DEPARTMENT OF HEALTH, >2pEDU>2p'CATION>1p, AND W>2p*>2pz>2p">2p->2p@>2p;>2pLE >2pP>2pU>2pB>2pU>2pC H>2pU>1pLTH S>2pU>2pV>2pI>2pC>2pE 28 October 1958 >2pl>2pi>2pa>2pd>2pe>2pn>2pd >2pl>2put>2pi>2pt>2pu>2pf>2pt of >2pM>2po>2ps>2pt>2pa>2pt Ralik A>2p"k>2pd>2po>2ps >2p&>2pu>2pe>2pa>2pm>2ph C>2pa>2pst>2pa >2pU>1p.L >2pf>2pt>2pb>2pu>1pc >2pHea>2pk>2pb >1pS>2per>2pr>2p;>2pc>2pe H>1po>2pe>2pp>2pi2>2pW must apologize for not writing to you sooner but, as you kno>2p%>2p,>2pi>1p, was away for most of the summer. Since my return the possibility has arisen that we may, get a new building >2p%>2p,>2pth>2pich would provide new space for research>2p'here>1p. I therefore have been working under multiple pressures and haventt had a great deal >2pof free ti>2pme>1p. Budget, To MY disappointment the >2pN>1p'ational Insti2tute of Mental >2pHe>2p-alt>2pH was not able to provide any additional funds to pick up any of the personnel currently in our project. I t>2p.>2piere>2pj>2p4>2p'ore continue to be dependent >2pon yo>2p->2pt>2pi>2ps I have asked NI>2pM>2p-H again to include a,! item for s>2p:>2pdlari>2pes of part or all of these employees in the budget for fiscal 1959>2p,>2p, but there Is.. of course) no way of knowing if this can be done. 'I will try to2 keep you Informed. LSD Congeners with Sedst>2pi>2pv>2pie Effects. I mentioned briefly In a Tet>2p-t>2pe>2pi>2p;>2p->2p->2pd>2p-ated >2p->2p2>2pE>2p->2pr>2pi>2pfa>2p->2pY >2p1>2p->2p->2p4>2p@>2pO the sedative effects observed with nds>1p.of this tv f these >1p(agroclavine and d>2pi>2p.>2piydro>1p- >2pc>2po>2pr>2pi>2pp>2po>2pu pe>1p. Two >1po agroclavine>1p) were obtained from Takeda Laboratories in Japan. A 2 third compound (No. 231>2p9>2p4>2p, Eli Lilly >1p& Co>2pmpany>1p) is very sim>2pila>2p,>2p- in structure to triseclavine>1p. We have now ccncluded preliminary experiments in which men who had slept all night received one of t>2p.>2pqese drugs (or place>1p.bo>1p) at >1p8 a>1p.>2pm>1p. Observations were made every half hourfor eight hours and consisted merely of checking whet>2p'>2p.>2p'>2p,>2p.er or not the men were In bed asleep, in bed aw2ake, or up and about. This was done to avoid any stimulation >2pwhich might obscure >2p- seda>2pt>2pive or hypnotic effect. Under these conditions the men slept more after all three drugs than after placebos. Lilly 23194 was the most potent c>1po>2pr>2p.>2p,pound>1p, >2p4>2p0 >2pm>2pcg>2p.>1p/>2pk>2pg>2p. causing an average increase hours slee>2po in the four hours between >1p(>1p5 patients) of 71>2p.7 >1p8 and 12 a.m. Agr>2paclavine >1p(50>2p-60 mc>2pc>2p]>1p.>1p/kg>1p.>1p) was the next most potent, causing an increase o>2pL>1p' 1>1p.2 hours >1p(6 patients). Dihydro>1p- agroclavin>1p'e >1p(60>2p-70 =g>1p.>1p/kg>1p.>1p) was least potent, causing an average >1p.>1p. . . ...................... Page increase of only >1p0>1p.>1p5 hours nts>1p)>1p. Onset of action was >1p(4 patie very rapid >2p4ith the two active drugs, the >2p,>2pnen being unabl>2pe to remain awake an half-hour after the drug was given. After 12 o'clock the men slept tittle, but reported subjective relaxation and drowsiness lasting through the afternoo2n. These results are of Interest because of the reversal of the predicted effect (excitation expected>2p,>2p,s>2pedat>2pion observed)., the discrepancy with animal tests (drugs are LSD-like in animals), and apparent high potency as hypnotic drugs In m>2pan>1p.>2p. You will note that the total dose of 23194 was only 2>1p-3 mg; the implica- tions are obvious. We are now extending these observations. The mIost potent drug >21p(Lilly>2p.>2p, 23194>1p) will be>1p-co>2prapared at two dose levels >1p(2 and >2p4 mg. per 70 kg.) with secobarbital >1p(>1p1>1p0>1p0 and 200 >2p,>2png>1p.>1p) and the dose range of agroclavine and d>2pihydroagroclavine will be further explored. In addition, we are also-adding studies on d>2p-Lysergic acid diethylamide>1p, which in preli>2pr>2p->2pi>1pina>1p.ry tests a>2pis>2pn>2p> see>2p'>2pged to have sedative effects in doses as low as 15>2p-20 mc2g>1p.>1p/kg>1p. Nine men will receive these drugs so that we will have figures w>2phich>2p. will have so>2pme statistical meaning. I then plan to attempt to attenuate the LSD reaction with Lilly 2319>2p4>2p, and may study some combinations of these drugs with alcohol and other hypnotics>1p.