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I am attaching for your information copy of a request to the Office of Naval Research for renewal of our project here. In the event the CNe feels the project should be conttnued l will arrange to have. the business office of the Natlonal institutes of Health send this on at the proper time, later in the spring.

You will notice that the amount of money requested is somewhat greater than in prevlous years. This is necessary in order to provide funds to cover the increase in Civil Service pay which went into effect in March 1955.

You have, no doubt, by now received a copy of my letter to Dr. Pogge of The Wm. S. Merrlll Company concerning efforts to reverse the LSD reaction wlth Frenguel. This experiment was undertaken for two reasons: (t) we had received persistent reports from other laboratories that large doses of Frenquel would ameliorate the LSD reactlon, and 12) because. the company clalmed that in our original blocking experiment the degree of mental effect was not sufflcient for the effects of Frenquel to be evident. As you see from the data in the letter, thls reversal experiment was a complete fallure. We were unable to distinguish Frenquel injections from placebo injections.

COMB INAT IONS OF HYOSCINE AND LSD

These experiments were carried out in an attempt to determine whether Hyoscine would ameliorate or enhance the LSD reaction. Two series of experiments were done. In the flrst series Il negro subjects received in randonized order Hyoscine olacebo plus LSD placebc: Hyoseine placebo plus LSD; O.42 mg. of Hyoscine plus LSD plecebo; 0.42 mg. Hyoscine plus LSD; O.64 mg. Hyosclne plus 1SD; O.85 mg. Hyoscine plus LSD. Both Hyoscine

C

IN REPLTING, AODRESS TKE ADDICTION RESEARCH CENTER NARIONALIMTITUTES OF HENTAL HEALTH U. E. PUBLIC HEALTH SERVICS HOSPITAL Box 2000 LEXINSTOA, KERTUCKY

partmant of HEALTH. EDUCATION. ND WELFARE. Public Health Servics NATIONAL INSTITUTES OF HEALTH

24 January 1956

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us reports.

Results are shown In left side of table. You will note that O.64 mg. and O.84 mg. of Hyoscine increased puplllary dtlatation seen after LSD, reduced blood pressure response, increased the number of posltive answers, and increased the clinical. grade of reactlon, but the last was not significant as compared with Hyoscine placebo and LSD.

In the second series of experlments l2. subjects were used and received in randomized order: Hyoscine placebo plus LSD placebo; Hyoscine placebo plus LSD;1.3 mg. Hyoscine plusLSD placebo; and 1.3 mg. Hyoscine plus LSD. Results were similar but more marked with lower doses of Hyoscine than in the first series. There was marked Increase in puptllary ditlatation, marked decrease in blood pressure response, marked enhancement In the number of positive questions, and an Increase in the clinical grade of reactlon which, however, was not statistically significant.

In this last series of experlments the side effects of Hyoscine were very prominent and included sensaflons of giddiness and dtzziness, marked blurring of vislon, marked dryness of mouth, absence of perspiration, and slight confusion. lt was yery easy to see that the patients had both LSD and Hyoscine effects. Impresslon was that of a combination of drug toxlcltles rather than of anyspeclfic enhancement of the LSD reaction. The Hyoscine.side effects probably make use of this comblnation impractical.

DL AMPHETAMINE AND LSD

These experiments were carried out because Hoch has stated that methamphetamine-ameliorates the LSD reactton and also because of a theoreticai consideratlon advanced by Dr. Wikler. Eleven subjects were used and received In rendomized order: dl-amphetamine olacebo plus tSD placebo; dl-ampletemine placebo pTusLSD: dl-amphetamine plus LSD placebo; and dl-amphetamine plus "LSD.Both drugs were- given oraily. The dose of amphetamine was 20 mg. and the dose of LSD was 60 mierograms. Dl-amohztamine was given one hour prlor to LSD to provide time for dl-amphetamine effects to develop. Results are shown in the table.The only signiflcant change with the combination as compared with LSD alone was Increase in the blood pressure response. Effects with this dose of dl-amphetamine alone in our subjects, however,

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were mlld and the work really needs repetitlon, elther using larce doses of dl-amphetamine or some more potent sympathomimetic amine, such as dextroamphetamine, in doses sufficient to induce a more definite reaction in our patients.

