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Since writing to you on 28 January 1955 we have completed experiments on the blocking of LSD-reaction with Rzserpine. a combination of LSD with C-9, and tolerance to LSD by prior admlnistration of LAE. Some further information is avallahle on C-9, and studies designed to shed light on the characteristics of the mental effects induced by C-9 are underway. Trials for the blockade of LSD-reactlon with "Frenquel" (4-piperdyldiphenyl-carbinot) are in progress and will soon be complete. Experiments are oeing carried on with cohoba snuff, but to date no reaction has been observed ia the doses used. Nore details of the descriptions of the experiments together with tables are given below.

Reseroine as ISD Slocking Agent.

In this experiment 12 negro subjects received the following combinations -of drugs: (l) Reserpine plecebo-LSD placebo; (2) Reserpine placebo-LSD; 131 LSD placebo-Reserpine; 14) LSD-Reserpine. Reserpine was given orally in a dose of I mg. ten hours, and l mg. two hours prior to administration of the LSD placebo, or 6O mcgm. of LSD. Placebos used for Reserpine were identical in eppearance with tablets of the ective drug. Experiment was conducted in double-slind fashion. Measurements were those previouslv deseribed from this laboratory lestimation nf knee jerk, measurement of pupillary size, measurement of systelic blood pressure, administration of questionnaire, hourly assessment of clinical grade of reactionl. Data were analyzed hy same methods.explained in previous reporis.

It cen be seen from the tasle thet Reserpine caused no significant change in any of thzsz measures. We therefore concluded that, in this dose, Resernire does not block the LSD-reaction. lt might be deslratle to repeat this work using a larger dose of Reserpine and.a longer pariod of administrafion pricr to testing with LSD. Of interest, however, is the fact that definite side effects were observed even with the small doses of Reserpine used.

ofHEALTH, EDUCATION.AREPebc Heal Serice NATIONAL INSTITUTES OF HEALTH

IN RRPLTING.ADDRESE THE ADDICTION RESEARCH CENTER NATIONALINNTUTES OF MENTAL HEALTH U. S: OILIC HIALTH StAYICE HOSPITAL Bcx 2000 LEXSNTON, KNTUCKY

23 May 1955

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LAE-32 as Blocker cf LSD-25 Effect.

Since LAE-32 is a relatively impotent drug wirich structurally Is closely related to LSD-25 it was felt that prior administration of a dose of LAE might block the receptor sites and thereby prevent
or modify the LSD-reaction. Tweive negrc patients were, therefore,
given In randomized order under double-bllnd technique: {l) LAE
placabo followed by LSD placebo; 12) LAE plecebo followed by 60
mcgm. LSD; (3) LAE, 500 mcgm. fo1lowed by LSD placebo;[4) LAE,
500 mcgm., followed In one hour by LSD, 60 mcgm. The LAE-32 used
in these experiments was in the form of enteric-coated pills rather
than in the form of solution in ampules. Suggestive evidence of
very mild LSD-llke effects was observed ln these sutjects with this
dosoge of LAE. The effects, however, were not slgnificantly
different statistically from those obtalned with placebo (see tablel
Also, there was no significant difference tetween placeto-lSD and
LAE-LSD, although a mild trend foward reduction of the LSD reaction
was observed which was not sufficiently great to warrant further. exploration. d

Cross Tolerance Between LAE-32 and LSD-25.

This experiment. was carried out at the suggestion of Dr. Haroid Abramson fn the hope that one might develop tolerance to LSD without incurring the unpleasant side effects associated with development of tolerance, with administration of LSD. Tweive negro patients, therefore, received in randomized order ty the dounleblind technique: (1) LAE placeto for one week; (2) LAE, S0O mcgm., for three days, followed by lOoO mcgm. LAE for four days. Patlents were then tested with the standard dose l60 mcgm.l LSD-25. lt was not felt that it was necessary to do the placebo-piacebo and placebo-lAE controls at this time, since they were fairly well covered by the first experiment. Methods of measurement of the LSD-reaction and analyzing the data were the same as prevlously reported.

During the week of administration of LAE-32 definite but mild LSD-like effects were reported by the patients. We have the Impression that these were as unplessant as the effecis of LSo-25, given by one of the schedules we have used to develop tolerance in the past. As can be seen by the table, there was a definite tendency for the intenstty of the LSD-reaction to he reduced following a weeks administration of LAs. Sinnificant reduction In knee jerks, pupitlery size and sysfolic blood pressure were observed and there were nearly signiflcant reductions in the number of answers to questionnalre and in the clinical grade of effect. It would appear that some degree of tolerance did develop. Toierance, however, was far less than that induced by repeated administration of LSD. This method, therefore, does not seem to .be a very practical way of inducing tolerance to LSD.

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Reproducihillty of the LSD-25 Pesponse.

