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STUDIES CN THE DIETHYLAMIDE OF LYSERGIC ACID. 111. EFFECT OF PHENCXYBENZAMINE CN LSD-REACTION IN MAN.

Harris Isbell, M.D.
C. R.Logan
and
E. J. Miner

From the U. S. Department of Health, Education, and Welfare Public Health Service National Instifute of Mental Health Addiction Research Center Lexington,Kentucky

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STUDIES ON THE DIETHYLAMIDE OF LYSERGIC ACID. I1I. EFFECT CF PHENOXYBENZAMINE ON LSD-REACTION IN MAN.

A number of the signs and symptoms observed after administration of LSD -- pupillary dilatation, elevotlon of blood pressure, gooseflesh, anxiety, sense of gastrointestinal oppresslon, ete.  suggest hyperactivity of the sympathetic ladrenergic) nervous system. Rothltn and coworkers Il) have postulated that LSD has central vegetative lautonomicl effects. Chlorpromazine partially ameliorates the LSD reaction {2;3,4), and since chlorpromazine is a peripheral 151 and posslbly a central l6) adrenergic blocker, one might hypotheslze that chlorpromazine ameliorates the LSD reaction by virtue of. central adrenerglc blocking effects.

Recently Elder st al. [7j and Gogerty et al. (8) have presenied some interesting findings in experimental animals. Pretreatment with chlorpromazine reduces LSD-induced hyperthermia in rabbits and "feline-mania" in cats. If lSD Is given to rabblts within fwo hours after reserpine, hyperthermla is accentuated. At this particular time, release of norepinephrine 19) and serotonin (l0) from brain is occurring. lf LSD is given

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fen hours after reserpine Iwhen norepinephrine and serotonin have been depletedl LSD effects are attenuated. Most important, phenoxybenzamine Idibenzylinel, en adrenergic blocker wtth no known central effects, attenuated "feline-manta" induced by LSD.

Since very large doses of LSD are required to induce definite behavloral changes in antmals, and since the relationship of. any behavioral change induced in animals to psychotic symptoms In humans is always doubtful, it seemed important to study the effect of phenoxybenzamine on the LSD psychosis in man. The purpose of the present report is to present data showing that pretreatment with phenoxybenzamine did aot alter signlficantly the mental symptoms produced by LSD in human subjects, despite definite evidence of peripheral adrenergic blockade.

GENERAL METHCDS

Subjects. All were former morphine eddicts serving sentences for viclotion of narcofic laws who volunteered for the experiments. All were physically healthy adult Negro males who presented no evidence of psychosis on psychiatric examination.

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Druas. LSD tartrate and LSD placebo were administered arally io solution to patients in the fasting state. Phenoxybenzamine end phenoxybenzamine placebo were given in capsules. L-Eplnephrine HCL and epinephrine placebo were administered subcutaneously. Speclfic details on dosage are given under the perticular experiments.

Experlments were "double-blind" \_- nelther the patlents nor the observers knew what drugs had. been given. In evaluating the effect of phenoxybenzamine on the LSD reaction the following combinatlons of drugs were edministered at intervals of seven days in random balanced order: LSD placebo plus phenoxybenzamine plecebo, LSD plus phenoxybenzamine placebo, LSD plus phenoxybenzamine, and LSD placebo plus phenoxybenzamine.

Methods of Measurement. intenslty of the lSD reaction was assessed by methods previously described llll. The followlng observatlons were. obtalned at hourly intervals twice before and eight times after administraticn of LSD, or LSD placebc: puplllery size, threshold for kneejerk, systolic blood pressure, number of positive answers on a modification of the questioanaire devised by Abramson et al.tl2l, and the clinical grade, based on a short mental status examination (ll). Areas under timeaction curves were calculafed by the mettod of Winter and flataker [13t and resutts expressed as mm, hours (pupils),

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mm. hours (blood pressurel, and degree-hours (kneejerk). In addition, resting pulse rates, resting systolic blood pressures, and pulse rates and systolic pressure after standing for one minute were determined and time-action areas calculated. These lafter measurements could not always be cbtained (experiment 4) due to postural.hypotensicn with resultant fainting on standing.

Effects.of eplnephrine were assessed by measuring pulse rate and systolie and diastollc blood pressure at the fotlowing inferydis: 10 minutes before,, and immediately before subcutaneous injection of epinephrine or epinephrine placebo; 5, 10, 15, 20, 30,40, and 60 minutes after injection of epinephrine or placebo. Time-action areas were also calculated for these measurements.

Experiment i. Effect of I ma./kg. of Phenoxybenzamine Reaction Induced by 0.5-1.0 mccm./kg. of LSD. Phenoxybenzamine or phenoxybenzaminc placebo was administered orally in capsules at ó a.m., and LSD or LSD placebo orally in soiution at 8 a.m., thus allowing three to four hours for adrenergic blockade to develop prior to expected peak of LSD effects. four patients received combinations of l.O mcga. of phenoxytenzamine or phenoxybenzanine placebo with O.5 mcgm./kg. of LSD.or LSD placcbo. Since the number of subjects was small, and since the results were similer to the group that received l.O mcgm./kg. cf LSD, the results will not be presented in detail.

