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(6)(3)

Since my last letter of l4 july l954 l have completed a considerable amount more work which is summarlzed below.

TOLERANCE TO LSD. These experIments, which were descrIbed in my letter of l4 July, have been completed and the data have now been analyzed. My concluslons were not altered by the statistical analysis, and are as follows:

I. Once tolerancé to LSD has been wall developed, it requires four to five tlmes the dose to which the patient ls tolerant to-restore the LSD-reaction to its originel intensiiy; zven then the duration of action is relatively short.

2. Tolerance to LSD is not ovarcome ty administerlng 200 mg. of the metabolie blocker SKF-525-A.

3. Tolerence fo LSD is lost in three days follewing discontiñuation of the drug.

4. No untcward tcxic effects were observed, even thougt the pallznfs consumed as much as ll mg. of LSD during the course of the experiment.

S. Evea though a high grede of tolerence was developed, no abstinence symptoms were cbszrved on withdrewal of the drus.

43

TH, EDUCATION, AND W FAR

FUBLIC HEALTH SERVICE

IN REPLYING. ADCRESS THE

Lexington,Kentucky 15 September 1954

NIMH Addictlon Research Center

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ANTIDOTES FOR LSO.

1. Corynanthine. Results with corynanthine -have been disappoinling. in l0 patlents no antidotel results were seen when 15 mg. corynanthine were administered 30 minutes before 40 mcgrm. of LSD. in a second experiment, 15 mg. corynanthine were administered 30 minutes before, 2 hours after, and 4 hours after 4O mcgrm. of LSD, using 9 subjects. Controls included three placebo capsules with 4C mcgrm. LSD, and fhree placebo capsules with a placebo drink. The timing of the placebo capsule was the same as that used when corynanthine was administered with iSD. Measurements included pupilhary size, knee jerks, systolic blood pressure, LSD questionnaire, and estimation of the cllnical grade of mental effect. Results are summarlzed in the table. These results were obtained by plotting the data on pupillary slze, knee jerk, and blood pressure, and measuring area under the curve over a 7-hour period. The questionnaire was evaluated by counting the number of positive answers (checks in questions not marked prior to administration of iSD). Clinical grades were assigned as in previcus work. Placebo effects ware eliminated by subtraction of the proper control. Statistical anelysis was done by the "t" test as opplied to differences in paired observations. A glance at the table shows there is no significant change in any of the messurements, indicating no significant antidotal effect of corynanthine against LSD.

l should like to learn if you wish me io try larger doses of corynonthine.

A-150

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2. Banthine. Banthine alone had no effect on LSD reactlon, nelther did a combinatlon of banthine plus corynanthine. Experiments, however, are still too few to permit statistical analysis.

3. Chlorpromazlne. In contrast, experiments with chlorpromazine are at least promising. Two seis of experiments have been completed. in one set, 50 mg. of chlorpromazine orally was followed in 30 minutes by 40 mcgrm. of LSD orally. In the other set of experiments, 75 mg. chlorpromazine orally was followed by 40 mcgrm. LSD orally. Controls have included lall tests being done in a randomized orderl placebo followed by placebo; placebo 二 measurements made. and method of analysis are the same as those described above. Inspectlon of the tables shows a significant reduction in the intensity of mental response Inumber of queslions and clinical gradel after 50 mg. chlorpromezinz as compared with the response after placebo plus LSD. Diminution in blood pressure and pupillary responses were almost significant, and very likely wouid be with o larger number of subjects. Afier 75 mg. chlorpromazine, significant reductions in all responses, except pupillary size, were obseryed. Failufe to obtain a siçnificant rzduction in pupillary response was due to an aberrani reaction in one of the 7 patients. The trend, however, Is toward reduction of the pupillary response. The antidotal effects of chlorpromazine persist about eight hours; efter this time LSD reaction may reappear.

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No significa zffects were observed with50 mg. of chlorpromazine alone. After 75 mg., definite drowsiness ensued which. however.was not accompanied by confusion and ataxia, as is the case with barblturates.

It seems to me that these observations need extension In the following ways:

i. Confirmation In other laboratories.

2. Extension of my own series to a larger number of subjects.

3. Study of a wider range of doses; first, using more chlorpromazinz, and finally more LSD.

4. Administratlon of chlorpromazine after LSD.

5. Administration of chlorpromazlne parenterally rather than orally.

It should be emphasized thatchlorpromazine is not a perfect antidote for lSD. at least in the dose combinatlons studled. lt does not completely obliterate the response in all subjects. The effect is anfidotal rather than competitive. With the larger doses of chlorpromazine. drowsiness becomes a definite drawback, even though patlents have received LsD. There is, however, no confuslon or motor incoordinatlon as is the case. with doses of barbiturates sufficiently larçe to allevlate.anxizty caused by LSD.

CA-lOl. Results with this interesting compound was partly summarized in my letter of 14 July l954, and since that time it has been discussed wlth We have eiso now made measurements of the blood pressure response on standing, before

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and after adminisation of CA-l0l. Results show that this compound induces profound postural hypotenslon in doses of only 2 mg. Further work with CA-lOl hes been deferred in order to concentrate on bufotenine. However, CA-lOl appears worthy of further study. Closer evaluaflon of mental effects utilizing a variety of definite psychological tests in a larger number of Individuals might be illuminating. A more detalled study of the cardiovascular response is also indicated In the hope of elucidating tfie mechanism. An antidote for drugs of this sort may also be needed.

BUFOTENINE We now have carrled out over one-hundred 二 preliminary trlals with this substance. This was done in an effort to locate a dose-range and to obtain some idea of the effects induced. The dose has been gradually elevated from 5 mcgrm. totar dose to 500 mcgrm. todal dose. With doses of less than 250 mcgrm. neither subjective nor objective effects were observed. Between 250 to 500 mcgrm., we have had scattered reports of dizziness, confusion and siight nervousness lasting for only an hour or two. As yet no consisfent eifzcts on the blood pressure, knee jerk, pupillary size, pulse rate, etc., have been observed. l intend to keep elevating the dose, following my return from Europe. As far as the work has gone, however, results with this compound are not promising.

x-147

Harris Isbell, M.D.

Hl:rn

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GIVEN BEFORE AND 2 HOURS AND 4 HOURS AFTER LSD-25

EFFECTS OF 15 NGM. CCRYNANTHINE ICC-11

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Means per cent on o patients: Values corrected for placebo effact. Under knee jerk, pupils and blood pressure, figures represent squere inches under curve. Guestions - Number of positive answers on. questionnaire. Grade - Clinical, grade.

.EFFEOS OF 5O MGM. CHLORPROMAZINE

GIVEN 3O MINUTES BEFORE 4O MCGRM. LSD

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EFFECT OF 75 MGM. OF CHLORPROMAZINE GIVEN 30 MIN. BEFORE 4O MCGRM. LSD