In the course of the experiments described above three triais of the effect of 60 mcgm. of LSD were carrled out on the same 12 patlents under nearly identical conditions. As can be seen from the table on reproducibillty of the LSD-response, the LSD-reactlon is an extremely consistent biological phenomenon. Reproducibility Is, of course, very Important in testing the effects of varlous antidotal drugs.

Combinatlon of LSD-25 with C-9.

The purpose of this experiment was to study possible enhancement of blocking of the LSD-response by combining the drug with C-9. The same 12 patients who were used in the LAE and Reserpine experiments received in randomized order according to the douhle-blind technique: (1) C-9 placebo-LSD placebo; 121 C-9 placebo-LSD-25; (3) LSD placeho-0.5 mg. C-9; 141 LSD, 60 mcgm., -0.5 mg. C-9; 15) LSD, 60 mcgm., -1 mg. C-9 1

In addition to the usual LSD measurements (pupillary size, estimation of knee jerks, measurement of resting blood pressure, LSD questionnaire,and assessment of clinical gradel, the pulse rate and systolic blood pressure of these patients were measured at oneminute intervals for five minutes after assuming the standing posttion. All measurements were made prior to administration of the drugs and once per hour for eight hours after administration of the drugs. It was realized that the observatlon perlod was not sufficiently long, but circumstances prevented extension of the observatlon period for more than eight hours after administration of the drug-

Results are shown in the table. It should be noted thot a significant number of answers on the questionnaire occurred with adminlstration of C\_9. Analysis of the answers showed, however, a very different pattern from that seen after LSD dose. High scores were obtatned on a group of symptoms resembling those seen after administration of Atropine (decreased salivation, dryness of mouth, dry taste in mouth), and on such questions as increase in zuditory aculty, drowslncss, and hunger. The familier LSD-oatiern of anorexia, neryousness, insomnia, plus visual perceptual distortion was not observed.

The cardiovascular effects of C-9 were apparent even with the O.5-mg. dose Isee tablel. Insofer as the data permit analysis, C-9 did not biock or accentuste the effects of LSD on the pupils. knee jerks or resting blood pressure. C-9 did block in part the rise in blood pressure on standing after LSD alone. LSD, on the other hand, partially blocked the drop in blood pressure on standing seen after O.5 mg. C-9 alone.

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of Marlhuana and Parzrxyl. The same klnd of cardiovascular effects Itachycardia at restsdachycardia and postural hypotension on standingl occur .afteadmfnistrafion of an alcoholic extract of marlhuana orally, after smoking af marihuane clgarettes, and after 45 mg. of parahexyl orally, as after the administratlon of C\_9. The.cardiovascular effects of C-9 are probably common to all actlve members of the cannabinol group.

14) Mental Effects of C-9. Effort is now underway to obtain a better delineation of the effects induced by C\_9. The subjective sensations Induced by the marihuana group have long been ohscure. The descriptions in most of the writings on marihuana with respect to the occurrance of vivid, depersonalized, halluclnatory or cataleptic siates have seldom been observed when these drugs have been studled under controlled institutional conditions. Ordinerily the subjective effects Induced by marihuana. in such circumstances appear to be rather mild, and so far descrlptions given by Institutionalized patients have not shed a great deal of light on the exact nature of the sensations experienced. For this reason, 12 patients were given a sentence-completion test, consisting of 二 incomplete sentences chosen to yield information with respect to mental status laffect, mood, bizarre thinking, etc), and somatic sympto: Idryness of the mouth, blurring of vision, changes in auditory aculty, etc). Validating questions and general drug questions are also included. Incompleter sentences which elicited consistently positive responses were selected from this original test and a new truz-false test consisting of over 300 ltems constructed. This true-false test is now being administered to 30 men. When the results are in, item analysis will be carried out and further work conducted based on leads obtained from the high scoring items.

(5) Preliminary Clinlcal Description of the C-9 Reaction. A description of the C-9 reaction based on observations made in 33 trials of 1 to 2.5 mg. of C-9 orally in 17 subjects has heen prepared and Is appended. It should be borne in mind that this description is preliminary in nature and may have to be modified greatly as further informatlon is aecumulated.

Future Plans.

In addition to studies on the C-9 reactlon, future plans include. studies of the effect of comblnations of Senpolamine and LSD-25. the use of Reserpine as a auieting drug. and the testing of new subsfances from the University of lllinois as they tecome available.

Very,sincerely, yours,

Harris Shell

Harris Isbell, M.D. Director of Research

Hi:ra

Enclosures

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EFFECTS OF 1 MGM. RESERPINE IO HOURS AND 2 HOURS PRIOP IO GO MOGM LSO 2E

of differences between Placebo-LSD and Reserplne-LSD are sianificant.

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e   Be  ts