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Six patients received combinations of l.0 mg-/kg. of phenoxybenzamine or phenoxybenzamine placebo with l.0 mcgn./kg. of LSD or LSD placebo. Results are presented in table. l. Both the number of answers and the clinical grade were less after the combination of LSD plus phenoxybenzamine, as compared wIth LSD alone. The differences, however, were not statistically significant. Phenoxybenzamine did reduce pupillary dilstation significantiy after LSO, but had no effect cn the LSD-induced rise in resting systolic blood pressure or on the decreased threshold for the kneejerk. Milosis, postural hypotensicn, and postural tachycardia indicated that some degree of peripheral adrenargic bicckade had occurred after phenoxybenzamine alone. LSD was an effective antidote for the postural hypotension after this dose of phenoxybenzamine.

Experiment 2. Blocking of Epinephrine by 1.0 mg./ka. of Phenoxybenzamine. Since no definite attenuation of the LSD reaction was observed In the previcus experiment, it seemed wise to determine whefher the dose of phenoxybenzamine used would significantly alter the response fo epinephrine. Four patlents were "challenged" with 0.4 to 0.6 mg./70 kg. of eplnephrine subcutanecusly before and three hours after ingestion of l.O mg./kg. of phenoxybenzamine. Results were controlled by plocebo injections before and after phenoxybenzamine. Nieasurements were those described above under general methods.

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Resuits are shown in table 2. As expected, no blocking of the increase in pulse rate. induced by eplnephrine was observed after phenoxybenzamine. Rise in systolic blood pressure after epinephrine was reduced by phenoxybanzamine, but the reduction was not significant statistically in this small çroup. The decrease in dlastolic pressure after epinephrine was enhanced after phenoxybenzamine. These resulfs indlcafed that some degree of adrenerglc blockade was present.

Experiment 3. Blocking of Epinephrinc by 2.5 mg./kg. of Phenoxybenzamine. Eight patients received 0.5, 1.0 and 1.0 mg./kg. [total of 2.5 mg./kg.1 of phenoxybenzamine at 26, 13, and 3 hours prior to challenge with 0.6 mg-/70 kg. of epinephrine. A second test with epinephrine was carried out five hours after the last dose of phenoxybenzamine. The results are shown in table 3. A definite diminution in the rise in systolic pressure after epinephrine was observed five hours after the last dose of phenoxybenzamine-as well as a merked enhancement of the decline in diastolic blood pressure after both test doses of epiaephrlne. ln addition, all patients were unäble to stand quietly for more fhan à minute without beccming dizzy or fainfing. Since these findings were compatible with a considerable degree of adrenergic blockade, this dosage of dibenzyline was used in experiment 4.

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Experiment 4. Effect of 2.5 mg./kg. of Phenoxybenzamine IDiylded Dosesl on. fhe\_LSD-Reactlon. Ten patienfs received 0.5, 1.0 and 1.0 mg./kg. of phenoxybenzamine lor phenoxybenzamine placebo) 24. 11, and 2 hours prlor to l.0 mcgm./kg. of LSD.

Results are shown In table 4. Although the effects of phenoxybenzamine were so pronounced that 5 of the patlents fainted on standing for less than one minute, there was no reductlon ia the number of symptoms reported or in the intensity (cllnicai grade) of the reactlon after phenoxybenzamine combined with LSD. A significant reductlon In pupillary diameter was noted but the other indicators of LSD effect, including the rise in systolic blood pressure, were unaffected. LSD tended to antagonize the effect of phenoxybenzamine on the pulse rate when standing.

DISCUSSION

No definife evidence of attenuation of the LSD-induced mental symptoms by phenoxybenzamlne was cbserved in the experiments described above. it hardly seems likely that thls could be due to lnadequate dosage of phenoxybenzamine, since signs of a considerable degrez of adrenergic blockade were present after phenoxybenzamine Imiosis, partlal attenuation of

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fhe epinephrine-induced rise in systolic biood pressure, accentuation. of epinephr.ine-Induced drop In diastolic pressure, and marked postural hypotension and.tachycardial.. Even though the adrenergic biockade may not have been complete, the doses of LSD used were small, so some.evidence of attenuation of the mental symptoms should have been detected.

Failure of phenoxybenzamine to blcck the meatal changes caused by LSD might indicate that the LSD reactlon is not medlated adrenergically, or that phenoxybenzamine lacks central adrenergic biocking actlons.-Since role of epinephrine end/or norepinephrlae as central synaptic transmltters is still speculatlve, these alternefives cannot be assessed at the present time.

