...... I I ' ' _ BOL 44/LSD 433

...... Arch. Neurol.Psychiatr._ Chic_go 78_ 653 (2_957).

Psychopharmacological Studies of Lysergic Acid Diethylamide (LSD-25) Intoxication

F..O:ectsof Premedication with BOL-I_8 (2-Bromo-d-l.ys,'rffic Acid [ Diethylamide), , , Amobarbital, and

UNCOLNO. CLARK,M.D.,and |UQ4NEL. BLISS,M.D.,SaltLakeCity

One consequence of the recent interest in the LSD-25 state of with potent de- drugs has been a search pressive action, such as amobarbital or for l)harmacological agents that will "block" chlorpromazine, one must differentiate be- -induced psychological disturbances and tween evidence of specific blocking from . Fabing a reported that aza- modest doses and masking or suppression ¢yclouol (Frenquel) in small doses pre- secondary to impaired awareness in heavily vented the occurrence of lysergic acid premedicated subjects. Another source of diethylamide (LSD-25) "psychoses" in difficulty is that LSD-25 intoxication is a man, although one of us (L. D. C.) was complex condition, offering a wide variety unable to verify this observation. 2 Other of behavioral and psychological changes that investigators have reported that LSD-25 may be observed and measured. When the intoxication is ameliorated by premedication object of the study is the modification of with chlorpromazine, a,4 serotonin, 5 and re- LSD-25 intoxication by other drugs, the serpine? However, it has also been reported choice made of what is to be measured may that serotonin e and reserpine a intensify lead to appreciably different results. For LSD-25 effects. Hoch 7 found that pre- example, if an investigator were to regard medication with amobarbital (Amytal) as an important aspect of LSD-25 sodium and chlorpromazine did not prevent intoxication, he would probably find chlor- I,SD-25 or mescaline intoxication but to be an effective "blocking" pointed out that such drugs produced sup- agent. Other investigators emphasize the pressive effects when given at the height of prevention of LSD-25 "psychosis" as the intoxication, though the latter were a predictable occur- Several reasons exist for this confusing fence. This may be justified if one defines state of affairs. There has been a failure "psychosis" as the appearance of the typical to distinguish between true pharmacological LSD-25 perceptual disturbances. However, antagonism (blocking) and suppression, in our experience, psychosis in the sense of For example, in studying the effects upon real behavioral disorganization occurs in Submitted for publication July 9, 1957. only occasional experimental subjects given From the Departlnentof Psychiatry,University LSD-25 in the usual 13,/kg. dose. of Utah College of , and Veterans' Ad- The experiments to be described in this ministration Hospital, Fort Douglas Division. Assistant Professor of Psychiatry (Dr. Clark). paper were further attempts to assay the Associate Professor of Psychiatry (Dr. Bliss), effectiveness of various drugs as blocking University of Utah College of Medicine. agents against LSD-25. Since there is little The LSD-25 and BOL-148 used in these ex- precise knowledge of the locus or mechanism opferSaimentsndozwPheraermsuapcpeliutedicalbys.TheMr. mHeascalinerry Altshulfooasete, of action of LSD-25, the choice of potential was supplied as a research grant from S. B. antagonists, while obviously guided by the Penick & Ccmlpany. New York. experience of other workers, was frankly 653 .4. M .t .4RCHII't-?; OF NEUROLOGY .4ND t',';YCttlATRY sl_culative and arbitrary. Tap water was et ai. s was completed by the subjects before employed as a c_mtrol. BOL-148 ¢2-bromo- the premedication, at 10:00 a. m.. and 11:30 d-lysergic acid diethylamide) was used, a.m. In addition, we made independent since it is structurally similar to I.SD-25 behavioral observations and mental-status but lacks the latter's hallucinogenic prop- evaluations at 15-minute intervals through- erties. Consequently, it was assumed that it out each experiment. An effort was made to might displace the LSD-25 at some hypo- observe a broad spectrum of the physiologi- thetical site of action in the central nervous cal, perceptual, and psychological effects system. On the other hand, mescaline sul- which may be produced by LSD-25. The fate. a drug with hallucinogenic activity subjects were also asked to record at regular similar to that of LSD-25, was given in the intervals their perception of any somatic subhallucinogenic dose of 0.1 gin. on the and psychological changes. These notes assumption that this quantity might be suffi- were later organized by the subjects into cient to preempt a common site of action, lengthy introspective reports. Am¢_arbital sodium, 0.3 gin., as a central The initial dose of LSD-25 was 1-_/kg. nervous system , and chiorproma- of body weight. However, after the first zinc. 50 rag., as a tranquilizer-depressant, experiment this was reduced to 0.5y/kg. were studied as drugs which might be ex- There were two reasons for this change.. petted to antagonize the stimulating effects First, one of the subjects experienced a of i,SD-25. Finally, atropine , 1.2 severe "psychotic" LSD-25 reaction, which rag.. was used as an autonomic blocking represented a real management problem. agent which might modify those aspects Second, it became apparent that the large _f the I.SD-25 experience due to parasym- dose produced such disruptive effects that pathetic discharge. All medications were the subjects were unable to complete the given orally. LSD-25 questionnaire accurately or to main- Modest doses of premedication were tain an adequate introspective record of chosen on the assumption that if true phar- their experience. While there were minor macological antagonism occurred, as is differences from one subject to another, the exemplified by the model of naiorphine- smaller dose of LSD-25 produced mild but , such amounts would suffice to characteristic effects. These consistently in- l_roduce recognizable "blocking" effects, eluded feelings of depersonalization, various There were also other advantages in this paresthesias, a persistent urge to stretch, choice. High doses of mescaline or atropine fedings of nervousness or general stimula- would have produced effects which could tion, and transient visual imagery when the easily be confused with those of LSD-25, eyes were closed. The effects of the larger while excessive amounts of amobarbital or dose were largely an extension of these chlorpromazine would have obscured LSD- effects, including more elaborate and per- 25 effects by producing nrmspecific cortical sistent visual and somatic disturbances. depression. After three experiments, during which The subjects were six medical students, each of the subjects received three different :\ "double-blind" design was followed, so premedications, a tabulation of the responds that neither the subjects nor the observers to the questionnaire and an analysis of the knew the exact order of the administration observer's protocols and the subjects' re- of drugs. All premedications were dispensed ports were made. With the possible excep- in 20(} ml. of tap water to fasting subjects tion of atropine, where fewer responses to at Ig:30 a. m.. and I.S1)-25 was given at the questionnaire occurred, the premedica- l0:0() a.m. tions failed to modify significantly any A modification of the extensive question- aspect of the LSD-25 intoxications. To nairc f.r 1.SD-2.g effects devised by Jarvik check the significance of the obmrvation on t_4 l'.l. 78, D,.c. 1957 L_ _'l:N(,l( .It I1_ IffI:TIIYI..I,'IIIDI: 1\7_L\It.ITI_).V

