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_8 Psychopharmacology frontiers. LSD 616/BOL_ed by: Kline, N.S.L_t_le, Brown & Co., Bost_/Toronto 1959, p. 361-365.

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EFFECTS OF VARIO(_S I)RU(;S ONTHE LS1) REAGTION

HARRIS ISBELL

_; diethylamide of lysergi{ acid (LSD) provides a simple and safe_;ayofindl ing in mentally normal persons a reversible psychoss,_;ith features resembling some of those observed in the functional.'s. It was felt that attempts to attenuate the LSD reaction by ad-'ing x:u ious drugs bctore or after LSI) might yield information of_ elucidating the mechanisms by which I.SD produces a psychiatri(also seemed possible that the LSD reaction might be useful as a

N_11_:i detecting new agents ot potential therapeutic value in psychia-IrT. _i purpose of this paper is to present the results of experiments in_:_ tempts were made to modify the LSD reaction with the follow-

_,gs: chh,rpromazine (Th,na,ine. Largactil), reserpine, azacyclo-nqt, cl), s(opolamine, dl-amphetamine, 2-t)rom-lysergic acid di-_tide (BolL and l-bcnzyl-2-methyl-5-methox)-tryptamine (BAS).blETItODS

_Lent of non-mental or autonomic effects of LSD_ Ltion ol systolic hh)od pressure, dilatation of the pupils, and de-

n the threshold for eliciting the patcllar reflex are consistently_d after LSD, and are readily measurable. Pupillary size was eval-_i)y comparing the diameter oi thc sul)ject's pupils with throe of_ _ircles ol' known diameter on a (,trd (or by photography), under_tons of controlled illumination and accommodation. The sxstolic

)ressure was nteasured I)y tim auscultatorv method alter _t.n min-Ut_ I_t in bed. Threshold for the l)atcllar retlex was measured b\ tlt'-II'_ing the least angle through which a hinged hamnmr mu_t hdl in

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362 PSYCHOPHARMACOLOGY FRONTIERSorder to elicit the knee jerk. These measurements were obtained athourly intervals for two hours before and for eight hours after LSD. Dataobtained were plotted against time. The average of two pre-drug read-ings was used as a baseline. The area under the time-action curve wasmeasured with a planimeter, thus reducing all data for a particularmeasurement to one figure.Assessment of subjective or mental effects of LSDThese effects were assessed by having patients check a list of symptoms

often observed after LSD for two hours before and eight hours after ad-ministration of the drug. The questionnaire was scored by counting allresponses after LSD that were not reported positively before the drug.In addition, short examiuations of mental status were done at intervals

after the drugs, and the degree of mental effect was graded according tothe follow ing system :Grade 1: Nervousness, anxiety, change in mood, difficulty in concen-

tration, without alterations in sensory perception.Grade 2: Same as Grade 1, with addition of changes in sensory per-

ception, but without hallucinations or delusions.Grade 3: Same as Grade 2, with addition of hallucinations (pseudo ortrue), delusions, and changes in perception of body image, but with in-s ig ht ma in ta in ed .Grade 4: Same as Grade 3, but with loss of insight.Validity of methodsThese methods have been shown to yield linear dose-response curves,

to be reproducible as long as the same subjects are used, and to have highinter-observer reliability.General experimental designAll experiments were conducted by the double-blind technique.

Evaluation of each dosage of every drug tested against LSD involvedfour experiments, utilizing the same group of subjects: LSD placebo plustest drug placebo; LSD plus test drug placebo; LSD plus test drug; andLSI) placebo plus test drug. These combinations were administered inrandom balanced order using a Latin square arrangement. Test drugswere administered at appropriate intervals either before (blocking orpreventive experiment) or after (reversal or therapeutic) the LSD ad-ministration.

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MODE OF ACTION 363

RESULTS

ChlorpromazineFour blocking experiments were done with chlorprom,lzine: 50 rag. of

chlorproma/ine against ,t0 /,g. of LSI) (6 patients): 75 rag. ot chb>rpro-mazine ag;dns! ,t0 /,g. of LSD (7 patients); 75 rag. ot chlorpromazineagainst 6) /,g. of LS1) (19 patients); and 10t) rag. ot thlorl,roma/incagainst 60 t,g- of LS1) (7 patients). "['he degree of mental effect was sig-nificantly reduced in all these experiments. Two reversal experimentsweree conducted: 75 nag. of chlorpromazine orally against 60 /,g. o[ LSD,and 25 rag. o[ chlorpromazine intramuscularly against 6{} to 150 p.g. o[LSD, Chlorpromazine orally had no significant etIect, whereas chlorpro-mazine given intramuscularly significantly reduced the intensity of theLSD reaction.Reserpine

Five blocking experiments were done: 2, 5, and 7.5 rag. of reserpine individed doses orally before 60 pg. of [,SI); 6 rag. of reserpine intramus-cularly in divided doses before 60 /,g. of LSD; and 6 rag. of reserpine in-traniuscularly bclole 0.5 /,g./kg. of LSD. No significant attenuation otthe LSD reattion was observed after any of these combinations. Actuall},patients seemed to have more intense reactions after the larger doses ofreserpine plus I,SD than with LSI) alone.AzacyclonolOne blocking experiment was done. Twentv milligrams of azacvchmolwas administered three times daily for seven days prior to I,SD..\bso-

lutely no effect on the intensity of the LSD reaction was observed. In ,treversal experiment, 100 rag. ol azac}clonol in divided doses was admin-istered intravenously after LSl). Again, no diminution in intensity of thereaction was observed.ScopolamineFour blocking experiments were done using 0.42, 0.fi.t, 0.85, and I.._

rag. of scopolamine (total close) subcutaneously against 60 t'g. of I,SII.No significant diminution or a_centuation ot the intensity of tim LSDreaction could be dem onstrated.AmphetamineOne blocking experiment was done using 20 rag. of dl-amphctamine

against 60 _g. of LSI). No significant attenuation or accentuation of tileI,SD reaction could be demonstrated.

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3(i4 P,';,Y{';tlOI'HAR\IAC{)IA){;Y FRO\ FIER,_2-1}rom-ly_,crgic acid dicth,darnidc (BOL_

In large tb}ses {t _