[PAGE 1]
February 1958 - Through January 1959

RESEARCH GRAITS:

\$36,800.00 1,000.00 \$37,800.00

SALARIES & FEES AND SOCIAL BECUAITY:

Salaries and Fees Social Security

15.178.90 302.23 15,786.

SUPPLIES AND SERVTCES:

Special Chemicals

TOTAL EXPENDITURES

554 272 C0f 700 mne o ot- C
6 5 2 1 0

[PAGE 2]
Fobruary 195e - Through Jonuary 1959

RESJARCH GRANTS:

SALARIES & FEES AND SOCIAL SECURITYI

Salarios and Fees Social Security

SUPPLIES AID SERVICEST

Spooial Chenicals:

TOTAL EXPENDITURES

[PAGE 36]
UUIU oooonónoa cmco0comt

[PAGE 44]
AUTHORITED S1ONATURR

[PAGE 54]
11 Hαa vccano 000710 の

[PAGE 58]
balary

[PAGE 59]
ssN E

[PAGE 61]
J 12121 ococma c89017 C 9 3 6

[PAGE 68]
NN O630V1O

A业NA

C

[PAGE 70]
te

[PAGE 73]
ttemket/30195s No

[PAGE 74]
U 5875007007
105の5199999
59587985
47のC090C
122112 1

[PAGE 75]
Washin 1058N 1505 Sevent Bonuo

[PAGE 78]
251508 \$972 7.Dll

[PAGE 79]
WashintonBiu1958No1509 \$119 Bollea

[PAGE 80]
9.1510 3-Pallers Ceraultanit

[PAGE 82]
U i2
011709990 N

[PAGE 85]
3 1958N2 C 897 25 Saliry

[PAGE 86]
Sicly 31195hNo (Ene hi Dodars Coneuttent

[PAGE 88]
U G4C0CC

6 810 f

[PAGE 90]
09512

[PAGE 93]
B Jane 301958N2 8100 Conoultand

[PAGE 94]
UURLUンン
0005C8570001N
009009990 mのe OCのEC 2 11221

[PAGE 95]
Masha:21058N 1469 E 818 Ce heen Salary

[PAGE 96]
Washinglen 101 1470 G

[PAGE 97]
Washingtn ig1058N1471 Salary

[PAGE 100]
41
057580005
an8t-80
640.00 2
11221 9

[PAGE 107]
B Murki31 1058 N2 E 8 1C0 lne Salemy

[PAGE 109]
1958N6 E 10 C \$169 1Goftars

[PAGE 112]
000550780005
000171990009

[PAGE 113]
HshinglomPE7iurury 281958No 1406 89775 ni 75Dolln Seli

"CR TRUST CO

[PAGE 115]
Washigtar1n158 N 1408 Cidiuns Lekerey

[PAGE 116]
1409
98

[PAGE 117]
Mishin172318.11410 Irtinns

[PAGE 118]
b

1444444555551 0000000000N10Nn000
7 4

[PAGE 123]
NashinytmnDC 1958 N2 1477 10 8Bolins wahlelltoh SeaDasinay

[PAGE 124]
Hashington DC. S uy. 231958N1486 deda 0000g oun Polla

[PAGE 127]
ton  olers 22195N1527 16 817528 98Dellirs Cn

[PAGE 129]
This check à Whiiton  Robe 4 105sNo 1540
obligation to
and must Le :
otDirs \$17599
Awe heer lrg 94Dellas
W.HTades.Cst

[PAGE 131]
一

[PAGE 132]
1.. C o CO Q Q  o  Q QQ OOOCOOOO UU\*IU
1, 5 0 0 41

110 0 .0 9 0 00 11 0 0 0

2092

[PAGE 133]
February 1, 1957 – January 31, 1958

Research Grants:

12,381.31

4.591.95 68,726.26

and Social Security

16,917.65

Travel and Keetinga:

Special Chemicalar

Supolies.

