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Dr. Rudolf Bircher Sandoz Pharmaceuticals Sandoz, Inc. Hanover, New Jersey

Dear Dr. Bircher:

We have finally completed our study on tolerance to psilocybin and LSD-25 and cross-tolerance. between these drugs in five suhjects, supplcnenting the earlier study of Dr. Isbell on five other subjects. The tables enclosed represent the combined data on all ten subjects.

As you will note in Table 3, there is no doubt that our subjecta developed tolerance to LSD-25 (1.5 ncg/kg), and after they became tolerant to this drug, they exhibited crosstolerance to psilocybin (150 cg/kg), with respect to al1 measures except possibly the temberature-elevating cffect of the letter drug. On the other hand, the evidence for developzent of tolerance to psilocybin is not so complete (althoughly strcngly suggastive), and on several measures (temperature, bloód pressure and knee jerk), the subjects remained reactive to LSD-25, after chronic administration of psilocybin for seven days.

One possible reason for the failure to demonstrate tolorance to psilocybin and cross-tolerence to LSD-25 on all mcasures. is suggested by the data in Table i which indicate that, at least with respect tò their effects on pupiliary size and responses to qucstionnaire, the maxiral doses of LSD-25 and psilccybin we used were not equipotont -- 1.e., LSD-25 (1.5 mcg/kg) produced grcater effects than psilocybin (150 mcg/kg),and/or, the period of chronic adninistration of psilocybin tas too short.

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25 January 1960

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Sincs the question of tolerance and cross-tolerance in reçard to psilocybin and LSD-25 is of considersble theoretical signirlcance, wo aro thinking or doing another study, with larger doses of psilocybin (possibiy up to 250 mcg/kg, aaximal dose) and longer curation of chronic intoxication (14 days). To do this in ths few months I still have remaining before my prospective sabhatical year abroad, we wiil have to use ten new subjects and begin the study within two weeks at the latest. Also, ke have caiculated that in addition to that we have lert or the supply of psilocybin you so kindly furnishud a few nonths ago, we would roquire about 2.0 grans for completlon of the experiment.

Unfortunately, we cannet begin the experimunt until we have the complete supply os psilocybin on hands since we must do some prelirirary assays of relative potency before committing ourselves tc such a long anc complicated experimuntal design. Therefore, the dacision whether or not to undertake the new study depends on the possibility of your being able to send us 2.0 grans of psliccybin within the next two weeks.

I realize that this is an extraordinary request and that you may not have that zuch psilocybin on hand. Howver, I shall be very grateful if you will let me kncw as soon as possiblc what the prospects are.

With many thanks for your assistance, past and present, and with cordial regards,

Sinceraly,

Abraham Wikler, M.D. Acting Director

AWtbws

Enclosures

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Er. Birahor

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Table I

Differences in Response to Control Doses of LSD and Psilocybin

Figures represent mean differences ± standard errors of the differences between means of responses to two control doses of LSD-25 (1.5 mcg/kg) and means of responses to twg control doses of Psilocybin (150 mcg/kg).

Note:=P < .02 =P < .01 +, indicates LSD-25 stronger in effect than Psilocybin -, indicates Psilocybin stronger In effect than LSD-25

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Table 2

Differences in Responses to Placcbo, 1.5 mcg/kg of LSD-25, and 150 mcg/kg of Psilocybin on first and second controls.

Figures represent the mean differences ± standard errors of the differences between measurements on the first and second controls in 10 subjects. None of the differences except that for temperature change after psilocybin were significant.

Indicates that the average measurement was increased on the second control,

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