>1p. C>1p-5>1p. >1p1 am attaching a long overdue report on C>1p-5>1p. As I told you this compound appears to be relatively inert in man. Ne2uro>2pDh>2pzsiological Studies on C>1p-9>1p. These studies are being undertaken by ur>1p. >2pI>2p.>2pIi>2piiiaM R. >2pi>1pv>2piartin as part o>2pA>2p" a larger project. Dr. Martin has >2p@>2po>2p@und that, in intact cats, 0>2p->2p2>1p-0>2p-4 mg./kg. of >1pC>2pr>1p9 Intravenously causes dep>2pr ession of body temperature, ataxia, relaxation of nictitating membrane, depression of the pinnal reflex, d>2piminished muscle tone, loss of righting reflex, so>22pr>2pr>2plno>1p- lence>1p, and taming. These effects appear after two hours and >2pr>2p.>2p->2pa>2py persist for as long as three days >1p(0>1p.>2p4 mg./kg.). Bradycardia>1p, which has been shown to be due to the temperature fall, Is also>1p- observed. In unanesthetized curarized cats with electrodes in cortex and In the reticular formation in the mesencephalon C>1p-9 causes marked EEG slowing; increase in'the threshold for- acti5vation of the decreased lengths and altered qua>1pl>2pl>2p'>2pty of the activation response; fall in blood pressure, with narrow pulse pressure; increased threshold for elicitation of a blood pressure rise by mesencephalic stimulation; and decrease in Dressure response once It has been elicited. pagz During a visit to the University of Rochester I have also learned that Dr. E>1p.>2p-S>1p. Boyd of the Department of Pharmacology has become interested in this group of drugs. He has >2ptsted the methyl>2p- and dimethyl>2p-heptyl>2p-derivatives and is atte>2pmpt>2ping to study the effects in cats with the view of investigating the metabolic fate of the compo2unds. You a-re doubtless aware of his work. K>1p-302>1p. A report on-this >2pm>2paterial>2p.>2p, and-on the crude form,, is attached. I told you previously, both the crude material and As K>2p-302 are active. Psilocv>2pbin>1p. Attached is a thermofax copy of letter from Dr. Henze o>2pT Sa>2pndoz indicating that psilocybin will be available to me in the near future. I should be able to undertake preliminary >2pi>2pi2o>2p.>2prk with this compound abo>2put the middle or end o>2pf November. Narcotics of Hich Potency. Dr. P. Janssen o>2pL>2p' Euphar>2pna Laboratories, Belgium'. visi>2pted us t>2pr>2pi>2pis month. He-told us about some benzim>1pi>1p- dazoles with analgesic properties of extre>2pme potency. >2pT>2phese co>2pmpounds belong to the series originally developed by C>2piba>1p. One of Janssents compounds is said to be 3>1p-thousand times as po>2p2f>2p-ent>1p. as morphine in monkey-; and anothe>2pr>2p, a rather unstable fluorinated compound,, is 300>2p-'thousand times as potent as morphine, I believe that Dr. Janssen talked with Dr. N. B. Eddy and with persons>1p.from the Army Chemical Center concerning these d>2prugs>1p. It Is quite li>2pkely t>2phat members of this series will come to us via the Drug Addiction Co>2pmmittee after testing in >2pmonkeys In Michigan has been 2 completed. Inve>2pi>2pitory for Subjective>2p->2pEffects of Dru>2pcs>2p->2p. My psychological staff is >1pa>1pt>1pt>1pe>2pm>2pi>2p3>1pt>1pi>1pn>1pg >2pt>2po deve>2plop a self>2p-administerea machine-scored "inventory" which will discriminate between the subjective effects of opiates, barb>2pi'turates>1p, alcohol, chlorpro>2pnazine>1p, amphetamines, LSD.. and pyrahexyl>1p. In Its present form the test consists of more than >1p5>1p0>1p0 true2 or false items and includes validating and ly>2ping scales. The number of items will be sharply reduced after item analysis has been done, and it may be possible to develop sub-inventories for each >1po>2p.>2p->2p&>2p" these >2pclasses of drugs. We hope t>2phat the inventory will improve our methods for measuring the subjective effects of the drugs and that the inventory can eventually become a quantitative Instrument. The project is howe2ver very long-range and may require as much as two more years for co>2pr>1pipletion>1p. I expect to be in Lexington for the next three months except for November 20 and 23>2p, when I will meet with the Council on Men>2p">1p.al Healths A>2pI>2pA>2p.A>1p. in Chicago. I would welcome a visit from you at any time. With kindest personal regards, Si rel 1 *De Enclosures Director