Total

[PAGE 134]
/p

[PAGE 137]
6 2 00m 8 0 q   o 090000

[PAGE 138]
epacielsme

[PAGE 139]
2 8
2 U 2
9 0 0
TOO+6L 1# n

[PAGE 145]
1
UU&IU
000855809850000008580009 A cgcnrer0ooonnrpce 27 1 の 1 N

[PAGE 154]
ET

[PAGE 155]
1.1 AS
N
1#

[PAGE 159]
U 112585 0 05 01299710102
588790536cc06049
173555 01

[PAGE 160]
328

[PAGE 162]
1325

[PAGE 163]
1 3 7 bo0mnooroo 否

[PAGE 168]
000N008607000n

[PAGE 169]
b

[PAGE 173]
1 5785980 0004587680000 UU\*IU
21121
1, 0 6 6

[PAGE 180]
1
4
9 0800G6280G

[PAGE 185]
000548790000 9 96
010 0 X

[PAGE 188]
12612112 0002000000 UU\*IU
1.92 9

[PAGE 194]
1195 C Har B C R SFATHET

1190 D C 量2

1987. 1 1193 D C

[PAGE 195]
1057.k: 1196 B

[PAGE 196]
00029410866869005

[PAGE 203]
1320 0 Suppleis

057/1202

[PAGE 210]
UUレ 000611861950 000765959600 77612075 11 2MMEN

2 Or 0000

Wohingln.OC 1348

[PAGE 211]
1338 (D \$17 Suppleesol

[PAGE 214]
1309

[PAGE 215]
8 9 6 nt\*0n

[PAGE 218]
1228

[PAGE 219]
1322 Wabirglen 0 EFpesti

[PAGE 222]
con o0on
0 0 9 0 0, 00
COHO 1
0000
0050 5
1111 4

[PAGE 227]
00000O00O

Heshirgton OC 1375

[PAGE 229]
B

[PAGE 236]
11  uthey tia 3 Lb s
199
bntengaltan"4 lub. 1000.80
2415D
2410
12

[PAGE 237]
4

Description

2 3933300 4.4 3500000

1 1

00 G6 35 5

:

2

1

1

: 20

.

52

[PAGE 238]
RESEARCH GRANTS:

SALARIES & FEES AND SOCIAL SECURITY:

Salariss and Fess Social Seaurity

SUPPLIES AND SERVICES:

Spesial Chemicalst

TOTAL EXPENDITURES

I certiry that this is s trus atatemeat.

[PAGE 240]
m

1

80 "000 'an\$ ires ese-s

296r Aseniqsi ieeipdex etsl

Esér r et sa

ers tt eds

[PAGE 242]
FINANCIAL REPORT

/vv 2/ Februsry 1, 1962 to January 31, 1903

FUNDS RECEIVED 840,000.00
Grents In Aid B 849,000.00

pebm1ttaa i have ensr 2 aa1

TSS/CheSia31 D1F

/1

[PAGE 243]
FINANCIAL REPORT

1NV 20 February 1, 1961 to Janusry 31, 19d2
1NV 19

446tge

420%

: i TeS/Ghalcal Divia

[PAGE 244]
Project Title Knocknst Mstariale Item Classification Thzungh Sacas

Project CryptoMLTR Crypto ClassifcationMo

Cost\$40,000.00 Completion Date Febraary 1963

Purpose: This projoct iuvolves the prodaction snd preliminery teetios of meterials which'affect tho "awarenoes" of bomae beings. The goal is a good "iickey Finn,"

Status: This project has bean delayed by the loss of However. isolation and prekminary tastiag of a promising material first tocatod by him. are bcing carried cut and preHminary faasibility should be ortablisbod approaimatoly on schedule.

m

dectessitcatian

[PAGE 246]
Cashier's Check No. 0SC 578 in the amount of \$40,000, dated February 28, 1962, drawm on E payable to B

Receipt is hereby acknovledged of the following:

3762

RECEIPT

[PAGE 247]
MEMORANDUM FOR: CHIEF, FINANCE DIVISION

VIA

: TSD/Budget Offalcer

SUBJECT

: MKULTRA, Subprojact 4S, Iavoice \$Z1, Allotment 2125-1390-3902

I. Invoice No. 21 is attached covering the above subproject. Payment should be made as follows:

Castier's check in the amount of \$40, c00. 00 drawn Mbank, payable to B

2. The check shouid be forwarded to Chief, TSD/ Research Branch, through TSD/Budget Olicer as soon as pogsible.

3. Thie is a final in-oico. Howevar. since it is anticivated that additional funds will be obligated for thia project the files should not be closed.

