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(b)③)

Cur experiments on tolerance to LSD-25 have been proceeding well, although l continue to be somewhat surprised by the resuits, which to me are the most emazing demonstration of "Lo druo tolerance I have ever seen. I have had 7 patients who i have now been taking the drug for more than 42 days. One of these patients receives I mcgm./kg. daily, 4 receive 1.5 mcgn./kg. dally, and 2 receive 2 mcgm./kg. daily. All 7 are quite tolerant to both the physiological and mental effects of the drug.

We have attemoted to break throuch this folerance by administering double, triple and quadruple doses. We have not yet observed full restoration of the LSD-effect with any of these doscs, which, in the case of one of the patients receiving 2 mcgm./kg. daily, amounted to 532 mcom. total dose. Increasinc the dose seems to restore the physiolocical effects to a greater degree than the mental effects. which are present in only mild degree and which do noi persjst for more than one or two hours. Discontinuation of the drug for fwo days in one patient was followed by almost comolete restoretlon of the inltlal effect. Administration of 200mg. of the metabolic blocker, SKf-525, did not overcome the tolerance.

We have also been attempting to study "antidotes" for LSD-25. We have done cuite a number of experiments in which O.2 Gn. of pentcbarbital was given JO minules prior to iSD. This druc appears to definitely alter the LSD reaction, in .that anxiety, nervousness. and insomnia are markedly reduced. However, the orice paid is that of partial drunkeness induced by the barbiturate.

We have completed two experiments with Corynanthine. The patients used were extremely. sensitive subjects who gove grade 3 to 4 reactions to a 40-mcgm. dose of LSD-25. They were given

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LEPARTMENT OF ¿ALTH, EDUCATION. AND VAF

IN REYLYING. ADORESS THE

PUBLIC HEALTH SERVICE Lexington, Kentucky

NIMH Addiction Research Center.

14 july 1954

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very long.period of time. They are described as conslsting of a sensation of mental relaxation accompanied, however, by "physicol" tenslon, increased appreciation of music, jokes, and other things. The characteristic behavior observed in marihuand smokers lgiggling, silliness) has not been seen, but the experimentai sifuation has not been conducive to the appearance of such behavior. No hallucinations, perceptual distortion, efc., have been reported.

With laroer doses {2 to 2.5 mg.} the symptoms became quite unpleasant in 6 of the 1l subjecis 6 to 8 hours after adminisfration.The unpleasant symptoms included dizziness, feeling of great weakness, marked drowsiness, nausea and vomiting. Weakness has persisted for 48 to 72 hours after administration of the drug. One patient fainted on going to the bathroom the mornlng after having received a 2-mg. dose.

Neurological examination in these patients so far has been negative with the doses used. However, gait could not be tested in some patients who became so weak they refused to get out of bed. There is a very definite tendency for the pulse rate to becomé rapid and a tendency for fhe blood pressure to fall. The results suggest that some cardiovascular disturbance. possibly postural hypotension, mêy occur. 1 hope to investicatz this in the immediate future. Because of the aooearance of thése toxis reactions, I am not planning to increase the dose beyond 2.5 mg., in fhe immediate furure.

It is noteworthy that the patients show the characferistic marihuana facies, which consist chiefly of marked conjunctival reddening and pseudoptosis

I hope soon to have some information on Bufotenine, but have not carried out any experiments as yet.

Sincerely yours,

Harris Iisbell, M.D. Director of Research

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