Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 1958 Tolerance, antagonism and the relation between D- lysergic acid diethylamide and mescaline George K. Aghajanian Yale University Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation Aghajanian, George K., "Tolerance, antagonism and the relation between D-lysergic acid diethylamide and mescaline" (1958). Yale Medicine Thesis Digital Library. 2328. http://elischolar.library.yale.edu/ymtdl/2328 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. MUDD LIBRARY Medical gill YALE MEDICAL LIBRARY ' Digitized by the Internet Archive in 2017 with funding from The National Endowment for the Humanities and the Arcadia Fund https://archive.org/details/toleranceantagonOOagha TOLERANCE, ANTAGONISM AND THE RELATION BETWEEN LYSERGIC ACID DIETHYLAMIDE AND MESCALINE George K* Aghajanian Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Medicine» Department of Psychiatry Yale University School of Medicine 1958 -7»T* /T77A __-_--0_ ._g ' - -:_:__: _-J__ __ in QJ5J 9 no 6 J • •• - • - ' 1 »Q L-- ’ £89X1 " - to! .. i b »*rii . ■ z lo * ;r ioibo lo nodorci ‘jo \*i^ j O s I _r j - o *i c >C7 '.'I i jJ. ' i c ,r. ce Oc iisrrsvinU ..1/7: v; T\V5 y\2- 'i\20 ACKNOWLEDGEMENTS Dr» Daniel X. Freedman guided the project in a most stimulating fashion. His interest in tolerance phenomena in schizophrenia was an impetus for the work. Dr. Nicholas J. Giarman was always willing to discuss problems arising in the work, and was generous with needed materials. Dr. Burton S. Rosner graciously provided equipment and laboratory space. Dr. George F. Mahl made useful suggestions concerning the presentation of the data. .'i* d i ■ : i ;-c ' '/i rlci he b Ljlt i ®oo; ri ( . : ■ 1 " 1 [ j . '■< ' , ri ' i , ' ‘i. ' : J : . CC ' : •: . : a* ./ ;>i ' < . v. j ' .... , id ■ i . :• i I ; i ill ft' j ' •> ■ 1 S3 9 Li . j • 0 . v, •) e- : . a <; i\ d : • ...; \; TABLE OP CONTENTS Chapter Page One INTRODUCTION. ........ 1 THE PROBLEM. ....... 1 PROGRESS TO DATE .......... 11 GOALS OP THIS STUDY. ........ 1? Two EXPERIMENT S ...... ....... 20 METHODS .............. 20 Introduction. .......... 20 Procedure in This Study ..... 22 Rope Glimbing As A Method .... 23 Deviant Results ......... 24 MATERIALS. .. 26 LSD-25. ..... 26 BOL-148 . ........ 26 Mescaline . .. 27 RESULTS .............. 27 Tolerance to LSD-26 ....... 27 Experiment 1: Effect of repeated daily Injection of a constant dose of LSD-25 ......... 27 Experiment II: Effect of repeated LSD-25 injections given at forty- eight intervals, at a constant dose level ........... 29 Experiment III: Effect of repeated LSD-25 Injections given at seventy- two hour intervals at a constant dose level ... 30 Experiment IV: Effect of an LSD-25 injection one hour after an initial injection of same dose .... 30 .. .1 ,'.LP.\ - eft0 . - ;• . ..t-.'. .. OT O-.SF •:>(:■ . ..-'.'.Lov-rsi'. .* . wJ.Josj"o*id 'I . eo ■- . c. • -j. : .<?J:1') e<: c - . ..3 y lua c-1 d- .1° j. / ... .S - 18 J . i ‘~uC€ .«••... .. : . ll - ' - ’ L' : V . ii Pag© Experiment V: Effect of giving ,130 mg/kg of LSD-25 twenty-four hours after an initial .260 mg/kg injection ............. 31 Experiment VI: Effect of giving three (constant dose) LSD-25 in¬ jections spaced, after the inital Injection, at one and twenty-four hours 31 Experiment VII: Decay of LSD-25 tolerance in a daily injection group ........... o • o • 31 Tolerance To Mescaline ....... 34 Experiment VIII: Effect of repeated daily injections of a constant dose of mescaline, ........... 34 Experiment IX: Effect of a mescaline injection given one hour after an initial injection at same dose. 35 Experiment X: Effect of giving a double dose of mescaline on day one, followed by the usual dose twenty-four hours later ...... 35 Gross Tolerance . ........ 36 Experiment XI: Effect of giving mescaline one hour after a single dose of LSD-25 o ........ 36 Experiment XII: Effect of giving LSD-25 one hour after a single dose of mescaline. ........... 