E CHECKIS IN THE AMOUNT OF G 4O 00O.0O RECEIVED

Chief TSD/Research Braach

Attachmeat: Invoice & Certificationn

Distribution:

1 CERTIFY HAT RHOS ARE AN-S CRUGATION LETCEO./ DG10   2725-1392-392

Orig & 2 - Addreasce

1 - TSD/FASS

. ALTHCRINNG OFFICER

2 - TSD/RB

ATSD/RB/(13 Feb 62)

13 Fabruary 1962

[PAGE 248]
CERTIFICATIONS

(1) It ia har aby csruified that this is lnvoice  2applyiax o Sub=projee? No. 45 ef MKULTRA. thar pericrmanss is meatctery. Chat services ara beiog acromplshed in accordance with mutual agree. menlo, thas à detaiied acsnda ct the paytcnte and receipts ia. on Nlls in.TSD/RB. that thie bill ia juet and corrset and that payment thetaol aes nct yat bera made.

Chiel. TSD/Reaeareh Branch

Date 13 February 1962

12) it as hereby ceruifed that thie lnvoice applies to Subprojsst45 of MKUl.TRt waich was duly approved, and that the preject ia belal sarrted cut 10 sccerdance with the mrmorandum of 13 April 195) ffdr: ths DC! to the DD/A, and the extension of this autheriry ia suhasçara:

For Servie20

Research iarectcr

M

[PAGE 249]
SUBJECT : Continuation of MKULTRA, Subproject No. 45

l. The scope of this subproject includes all those activities now engaged in by B under the lirection of TSD/RB with the exception of those cutout functions specifically mentioned in connection with other MULTRA subprojects. In general, the research effort under this subproject will continue along the lines laid down in previous years. These iovolve the synthesis and pharmacological and clinical evaluation of compounds of those chemical families known to have epplication in the psychochemical and "K" fields. During the coming year it is planned to concentrate more directly on the more practical aspects of the "knockout" problen. Enough ney potent substances have become available lately to make such a change in emphasis worthwhile. In connection with this change it should be noted that certain findings made in project atwhich cannot be further exploited at that facility will be pursued at in the future. For this reason it may be necessary to supplement the findings of this subproject from time to time during the year due to increases of scope.

2. also serves as a general consultant to the Agency, provides services of a sensitive nature on an ad hoc basie, and serves as a cutout in procurement problems.

VV

A

Downsraded toesNHD by authopy cato:

E2 IMPDET; CL BY 187475

MEMORANDUM FOR: THE RECORD

E2 IMPDET; CL BY 187475

[PAGE 250]
3. The total cost of this project for a period of one year will not exceed \$40,000.00. Charges should be made against Allotment 2125-1390-3902.

C 4. has been requested to submit a summary accounting or a copy of the Fund's annunl audit report for the sponsor's. inspection. Also, it has been requested that any unexpended funds shall be returned to the Agency.

5. Title to any permanent equipment purchased by fuods granted

shall be retained by

in lieu of higher overhead rates.

6. It was mutually agreed that documentation and accounting for travel expenses wbich are normally reimbursable by shall conform with the accepted practices of the Fund.