Failure to confirm amelioration of the LSD-reaction ' observed In anImals after phenoxybenzamine emphasizes that care Is necessary in extrapolating behavioral changes in animals to mental symptoms in man.

SUMARY

1.0 mg./kg. of phenoxybenzamine or 2.5 mg:/kg. of phenoxybenzamine ldivided in three doses) did nof attenuate significantly mental changes induced by 0.5 to 1.0 mcgm./kg. of LSD-25.

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1. Rothlin, E., Cerletti, A., Konzett, H., Schalch, W. R. and Taeschler, M.: Zentrale Vegetative LSD-effekte. Experientia. 12:141 154, 1956.

2. Hoch, ?. H.: Experimental Psychiatry. Am. J. Psychiat. 111: 787-790 (Apr.1 1955.

3. Schwarz, S. E., Bickford, R. G., Rome, H. P.: Reversibility of Induced Psychoses with Chlorpromazine. Proc. Staff Meet. Mayo C11n. 30: 407-417 (Sept. 21 1955.

4. Isbell, H., and Logan, C. R.: Studies on the Diethylamide of Lysergic Acid. Il. Effects of Chlorpromazine, Azacyclonol and Reserplne on the intensity of the LSD-Reactlon. A.Mi.A. Arch. Neurol, & Psychiat. 77: 350-358 [Apr.) 1957.

5. Courvoisier, S., Fournel, J.,Ducrot, R., Kolsky, M., and Koetschet, P.: Proprietes phermecodynamiques du chlorhydrate de cloro-3-(dimethylamino-3-propy1)-10-phenothiazine {4.560 R.P.1. Arch. Internat. de Pharmacodyn. et detherap. 2: 305-36l, 1953.

ó. Bonvallet, M,, Dell,P. and Hiebei, G.: Tonus sympathique et activite electrique corticale. EEG Clin. Nzurophysiol.6:119-144,1954.

7. Elzer, J. T., Gogerty, J. H., and Dille, J. M.: Survey of D-Lysergic Acid Diethylamide iLSD) Antagonists. Federatlon Proc. 16: 293-294 [Miar.) 1957.

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REFERENCES

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8. Gogerty, J. H., Elder, J.-T., and Harita, A.: Modification of Actlons of LSD-25 by Reserpine. Federation Proe. 1ó; 300 (Mar.1 1957.

.9. Brodle, B. B., Olin, J. S., Kuntzman, R. G. and Shore, P. A.: Possible lnterrelationship between Release of Brain Norepinephrine and Serotonin by Reserpine. Science 125: 1293- 1294 (Jun. 28) 1957.

1O. Pletscher, A., Shore, P. A., and Brodie, B. B.: Serotonin as a Medlator of Reserpine Action In Brain. J. Pharmacol. and Exper. Therap. 116: 84-89 {jan.) 1956.

II. Isbell, H., Belleville, R. E., Fraser, H. F., Wikler, A., and Logan, C. R.: Studles on Lysergic Acld Diethylamide ILSD-251: I. Effects In Former Morphine Addicts and Development of Tolerance During Chronic Intoxlcation. A.M.A. Arch. Neurol. and Psychiat. 76: 468-478 1Nov.1 1955.

12. Abramson, H. A., Jarvik, M. E., Kaufmen, M. R., Kornefsky, C., Levine, A., and Wagner, M.: Lysergic Acid Diethylamide IlSD-25): 1. Physlologicel and Perceptual Responses. 1. Psychol. 40:53, 1955.

13. Winter, C. A., and Flataker, L.: 'Studies on Heptazcne tó-mor,phslinc-4,--dlphenyi-3-heptanone hydrochloride) ia Comparison vith Other Analgesic Ageats. j. Pharmocol. and Exper. Therap. 98: 305-317 (iviar.) 1950.

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1nduced by 1.0 Mcgm./Kg. of LSD Effect of I.O Mg./Kg. of Phenoxybenzamine on the Reactlon TABLE I.

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Effect of 1.O Mg./Kg. of phenoxybenzamine on Pespons.

Figures are means f standard errors of observatlons on 4 subjects. They represent flme-action calculations lareas) expressed as beat-mlnutes (pulseì and mm. mlnutes (blood pressurel. A posltive figure Indicates an increose over

predrug measurements; à negative figure, a decrease'.

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Effect of 2.5 Mg./Kg. IThree Divlded Doses) of Phenoxybenzomine on Response to O. Mig. EpinephrIne /70 Ky.

.8 sublects. Flgures are means ± sfandard errors of observatlons on 121 Tested five hours after last dose of phenoxybenzamine. (l) Tested two hours after last dose of phenoxybenzamine.

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TABLE 4.

Effect of 2.5 Mg./Kg. (Three Dlvided Doses) of Phenoxybenzamine on fhe Reactlon Induced by 1.O Mg./Kg. of LSD.

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