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CSr71,:\i~n,;.::::'iT OF / " ,C::AL''fH, EDUCATION+ AND V~---,_,·AF\ .. PUBLIC HEALTH SERVICE Lexlnston, Kentucky IN REl't.YiNG, AOCRESS THE! NIM; Addiction Research Center. 14 july 1954 Cur experiments on tolerance to LSQ-25 have been proceeding }~-._...;: well, although I c~nti·nue to be somewhat surprised by the J' ' results, which to me are t~e most amazing demonstration of 0°~~ drug to I e r a n c e I h a v e eve r s e en • I h a v e had 7 p n t i e n t s who jJt--'1~ have now been .. taking· the drug for more than 42 days. One of · these patIentS receives I mcg!}1./kg. da i lv, 4 receive 1.5 rr.cg,..,./lg. daily, and 2 receive 2 mcgm.Jkg. daily.· All 7 are quite to.leranr~ t o bo t h t h e ph y s i o l o g i c a I a n d me n t a I e f f e c t s o f. t h e d r u g • We have attenf¢,ted to break through this tolerance· 5y adminisrer- i n g d o u b 1 e , {· r i p I e d n d · q u a d r-;0 p I e do s e s • 'W' e h c1 v e n o t y e t o b s e r v e d full resto!'dtiC?r. of .Jhe LSD-effect with any of th?.se dos<2s, which, in the case of one of the p a t i ~ n t s r e c e i v i n g 2 m c gm. /kg. d a i I y, amounted t0 532 rnccm g : rota! dos~. l'ncreas incc the dose seems to r e s t o r '-.! t h e p h y s i oJ o· i c a I e f f e c t s t o: a g r e a t r d e s r e e r h a n t h e mental eff-2cts, which are pres·cnt in only mild d~srce and which do nor persist for more than one or two hours. Discontinuation of the dr.u{for two days in one patient was followed by almost complete restorction of the initial effect. Administration of 200 mg. of the metabolic blocker, SKF-525, The image displays a digital representation of a document, featuring the title "THE BLACK VAULT" in stylized white text. To the left of the text is a graphic of a vault door, complete with a complex locking mechanism and a neon blue glow emanating from its edges. The main body of the image consists of white text describing the origin and content of the document, including a hyperlink. The entirety of the visual content is presented against a black background. The document is a typed report with handwritten annotations. A stamp with "37" in a circle is present in the upper right corner. There are also handwritten notations in parentheses "(b)(3)" and an illegible annotation near the top right. The text discusses experiments with LSD-25 and its effects on patients, including dosages and observed reactions. There is no visual evidence of experimental procedures, equipment, facilities, or photographs of people or locations. e mental eff-2cts, which are pres·cnt in only mild d~srce and which do nor persist for more than one or two hours. Discontinuation of the dr.u{for two days in one patient was followed by almost complete restorction of the initial effect. Administration of 200 mg. of the metabolic blocker, SKF-525, did not overcome the tolerance •. We have also been attempting to study nantidotes" for LSD-25. We h a v e do n e q u i t e a n u m be r o f e x p e r i me rd s i n wh i c h 0 • 2 Gr:-: • c f pc;;~ob.::rbi~Jl ;:;us .:;iv..::n :;c ft!if1vl'Gs orior to LSG. Trlis drvc a p p e d r s t 0 d e f i n i t ~ I y d \ r e r t h e L s D . r e d c t. i 0 n , i n . r h a t d n X i e t y ' ner.vousness, and insomni.:: are mtlrl::~dlv r~duced. However, the prf-c,~ paid is that of partial dr•;nkeness induc~d by the barbit urate. We have completed two ex~eriments with Corynanthine. The patients used were exrrem~ly s~ns itive subjects who cave crade 3 to 4 reactions to a 40-mcgm. dose of LSD-25. TheyJwerewgiven d-!J( /r I · . ...;;..: in a. random-ized order· IS mg. Corynanthine followed by placebo; ·placebo followed by 40 mcgm. LSD; Corynanthine~ IS mg., followed by 40 mcgm. LSD. There \~dS no evidence of any diminution in either the mental or physiolooical effects of the LSD. Other experiments are to be done, using tess sensitive subjects. r As yet we have not had an opportunity to try Banthine. -While in Washington recently, I had a very interestino visit with Dr. Edward Evarts who is working with LSD and Sufontenine. As you know, he has been able to demonstrate very definite effects of both drugs .in dogs and monkeys. As a result of this, ·neurophysiological studies have been undertaken. Th·ese include the effects of LSD on peripheral nerves. In the frog, LSD ·. ~ . ·._ _a ppdrently rai_ses the threshold but does not change height of ·the action pof~ntial once the threshold is crossed. Other neurophysiological work is cohcerned with the effects of LSD on the en t i r e o p t i c The document is a typewritten page with handwritten annotations in the margins and at the bottom. The primary content is a report detailing research on LSD and other substances, including dosages, effects on subjects like dogs, monkeys, and humans, and observations of tolerance. Handwritten notes on the left include "5 cogies" and "unwrtten-" possibly indicating a request for copies or a status update. At the bottom right, a handwritten notation "A-133" appears, potentially an identifier or classification mark. There are no official stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures or equipment. nerves. In the frog, LSD ·. ~ . ·._ _a ppdrently rai_ses the threshold but does not change height of ·the action pof~ntial once the threshold is crossed. Other neurophysiological work is cohcerned with the effects of LSD on the en t i r e o p t i c a I t r a c t , from l he o p t i c n e r v e a I I t he way back to the o.pti.cal cortex. Apparently some kind of results are being obr~ined, but as vet they ar~ not clear-c•Jr. Other stc!!tements includz or:~· that,:/ in hu1ndn subjects, LSD caused marked slowing of simp!