Chief TED/Rescarch Branch

APPROVED FOR OBLIGATION OF FUNDS:

Attachment: Propoeal and Budget

Distribution: Original only

[PAGE 251]
PROPOSAL 1962

It is proposed to continue exploration and pilot work along lines which have been developed in the investigations of the past few years in cooperation with other projects of interest to the Sponsor. The primary field of vork involves the effects of stress on human beings. Major items of interest presently involve the following areas:

(a) Creation of reliable research "tools" for study of stress phenomena in animals and man with the end in viev of understanding these phenomena to the extent that practical applications can be realized in interpreting and controlling human bohavior.

(b) The production and study of new chenical and physical agents of significance in connectiou with the stress reactions.

(c) The allied investigation of chemical end pbysical agents related to the "state of avareneas" of buman beings. The particular interest in this relationahip is to obtain and define a separation between general activation or depression of he vhole animal and the very specific "perceptual" depression or activation desirable from the peychologists' point of view.

A reasonable anount of progress is being made in the several arcas indicated above and it is expected that continued efforts of the sort which have proved efficacious in the past year will yield further significent results.

WARNING NOTICENSITVA INELLIGENGSOURCES ANDETHODS OLVED

[PAGE 252]
WARNING NOTICE FASITIVEINELLIGENCE SOURCES AND ETHODS INOLVED

[PAGE 253]
MEMORANDUM FOR: THE COMPTROLLER

ATTENTION : Financa Division

MKULTRA, Subp

Under the authority granted in the memorandum dzted 13 April 1053

fron the DCI to the DD/A, and the extension of this authority in aubsequent

memoranda, Subprojcet has been approved, and \$0,000.00

of the over-all Project MKULTRA funds have been obligated to cover the

subproject's expences and should ba charged to cost center a125-1390-3902

Chief TSD/Research Brench

APPROVED FOR OBLIGATION OF FUNDS:

Research Director

Date:\_

Distribution: Original & 2 - Addressee 1 - TSD/PASS 2 - TSD/RB

SECRET

[PAGE 255]
MEMORANDUM POR: TEE COMPTBOLLER

ATEITION : Pinance Division

SUBJECT : XULIRA, Subproject45

Under the authority granted in the wemorandum dated 13 Ayril 1953 from the DCI to the DD/A, and the extension of this autbority in subsequent nenoranda, Subproject 45 has beon approved, and 20.000, 00 or the over-all Project NULTRA funds have been obligated to cover the subproject's expenses and should be charged to cost center 212s-1390-39

Chief TSD/Research Hranch

APPROVED FOR OBLIGATION OF FUNIS:

I CERTIFY THAT CNDS ARS AVARLATE OBUOLNON R CANCE to L." Ns.

Research Director

Date:\_

Distribution: Original & 2 - Addressee 1 - TSD/FASS 2 -TSD/RB

Date: 3 Octobar 1961

BBCRET

SECRET

[PAGE 256]
MEMORANDUM FOR:THE COMPTROLLER

ATTENTION : Finance Division

SUBJECT MKULTRA, Subproject Allotmut  2125-1390-3502

Uader the authority granted in the memorandum datod 13 April 1953 from the DCI to the DD/A, and the extension of this authority in subsequent memoranda, Subproject 5has beea approved, and o,000.00 of the over-all Project MKULTRA funds have baen obligated to cover the subproject's expenees and should be charged to cost center 2125-l390-3902

A

Chief TSD/Rssearch Branch

APPROVED FOR OBLIGATION OF FUNDS:

Researco Lirector

1 CADFY THAT RES ACE AC ORCANON  K
DHCI 10 ONSNT N.

Date:

ALTHCRIEING OITICER

Distribution: Original & 2 - Addressee ¿Y-TSD/PASS 2 - TSD/RB

SECRDT

SECRET

[PAGE 257]
Receipt is hereby acknowledged of the following:

[PAGE 258]
SUBJECT : Continuation of MKULTRA, Subproject No. 45

1. The scope of this subproject includes all those activities now engaged in by B under the direction of TSD/RB with the exception of those cutout functions specirically mentioned in connection with otber MKULTRA subprojecta. In general, the research effort under this subproject will continue along the lines laid down in previous years. These involve the aynthesis and pharmacological and clinical evaluation of compounds of those chemical familiee known to have application in the psychochemical and "x" fields. During the past year isportant progresa has been made in the area related to stressor compounds and the relationship or these materiala to tbe physiological pathways through wiich both stress and the reaction to it are mediated in human beings. Also, several new and important animal acreening techniqu adapted to the study of materials which depress the general awareness of animals without producing any acccapanying physical depression have been made available for vork on "knockout" materials. In addition, some progress has been made in relating certain organic chemical structures to observed effects on animals. A conaiderable part of next year's effort will be aimed at extending our ability to understand the structur activity relationships among these sleep-producing materials.

m eate:  1977

E2 LiPD; CL BY 187475

MEMORANDUM FOR: THE RECORD

ES IMPDET; CL-BY 187475

[PAGE 259]
the Agency, provides services of a sensitive nature on an ad hoc basis, and serves as a cutout in procurement problems.

3. The total coat of this project for a period of one year will not exceed \$40,000.00. Eowever, at the present time the project will only be extended for a period of three months. The cost of this project for this period wil1 not exceed \$20,000.00. Charges should be made against Allotment 1125-1390-3902. (It is anticipated that the remainer of the funds for the project year will be made available from FY-62 money when available.

4.as been raquested to subait  ary Baccounting or a copy of annual audit report for the sponsor's inspection. Also, it has been requested that any unexpended funds shall be returned to the Agency.

5. Title to any permanent equipaent purchased by funds granted shall be retained by B in lieu of higber overhead ratoa.

6. It was mutually agreed that documentation and accounting for travel expenses which are normally reimbursable by shall conform vith the accepted practices of B

APPROVED FOR OBLIGATTON OF PUNDS:

ResearchDirector

Chier TSD/Research Branch

Date

APPROVED FOR ADDITIONAL OBLIGATION OF FUNDS: (\$20,000.00 againet Allotment 2125-1390-3902

Bown raded o: CONFMnIAL by authorty of:107475 ate: na 1977

E2 ADET; CL BY 187475 2.

Date

Research Director

FES INPDST: CI BY 18775

[PAGE 260]
It is proposed to continue exploration and pilot vork along lines vhich have been developed in the investigations of the past few years in cooperation with other projects of interest to the Sponsor. The primary field or work involves the efrects of strea on human beings. Major items of interest presently involve the following areas:

a) Creation of reliable research "tools" for study of stress phenomena in animals and man with the end in view of understanding theee phenomena to the extent that practical applications can be realized in interpreting and controlling human behavior.

b) The production and study of new chemical and physical agents of significance in connection with the stress reactions

c) The allied' investigation of chemical and physical agenti related to the "state of avareness" of human beings. The particular intereat in this reletionship is to obtain and define e seperation betveen gezeral activation or depression of the whole animal and the very speciric "perceptual depression or sctivation desirable from the psychologists point of view.

A reasonable amount of progress is being made in the several areas indicated above and it is expected that contimued efforta of the sort which have proved efricacious in the ruat year will yield further eigniricant reeults.

As indicated in the attached budget, the total research effort wil1 amount to \$71,500.00. We are requesting that the present Sponsor fund only \$40,000.00 of this effort with theremainder to be provided from private sources.

FROPOSAL 1961

WARNING NOTCE SERSITIVE INTELLIGENCE SOURCES AND METHODS INVOLVED

[PAGE 261]
L. PHARMACOLOGY AND TOXICOLOGY

WARMINGNOTICE SESSTIVEINTLLIGENC SOURCES AND METHODS INVOL

[PAGE 263]
5 October 1961

MEMORANDUM FOR: CHEF, FINANCE DIVISION

: TSD/Badget Oflcer

SUBJECT

: MKULTRA, Subprojoct 45, Invoica No. 20 Allotmant 2125-1390-3902

L. Ixvoico No. 20 covering the shove subproject is attached. Payment should be made as followe:

Gastiar's chock in the amoumt of \$20, 000. 00 drawn on a lecal ben)

