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The National Institute of Mental Health (Mr. Gordon Klovdahi) has informed me that he has asked the NIH budget office to forward the request for renewal of the synthetic substitutes for codeine project to the Office of Naval Research. The amounts requested will be identical with those given in the budget that 1 left with you.

The Institute has requested an increase in their appropriation in the hope of being able to take over some of the personnel assigned to this project, but this matter cannot be settled until the budget for fiscal 1959 is known exactiy. In case they do take over any of the personnel then arrangements wiil be made to return whatever part of the funds that wili not be required. Please let me know if this meets with your approval.

I am enclosing a print of the siide that I used in a Seminar at Bethesda. Although of not great interest, it does show the comparative psychotomimetic potencies of all the compounds I have tested for the Sandoz Company.

I currently have been working with the Japanese compounds from the TakedaCompany (agroclavine and dihydroagroclavine). Neither compound has shown any psychotomimetic potency in doses ranging up to 50 mcg./kg. of body weight. On the contrary, agroclavine may have sedative properties. Another compound

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DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Nareal lastitute of Mealad Hesita Addictica Reretrch Ceaiet U.3, Pub Henth Service Hopit Lesiso, Ka

PUBLIC HEALTH SERVICE

26 May 1958

[PAGE 2]
obtained from Eli Lilly and Company, in which the acid amide group of LSD has been replaced with the methyl and a hydroxyl, has also sedative rather than psychotomimetic properties. I am going to try agroclavine and the Lilly compound as possibie biockers of LSD.

I will be leaving June 5th for an extended trip to the West coast and will not return to Lexington until the middle of July-

With kindest personal-regards,

Sincerely yours,

Harris isbell, M.D. Director

Hi:1w

Enclosures

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Design. A randomized, double-blind design was used in.

both experiments. In both, two drug combinations were used:

BOL plus LSD, andBOL placebo plus LSD. The combinations or

BOL placebo plus LSD placebo and of BOL plus LSD placebo were

not done because previous data indicate there was no change of

significant degree after either combination.

Heasurements. Systolic blood pressure, pupillary size and

threshold for kneejerks were determined twice before and at

hourly intervals for sight hours after LSD by methods previousiy

described. A modification of the Jarvik-Abramson questicnnaire

was given twice before and 1/2, 1-1/2, 2-1/2, 3-1/2, 4-1/2,

5-1/2, 6-1/2 and 7-1/2 hours after LSD. Short mental status

examinations were conducted at these times, in order to assign

a "elinical grade" to the reaction.

Analysis of Data. Areas representing.change from predrug

controls were calculated for date on blood pressure,-patellar

refiex and pupillary size. The number of questions scored

positively after LSD were counted, eliminating any which were

also scored positively before LSD. Grades were assigned

according to the system previousiy described. The usual statis-

tical treatments were performed on the data. The t-test for

paired observations and non-parametric tests (Wilcoxon) were

used in evaluating the significance of resuits.

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RESULTS

Experiment 56-D. The results of this experiment are showm in tables 56-D1 and 56-D2. Al1 aspects or the LSD reaction were reduced but not to a statistically significant degree. This result is similar to that observed in our first experiment in which a larger dose cf LSD was used.

Experiment 56-E. The results are showm in. tables 56-El through 56-E3. Significant reductions (t-test) ware observed in every aspect of the LSD reaction except for the patellar reflex. The non-parametric tests were also significant for every aspect except the clinical grade. Time course of the LSD reaction (table 56-E3) was not greatly altered by BOL, despite the evident attenuption..

DISCUSSION

The results show that pretreatment with BOL for five days does reduce the intensity of the reaction induced by 1 mcgm./kg. of LSD. The results strongly suggest that the longer BOL is administered the greater is the reduction in intensity of the reaction. Such results are more compatible with the development of some degree of cross tolerance between BOL and LSD than with direct competition of these drugs for receptor sites. The degree of cross tolerance to LSD conferred by pretreatment with BOL is, however, not complete. Even after

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five days pretreatment with gOL significant changes over control occurred in blood pressure, pupillary size, and mental responses. There was also a marked variation between individuals. In several patients cross tolerance appeared to be almost complete; in others, only, partial tolerance was observed.

CONCLUSICN

Pretreatment with 1 mg. of BCL threa times daily for five 'days causes a significant reduction in intensity of the reaction induced by 1 mcgm./kg. of LSD.

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TABLE 56-D1.

Attempted Blocking of Reaction Induced by 1 mcgm. of LSD By Administration of 1 mg. of SOL t.i.d. for Two Days.

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TABLE 56-D2.

Number of Patients in Which Change After BOL Placebo Was Greater Than After BOL.

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TABLE 56-E1.

Attempted Blocking of Reaction Induced by 1 mcgm./kg. of LSD By Five Days Pretreatment with 1 mg. of BOL t.i.d.

MEASURE BOL AID LSD BOL PLACEBO AND LSD

Patellar Reflex $5 . 0 \hat { \odot } \pm 1 . 7 4$ 6.6±1.33

Pupillary Size 9.55 ± 1.65 15.97 ± 1.78

Systolic Blood Pressure $5 0 . 3 \div 1 1 . 8$ $9 9 . 5 \pm 1 7 . 1$

Nunber of Questions $2 8 \pm 1 4$ $6 6 \pm 1 3$

Clinical Grade 0.9 ±0.45 2.0 ± 0.36

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TABLE 56-E2.

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Time Course of LSD Reaction after Pretreatment with BOL or BOL Placebo for Five Diys.

Figures are averages of results on 10 patients. BOL dosage was 1 mg. orally three times daily for five days prior to LSD plus 1 mg. two hours prior to LSD. LSD dosage was 1 mcgm./kg. C  Control (predrug) measurement.

TABLE 56-E3.