~ reaction time, but had lit~le effect on flicker fusion fi~quency. D r • C h o I d e n , a me :i} be· r o f t h e N 11/rl s t. ·a f f a n d w h o i s us i n g l S D in the tr..::atment of iJSychoric·.·patients, sou3ht me out while I was in Bethesda. He has apparzntly observed the dev~lopmznt of to I e r a_n ce to LSD i n t he s e !J s y c h ·:l t i c p a t i en t s • 8 e c a us e of the development of tolerdnce, he atternates LSD and mescaline. He s· t a t e s t h e r e i s n o c r o s 3 t o I e r a n c e t o H e s e t wo d r u g s • -~~ r e r e c e n r I y o b t a i n e d a s m a I I s up p t y o f a n i n e r e s t i n g s u b s t a n c .z in the cannabinol ~eries which appears to be extremely potent. ,• ,. . ~· t have now given I l subjects doses of I to '2.5 mg. of this "'/~ . ',. / d r u ~ • T he f i r s t 2 p a t l e n t s o r om p t i v i d e n t i f i e d r The document is a typed text with handwritten annotations. There is a signature and a typed name and title below the main body of text. There is a handwritten number "A-132" in the bottom right corner. The document appears to be a report or memo, detailing observations and findings in relation to experiments, possibly with drug use, referencing doses and patient reactions. The handwriting includes what appears to be a signature and a name with credentials "Harris Isbell, M.D. Director of Research". There are also some faint marks and scribbles throughout the document that are difficult to decipher. of I to '2.5 mg. of this "'/~ . ',. / d r u ~ • T he f i r s t 2 p a t l e n t s o r om p t i v i d e n t i f i e d r ~ e e f i e c t s • as bei!ig like those of marihuln.3 and, naturally, all p.ari~nrs l:fsc,-roJ,Y, since the first 2 have expected marihuana-!i 1<e effects. ~~- Pat.. ients_ begin to r•Zi)ort the subjecrive effects within 2 to .~v-"" ' :_.z 4 hours. Eff.zcts aoozar to -?e rnost ororninent 6· to 8 hoiJrS l ;:.:../ o ft ~ r t he. drug i s ad~ i n i s r e r ~ d a n d d 'r '! s t l I I pres ~ n t '2..: r o 3 6 hours·!atzr; and i:1 sor:1~ ca·_;cs eve'l Ienger. Descriprion of rh~ subj~ctive effects ts very ·vagu~, except t.h~.t the subjects an: very positive thzy resei"i!bl~ thos.z ·of marihudna. They say the effecrs of I me. are eaual to one or two cicarettes of rhe besr marihudno~ cxc~pt that 'th~y appear slowly a;,d pcrs i3r for a very long.pertod of ti:ne. They are described as consisting of a sensatio~ of mental relaxdtion accompanied, however, by "physiccJI" tension, increased appreciation of music, jokes, and other thinds. The characteristic behavior observed in ma r i h u a n a· s mo k ~ r s ( g i g g I i n g, s i I I i n e s s ) has no t been s e e n , but the experimental situation has not been conducive to the a p p e a r a n c e o f s u c h be h a v i o r • No h a l l u c i n a t i o n s , p e r c e p t u a I distort ion, etc., have been reported. With larger doses (2 to '2.5 mg.) the symptoms became quite unpleasant in 6 of the II subjects 6 to 8 hours after adminis tration. ·The unpleas.ant symptoms included dizziness, feeling of great w~akness, marked drowsiness, naused and vomiting. Weakness has persisted for 48 to 72 hours after administration _ of .the drug. One patient fainted mg.) the symptoms became quite unpleasant in 6 of the II subjects 6 to 8 hours after adminis tration. ·The unpleas.ant symptoms included dizziness, feeling of great w~akness, marked drowsiness, naused and vomiting. Weakness has persisted for 48 to 72 hours after administration _ of .the drug. One patient fainted on going to the bathroom g. ·- t he morn 1 n g a f t e r h a v i n g r e c e i v e d a 2-m dose • Neurological examination in these patients so far has been negative witJ1 the doses used. However~ gait could not be- tested in scffne patients wh.o b.ecame so wea~ they refused to g e t o u 7 o f bed • T h e r e i s ~-, v e r y d z f i n i f e t e n d e n c y · f o r t h e pulse rate to becomi rapid'and a tendency for the blood pressure to fall. 1he r.zsulrs- suggest- tha-t some- cardiovasc1JI~r disturbance, possibLy posturdJ hyp0.tens ion, may occur. I hope to ir.,testiaate ti1iS' in th·Z i;"!1mediar-z future. Becd•Jse of rhe appearancevof thise toxic r~~ctioni, I am not planning to increase the dose beyond 2.5 mg., in the immediate future. / I t i s no·t e w o r t h y t h a t ~ h e p a t i e n t s s h o w t h e c h a r a c t e r i s t i c marihuana facies, which consist chiefly of marked conjunctival redden i n g a n d p s e u do p t o s i s • /-:>'':-.... ~ ,-'_./ ;/ ........... 1· hope soon to have some information on Bufotenine, but hav.z not carried out a~y experiments as yet. Sincereiv yours, ·- Ha r r is I s be I I , !vi. D. DirectQr of Research HI: rn 4-f.J 2.