Z. The chsck should be forwarded to Chiel. TSD/Researeh Bran throagh TSD/Bodget Omcer, ss soon as possthle.

3. This is a final invoice, However, since it is anticipated that adiltional funds will be sbligated for tais project the flles should not be closnd

Caiad TSD/Research Branch

一 Attachment:Anrolce & Certiacatioas

Distribation: Orig & 2 - Addressce

CRA

1- TSD/FASS
2-TSD/RB

TSD/RB/ (5 October 1961)

A

[PAGE 264]
20,000.00

CERTIFICATIONS

{l1 It is heroby certifod that this is invoice 20appiying to Sub-project No. \_45 of MKULTRA, that performance is satisfectory. that services are being accompliahod in accordance with mutual agreements, that a detailed agenda of the payments and receipts is cn file in TSD/RB. that this bill is just and correct and that payment thereef bas not yet been made.

Chiof, TSD/Roscarch Branch

Date:\_

(2) It is hereby certifed that this invoico applies to Subproject 45 of MKULTRA which was duly approved, and that the project is being carried out in accordance with the memorandum of 13 April 1953 from the DCI to the DD/A, and the extansion of thie authority in eubaequent memoranda,

Date:\_

For Services

SECRET

INVOICE

5 October 1961

SECRET

[PAGE 265]
BECRBT

MEMORANDUM FOR: THE COAPTROLLER

ATTEFTION : Pinance Division

SUBJECT : MXULTRA, SubproJect45

Under the authority granted in the memorandum dated 13 April 1953 from the DCI to thie DD/A, end tbs extension of this authority in subsequent mcmoranda, suuproject sa has been approved, and 2o o 0 or the over-all Froject HWLIRA funds have been obligated to cover the subproject's expenses and ahouid be charged to cost center-aies-1390-39

APPROVED FOR OBLIGATION OF PURS:

TSD/Research Branan

Research Director

Date:

Distribution: Originai & 2 - Addressee 1 - TSD/FASS 2-TSD/RB

SECRET

[PAGE 266]
RECEIPT

Receipt is hereby acknowledged of the following.

Check in the amount of \$20, 000, dated 14 April 1961, drawn on the payable to the

[PAGE 267]
SECRET (When Filled In)

SECRET (When Filled In)

[PAGE 268]
KDORARDUM FCR: TE COFTROLLER

AFIENTICH ; Finance Divisica

Uoder the authority granted in the memorazdua dated 13 April l953 Irom the DCI to the DD/A, aná the axteneion cr this authority in subsequent Eocorands, Subproject 42 has been spproved, and \$00,000.00 of the over-all Project MuLTA funis have boen obligatel to cover the subproject'a expenses ard should be charged to coet certer 1125-1390-390

ChieT TSD/Recaarch Dreneh

AFPROVED FOR CLIG/TION

ICETFY THAT FUNE ARE AVAILAELE ORIGATCH RETRECS CHAICE TO ALCTNENT

Pescarcn Direetor

AUTHORNCNU OFICER

Datet

Distrlbutien: Orig. & 2 - Adárasces

SBCRBS

[PAGE 270]
MNORANDUM FOR : TE CONPTROLLER

ATIERTION : Finance Diviaion

SUBJBOT : HULERA, Subproject 45

Under the authcrity granted in the memoraräun Sated 13 Ayril 1953 from the DCI to the DD/A, and the extension oP this euthority in subsequent erorende, Subproject 15 has been arproved, and D,000.00 of the over-all Project MuLmA funda have been obligeted to cover the aubproject's expenses and should be charged to ecat centar 1125-1390-3902.

Chie? TSD/Recsarch Branch

APFROVED FCR OBLIGAEION GF FUMDS:

Date:

Distribution: Crig. & 2 - Addrassee

43417

SECRBT

SECRET

[PAGE 271]
MOCBANDUM FOR: CHIEF, FIRAECE DIVISICE

VIA : Tou/mudget Orricer.