36 Antagonism. Experiment XIII : Antagonism of LSD-25 by BOL-ll|,8. Experiment IV: Antagonism of mescaline by B0L-14B ....... DISCUSSION OF RESULTS ........... Ipl Tolerance and Learning. ....... IpX Acute and Chronic Tolerance . , . ij.2 Effect of Time Interval and Dose Level , . @ . , o , . * . b3 ' - • : ' • / - ■ ' - ;■■■ ♦ . .. 1 £■ ' J a } - . o£qa in o t. • « . - •.. a a nor: - . • • : IIX b ... 3. ;.c : * jno L*x ' : » • » <■■>- ■ • ' J ~c- c" . .L' ) A. •. ■■ ... C / ■■ . ' . , • n - o„ « * —- - i V-1' <' • - ' . - - • -• Ill Page Gross-Tolerance. 45 Antagonism .o..o.ao«oo. 45 Three THEORETICAL DISCUSSION AMD CONCLUSION . 47 DISCUSSION, ............. 47 Receptors, An Assumption . 47 The Tolerance System ....... 49 Relationship Between LSD-25 and Mescaline Sites Of Action . 51 CONCLUSION.... 53 SUMMARY ...... 56 BIBLIOGRAPHY. ...00. 59 .:'l! 'I:- A. ' • » • * 1 .. » . t . c ’. j r . • C-. 1.10;; ;0:- -1- Chapter One: INTRODUCTION THE PROBLEM It is remarkable how wide a variety of chemical agents may induce a psychotic state<> A list of some of these not only reveals great diversity, but includes members of other*- 1,2 wise opposing pharmacological groups: depressants: barbiturates, bromides, chloral hydrate; stimulants: amphetamine, caffeine; autonomic activators and blockers: atropine, scopola¬ mine , DFP; local anaesthetics: cocaine; oxytocics: ergot alkaloids; heavy metals: lead, arsenic, mercury; hormones:' thyroid, adrenal cortical; anti-malarials: atabrine; water: excess* These substances, mostly drugs in common clinical use, have not stimulated the great interest in drug psychoses as has the group of so-^call ’’phantasticums" or ’’hallucinogens,” of which d-lysergic acid diethylamide (LSD-25) and mescaline are the principle members® There are several reasons for this® The effects of LSD-25 and mescaline are relatively constant and reproducible, whereas with the other agents cited there are great differences in sensitivity between .individuals, and great variations of response in the same ; nO nnj c ; OJ meilo If . 1' : iici. rd mxt i —* >” di - don 9 13 lo 9i ;c;i lo \J - J • ID do oldo o\s- 3 )ilj a c lo . ) [d j 1 - -.[ ' -x. 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T •V *■■'. 2 GOO / V o jo, ass ni 2 ~ 0: OTOll if) jf>9T,3 ,91 3'to id .6 odio c1 li J 1 r GO02 '1 ox.oij ittsv dsoiq forts C [ ■ &J' j : -2- individual from time to time* Moreover, it is felt by some, the reactions produced by LSD-25 and mescaline resemble the •’functional" psychoses (particularly the group of schizo¬ phrenias) more closely than do the reactions, traditionally 3 A labeled "organic,” produced by the other agents., Inde¬ pendent of this issue of clinical classification, a reason for the great interest in LSD-25? in particular, lies in the fact that an extremely minute dose of the drug is high-» ly effective in producing a psychotic reaction.. In humans less than 10 ' grams per kilogram of body weight can cause a marked reaction* In contrast, the dose of mescaline customarily used in humans is about 10"3 grams per kilo¬ gram*^ This is in a cdLose range of about ten thousand times that of LSD-!*25« The fact that an almost molecular quantity of a drug, LSD-25? can induce a profound disturbance in mental status has in itself revoked interest in a possible "organic" etiology in schizophrenia*''' Of course, there have been many so-called "organic" theories suggested by the fact that drugs can cause a psy¬ chotic reaction* The simplest theory is one postulating the existence of an endogenous- substance, a "toxin," of which the psychosis inducing drugs would be exogenous counter¬ parts* Going beyond the level of analogy, one worker has o even formulated a possible pathway of LSD--25 biosynthesis* Another attempt to directly relate the drugs to biological systems turns on the structural similarity of mescaline to c • ' ~ ■ •: ' ■ ■ . 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