of a relative increase in hemoglobin concentration because of a loss of plasma volume remains undetermined. In any case, a similar com- bination of changes has been found to occur during the infusion of /-norepi- nephrine in man.2° This similarity of effects between LSD-25 and /-norepi- nephrine may be of interest in view of the suggestion by Rinkel and his associates” that the action of lysergic acid may be related to its interference somewhere in the adrenalin cycle. Although it must be pointed out that the 476. Annals New York Academy of Sciences elevated blood pressure and the hemoconcentration could both be explained by the increased motor activity that our subjects and patients exhibited under the influence of LSD-25, these findings are not inconsistent with the concept that LSD-25 exerts its effect through some involvement in the epinephrine system. Summary (1) Studies of the cerebral circulation and metabolism during a control period and during the height of action of intravenously administered LSD-25 were performed in 13 normal or nonpsychotic subjects and 9 schizophrenic pa- tients. (2) Despite the occurrence of the characteristic psychological and mental effects of LSD-25, there were no changes produced by the drug in cerebral blood flow, vascular resistance, oxygen and glucose utilization, or R.Q. in either the nonpsychotic or schizophrenic subjects. (3) Except for mydriasis, a slight elevation in mean arterial blood pressure, and a moderate increase in arterial hemoglobin concentration, the latter asso- ciated with a comparable rise in blood-oxygen content, LSD-25 did not produce any changes of significance in the various physiological functions and blood chemical constituents studied in both groups of subjects. Acknowledgments The authors express their appreciation to Robert Butler for his valuable aid in the selection and management of the schizophrenic patients and to June Gans, Mary Sultzer, Gladys Ellis, and Carolyn Smith for their technical assistance. References 1. Stort, W. A. 1947, Lysergsiure-diithylamid, ein Phantasticum aus der Mutter- korngruppe. Schweiz. Arch. Neurol. Psychiat. 60: 279. - Rinker, M., H. J. DeSnon, R. W. Hype & H. C. Sotomon. 1952. Experimental schizophrenia-like symptoms. Am. J. Psychiat. 108: 572. . Hocu, P. H., J. P. Cattery & H. H. Pennes. 1952. Effects of mescaline and lysergic acid (d-LSD-25). 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