BUBJECT MLR, Subprojeet 45, Ivoice 30. 19 A11otment 1125-1390-3902

l. Imvoice No. 19 covering the above subproject is attaohed. Payuent should be usde as follovs:

Cashiar's check in the amount of \$20,000.00 dres on a locai bank.

De check should be made peyable to the

2. The check should be forwarded to Chief, T8D/Besearch Branch, throuch TD/Budget Orricer, no later then Tnursdar, 13 April 1961.

3. This is a final invoice. Zouever, since it is anticipated thet additional funds vill be obligsted for this project the files shoulá not be closed.

Chier TaD/Besearch Branch

Attachnentt Invoioe à Certifieaticns

Distributions . ... Crig & 2 - Addressee

TSD/PASB -TSD/RB

TSD/RB/(7 Apr11 1961)

CHEOK 之口 N T CF S204CO RECEIVE

7 Apr11 1961

[PAGE 272]
20L3

-1 in bery cersd tat this is oce 19 45. 0012

(21 T 1 boabr dertl tras ts-invra C Soooct at lta vhfch was dulv spevel, aod toat e jnes is irs l a In éeeriezce dta the mocerndu ef 13 Apri 1653 dee (o UT t to DA, sod the srtensico c thls suthority ic scbseque. rrraazic

SECYET

[PAGE 273]
S2CRBT

ATTENTICS

SUBJECT

Under the authority granted in the zemcraráun dstad 13 April 1953

froas the DoI to the DD/A, and the extansion cr this authority 1n sudsequent cacorecde, Subproject 5 bas been suprovel, and \$20,000.00

of the over-all Project MALTA funds have been obligatel to cover the subproject's expences and ahould be charged to cost center 1125-1390-3902

APPROVED FCR OBLIGATION FURDS:

Dete:

Distribution: Orig. & 2 - Aaracces

SEORET

[PAGE 274]
FINANCIAL REPORT JANUARY 31, 196O - FEBRUARY 1, 1961

I certify to the best of my knowledge that this statement is correct.

Date: (%/,

[PAGE 275]
一

Rec   n nt  n

RCITRT

[PAGE 276]
MEMORANDU POR: CHIEF, FINARCE DIVISICE

VIA 1 rp/Buiget Officer

SUBJECT MULIRA, Subproject h5, Invoico Nc. 18 Allotment 0525-1009-b902

1. Invoice So. 18 covering the above subproject is attached. Paymtnt sbould be made as follovet

Cashiar's check in the asount of \$23,83h.00 dravn F bank.

cd

2. The check should be forvarded to Chief, TsD/Hosearch Branch, through Tsp/Budget Ofricer, no later than Thursday, 25 August 1960.

3. This is a finsl invoice. Bovever, since it is anticipated that additional funds will be obligated for this project the fiies should not be closod.

Chiet TsD/Researoh Braoch

Attachoent: Invoice & Certificstions

Distributiont Orig & 2 - Addressee 1 - TSD/PASB

I CERTIFY THAT FUNDS ARE AVAILABLG AUG : OBUGATICN REFERENCE N 1226 i 2 CANCE 10 ALOINENT . 2225-1909.4912

AUTHORILING OFFICER

25 98 RECEIVED.

ISEGRET

11 August 1960

[PAGE 277]
For Services

CERTIFICATIONB

(1) It is hereby certified thet this 1s Invoice No. 18 applying to Subprojoct 45 or MuLIaa, that performance is satisfactory, that services are being accoaplished in accordance with mutual agreements, that a dotalled agendm of tbe paysants and receipts is on file in TsD/ks, that this bill is just and correct and that payment thoreof has not yet been made.

C/280/Besearch Branch

Date!

(2) It is hereby cortiriod that this lovoics applies to Subprojoct is of sul which vas duly approved, nd that the project is being carried out in accordance with the mesorandun dated 13 April 1953 froa the DCI to the Do/A, and the exthnsioa of this suthoráty in subsequent menoranda.

