_8 Psychopharmacology frontiers. _ed by: Kline, N.S. L_t_le, Brown & Co.

, Bost_/Toronto

LSD 616/BOL 1959, p. 361-365.

57
EFFECTS THE OF VARIO(_S LS1) I)RU(;S ON 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 psychiaIrT. _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: enqt, chh,rpromazine cl), s(opolamine, (Th,na,ine. dl-amphetamine, Largactil), reserpine, 2-t)rom-lysergic (Bol L and l-bcnzyl-2-methyl-5-methox)-tryptamine
blETItODS

_tide

azacycloacid di(BAS).

_Lent _

of non-mental

or autonomic

effects of LSD

Ltion ol systolic hh)od pressure, dilatation of the pupils, and den 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 minUt_ 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

362

PSYCHOPHARMACOLOGY

FRONTIERS

order to elicit the knee jerk. These measurements were obtained at hourly intervals for two hours before and for eight hours after LSD. Data obtained were plotted against time. The average of two pre-drug readings was used as a baseline. The area under the time-action curve was measured with a planimeter, thus reducing all data for a particular measurement to one figure. Assessment of subjective or mental effects of LSD

These effects were assessed by having patients check a list of symptoms often observed after LSD for two hours before and eight hours after administration of the drug. The questionnaire was scored by counting all responses 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 to the following system: Grade 1: Nervousness, anxiety, change in mood, difficulty in concentration, without alterations in sensory perception. Grade 2: Same as Grade 1, with addition of changes in sensory perception, but without hallucinations or delusions. Grade 3: Same as Grade 2, with addition of hallucinations (pseudo or true), delusions, and changes in perception of body image, but with insight maintained. Grade 4: Same as Grade 3, but with loss of insight. Validity of methods

These methods have been shown to yield linear dose-response curves, to be reproducible as long as the same subjects are used, and to have high inter-observer reliability. General experimental design

All experiments were conducted by the double-blind technique. Evaluation of each dosage of every drug tested against LSD involved four experiments, utilizing the same group of subjects: LSD placebo plus test drug placebo; LSD plus test drug placebo; LSD plus test drug; and
LSI) placebo plus test drug. These combinations were administered in

random balanced order using a Latin square arrangement. Test drugs were administered at appropriate intervals either before (blocking or preventive experiment) or after (reversal or therapeutic) the LSD administration.

MODE RESULTS

OF

ACTION

363

Chlorpromazine Four blocking experiments were done with chlorprom,lzine: 50 rag. of chlorproma/ine against ,t0 /,g. of LSI) (6 patients): 75 rag. ot chb>rpromazine ag;dns! ,t0 /,g. of LSD (7 patients); 75 rag. ot chlorpromazine against 6) /,g. of LS1) (19 patients); and 10t) rag. ot thlorl,roma/inc against 60 t,g- of LS1) (7 patients). "['he degree of mental effect was significantly reduced in all these experiments. Two reversal experiments weree 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 chlorpromazine given intramuscularly significantly reduced the intensity of the LSD reaction. Reserpine Five blocking experiments were done: 2, 5, and 7.5 rag. of reserpine in divided doses orally before 60 pg. of [,SI); 6 rag. of reserpine intramuscularly in divided doses before 60 /,g. of LSD; and 6 rag. of reserpine intraniuscularly bclole 0.5 /,g./kg. of LSD. No significant attenuation ot the LSD reattion was observed after any of these combinations. Actuall}, patients seemed to have more intense reactions after the larger doses of reserpine plus I,SD than with LSI) alone. Azacyclonol One blocking experiment was done. Twentv milligrams of azacvchmol was administered three times daily for seven days prior to I,SD..\bsolutely no effect on the intensity of the LSD reaction was observed. In ,t reversal experiment, 100 rag. ol azac}clonol in divided doses was administered intravenously after LSl). Again, no diminution in intensity of the reaction was observed. Scopolamine Four 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 LSD reaction could be demonstrated. Amphetamine One blocking experiment was done using 20 rag. of dl-amphctamine against 60 _g. of LSI). No significant attenuation or accentuation of tile I,SD reaction could be demonstrated.

3(i4

P,';,Y{';tlOI'HAR\IAC{)IA){;Y acid dicth,darnidc

FRO\ (BOL_

FIER,_

2-1}rom-ly_,crgic

In large tb}ses {t _<) 8 rag., 70 reaction, l'w{} 1}h,<kingcxperiment_ m_..70 kg. {)1 1',{)I+ w:l, _iv{'n of I.S1}. N{} {.vidc_R:e of l}l:}{;kin_ I rag. {,t B()I+ was a{lmiHis/crcd

kg.) BOI. in{luted ,t were {arricd out. simull;m{',} ,Iv wiib was observed. In the three tim('s daily h}r
1.O ;tH{'IIll;IIi{}ll

ve]'y mild I,Sl)-like In the first, u to-1 I}.5 t,} 15 _g kg. sc{ond ex]}mimcnt. three days prior to

1 to 2 _g..:k_,. of l+SI}. A _tt{}ng lrtqld wa_ observed. This, however, was not

_t:_tiB/icallv

O[ [hu LSI} le_.lttioll siguifi{:ant. F,dhtre of .t {}t the 8 sub.ie{:ts

Ibis l:+_t cx]}criment nl3x ]lave been due to the fit{t that provc{l to bc rcsistimt t<}c_cn 2/,g./kg. {}t 1.SI}. l -bcnzyl-2-methyl-5-melhoxy-tryptamine {BAS)

'Ibis _crot(mb] antalouist did n(}t D_(luce LSD-Iike symptoms when given at{me, t}ut did cause weakness, ladguc, {liz]incss, mental dullness, .qause;t, and diarrhea. Six hundred rag. ol BAS in di_i(lc{t (l{}_{!s did not ;tttcrl',t;lt{: {}r ;l{_cnlu;tI{: the l{'a(ti,m imh,{cd I}v 0,5 to 1.5 p/. {}f LSI), although it did lnat kcdlv re{ha c the ciev,ltion St MMA]_" O[ lhe drugs st,t{Ii{:(l, only chlorpromaziBe {aused a {:lcar-{ut reduction ot blood pressure.

in thc I.Sl) reactitm. F,dlure of reserpine tO ameliorate the l.S1) psychosis may ]]man that l.Sl) cimnot be used as a screen for dete{ting new agelltS that would 1},' tt_clul iu ps}chiatry. Rt'suh., with BOI+, B,\S, :_ll{I rc-serpine arc not {{}ml}z_tible with the thcor) that he 1,5D psychosis is due to ser<}tonin {letiticm) in the cenIral m:rvous system because ol {ompctition ot 1,SD with scrotonin for recel}t{}_ sites,