;ttrol)ine, Ihrt_' more experhnents were run. REFERENCES .\11 six subjects were studied under the I. Fabing, II. 1).: Nerve Blocking Agent Agams! influence of I.$1)-25 O.57/kg. alone, afro- Ihc l)evelolm,ent of 1.SI)-25 Psychosis. Scienct' l,ine 1,2 rag. alone, and atropine followed 121:2[_, 1955. by I.SD-25. These experiments failed tl) 2. Clark, 1.. I). : Further Studies of the l'_,y- confirm the initial iml)ressi(m. Atropine did vchiewoh}gic(if alPrEffeviousecls R(,fe|K)Frrtenqs, uelJ. Neml(rvI. a&CriticalMerit. DiRes- not decrease the resl_)nse to l.SD-25 but. 123:557, 1q56. instead, caused additional disagreeable auto- .I. I_bell, 1|. : Effect (,f Chh,rpr(maazine, Reser- nomic effects, which actually made the ex- piuc, :u_l "Frenqttel" on I.SD Reacticm, Fed. l'roc. l,erience more unpleasant. 15:442, 1956. 4. Giberti, F., and Gregoretti, L.: Prime l'speriel_ze di aa_tagonismo psieofan_mcxdogico, Summary Sistern:t nerv. 7:301, 1955. 5. Montanari, C., and Tonini, G. : Aziotfi della l'remedication with m(_lerate amounts of 5-idrossitriptanaina sul sisteraa nervoso centrale: I_O1.-148 (2-bromo-d-lysergic acid diethyl- stlo impiego in psichiatria sperimentale, Riv. sper. amide), amobarbital sodium, chlorpromazine, freniat. 79:465, 1955. mescaline sulfate, and atropine sulfate did 6. I'oloni, A.: Serotonina e sdfizofrenia: Os- not significantly influence the somatic and _ervazioni sulle interferenze fra I'azione della psychological disturbances induced by either serotonina e della dietilamide dell'acido li_rgico " _I.SD-25), mescalina e bulbocaprina nell'uomo e large or small doses of lysergic acid diethyl- tlell'anim',de, Ce_'ello 31:271, 1955. amide (I.SD-25). There was no evidence 7. Hoch, P. H.: Experimental PsychiatD, , Conl- of a blocking effect, such as might have been ments, Am. J. Psychiat. 111:787, 1955. anticipated if these agents had any specific 8. Jarvik, M. E. ; Abramso_ H. A., and Hirsch. N. W. Comparative Subjective Effects of Seven pharmacological antagonism toward I.SD- 25. Drugs Including Lysergie Acid Diethylamide _LSD-25), J. Abnorm, & Social Psychol. 51:657, 156 \_eslminster Ave. (15). 1055.

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