RESERPINE AND LSD

The experiments prevlously reported have been amplified using larger amounts of Reserpine. It was felt that thls work is important because of reports by Brodie, Himwich, Wooley and others on the possible relationships between LSD, Serotonin, and release of Serotonin by Reserpine. In these new experiments 12 negro subjects received in random balanced order: Reserpine placebo plus LSD placebo; Reserpine 5 mg. orally plus LSD placebo; Reserpine placebo plus LSD; Reserpine 5 mg. orally plus LSD; Reserpine 7.5 mg. orally plus LSD; Reserpine ó mg. orally plus LSD. Dosage times are shown in the fable. lt is evident that there was no blocking of the LSD effect on any of our measurements.

The most interesting observation was that the patlents seemed to be worse when they recelved- 7.5 mg. of Reserpine orally or 6 mg. intramuscularly plus LSD. The intensification of the reaction was mosf prominent in the group that recelved Reserplnz Intramuscularly. In both these grouos, patients developed tremors and ankle clonus. Mentally, nervousness, confusion, apprzhension, and more frequent- and more vivid hallucinations were reported. These changes are not apparzat in the figures in the fable becausz our methods of measurement are not adequate to reveal them. In rating knee jerks, nothing is allowed for tremors or for clonus. ln assigning clinical grades, no allowance is made for the intensity of symptoms. At the present time we are unable to determine whether the incraase represents a specific enhancement, of the LSD reaction by Reserpine, or represents merely a combinstlon of twe drug foxielties.

We feel that this observation has greet theoretical importance and may possibly have some practical use. We plan: ll) to attemot to estaslish the deleterous effect of Reserpine on the LSD reaction firmly by studying the effect of Reserpine combined with mininal doses of LSD, [2) to develop rating systems which will allow for the neurological changes and alterations in intensiiy and quality of symptoms, (3) if we can, firaly establish that Reserpine makes the LSD reaction worse, and study the effects of Reserpine on tolarance to LSD.

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cn observed with doses of l0 mg. of this Nb effects have substance orally. We have now been giving the drug intramuscularly and have gradually increased the dose to 15 mg. Mild toxle symptoms have begn observed whlch Include sensatlons of a "band around the head," nausea, and perspiration. Effects are apparent within ten minutes and last less than two hours. One of 4 patlents reported seeing spots of color on the wall. We are still gradually increasing the dose.

OL 1OL IQUI

We have been asked by Doctor Kety of the Natlonal Institute of Mental Health to study the effects of this crude drug. Preliminary exploration is now golng on. Doses of O.8 gram of the ground seeds lapproxlmately 20 seeds) caused no discernible effect other than subjective reports of blurred vislon in 2 of 4 patients. We are continuing to Increase the dosegradually and will report if any striking results are abtained.

NEUROSURGICAL PROJECT ATTHE NATIONAL INSTITUTE OF NEUROLOGICAL DISEASES AND BLINDNESS, NIH.

I have discussed this project with Doctor Wikler. It has been proposed to study the effects of drugs on perceptual tracts, pathways, and responses using neurosurgicat patients in whom corfical exploration and extirpatlon is carrled out for epllepsy. Both Dr. Wikler and myself believe that this would be a very important project which would have great theoreticat significancz. It is certainly worthy of support, but neither of us are in any position to advise as to whether or not It can be supported financially.

Sincerely yours Aaurui Dbeel

Director

BUFOTENINE

Hi:en:lw

Enclosures: 3 Tables. Copy of Prol: Deseription f.y. 1957.

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EFFECTS

ITH 60 mcgm. LSD

All figures are means on ll subjects.

Knee jerk, puplllary size,,and systolic bload pressure expressed as area under time-actlon curve during first 8 hours after administration of LSD. Clinical'grades on basis of I - 4.

Statistically significant fromplacebo-placebo.
StatistIcal-lysignificant from placebo-LSD.

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2.5 mg. oral1y 22, 10 and 2 hours prlor to LSD. 2.0 mg. Intramuscylarly 22, 10 and 2 hours prlor to LSD.