Besearch Director

SEGRET

[PAGE 279]
RECIP

Ac      ck:

[PAGE 280]
MEMORANDUM FOR:CHIEF, FINANCE DIVISION

: TSD/Budget Offlicer

SUBJECT

MKULTRA, Subprojoct45, Invoice No.17
Allotment 0525-1009-4902

l. Lavoice No. l7 covering the above subproject ls attached. Othar lavoices wllt follow. Payment should be made as followe:

Caebier's chock in the amount of \$23,833.00 drawn OR bask.E

The. check should be made payable to the B

2. The check should be forwarded to Chief, TSD/Chemical Braach, through TSD/Budget Officer, no later than 27 April 1960.

Chlof TSD/Chemical Branch

Attachent: Invoice & Certifications

Distribution: Orig à 2 - Addressee

1 - TSD/FASS
2 - TSD/CB

I CERTEY THAT FADS ADS AVARARLE
CHARGE TO ALCT ONT N. OBICATION N 15196 Crficea

TSD/EB/A

CHECK THE AMOUNT OF S23 RECEIVED.

SEGRET

13 April 1960

[PAGE 281]
For Services

CERTIFICATIONS

(l) It is hareby certified that this ls Invoice No. 17 applylag to Sabproject 45 of MKULTRA, that performance is satisfactory, that services are beiog accompliehed in accordance with mutual agreemants, tbat a detailed agenda of the payments and receipts is on file in TSD/CB, that this bill is just and correct and that pzyment thereof has not yet been made.

C/TSD/Chemical Branch

Dete:

(2) It is herehy certified that this invoice applies to Subproject 45 of MKULTRA which was duly approved, and that the project ia being carried out ln accordance with the memorandu dated 13 April 1953 from the DCI to the DD/A, and the extensioa of this authority in subacquent memoranda.

Research Director

SEGRET

[PAGE 283]
MEMORANDUM FOR: CHIEE, FINANCE DIVISION

: TSS/Budget Officer

: MKULTRA, Subproject 45, Invoice No. 16 Allotment 0525-1009-4902

1. Involce No. 16 coveriag the above subproject ls attached. Othor involces wlll follow. Payment sbould be made as follows:

Cashier's chock in the amount of \$23, 833, 00 drawn

The chack sbould be mado payable to the

2. The check should be forwarded to Chief, TSS/Chemical Divixion, through TSS/Budget Officer, no later than 18 January 1960.

Chiof TSS/Chemical Divlsion

Attachment: Invoice & Certiflcatlons

1 CERTIFY THAT FUNDS ARE AVAILABLE
ONUIGATION REFERENCÉ N
CHARGE TO ALLOIAENT N

Distribution: Orig & 2 - Addressee

AUTHORZING OFCER

TSS/FASB 2 - TSS/CD

CHECKTR THE AMOUNT OF BSRS
RECEIVED. 18.J0

SECTET

4 January 1960

SEORET

[PAGE 284]
INVOICE

CERTIFICATIONS

(1) It ls hereby certified that this is Invoice No. 16 applying to Subproject 45 of MKULTRA, that performance is satisfactory, that services are being accomplished in accordance with mutual agream that a detalled agenda of the payments and receipts is on file in TSS, that this bill is just and correct and that payment thereof bas not yet been made.

C/TSS/Chemical Division

Date:

(2) It is hereby certified that this involcs applies to Subproject being carried out in accordance with the memorandum dated 13 Aprll 1953 from tho DCI to the DD/A, and the extenalon of this authority in subsequent memoranda.

Research Dlrector

SEGRET

[PAGE 285]
L7 autnor11077 Cte: Jund 151y E2 IMPDET: CH P

1. The scope of this subproject includes all those activities now engaged in by TSD/RB under the direction of TSS/CD with the exception of those cutout functions specifically mentioned in connection with other MKULTRA subprojects. In geaeral, the research effort under this subproject will continue along the lines laid down in previous years. These involve the synthesis and pharmacological and clinical evaluation of compounds of those chemical families known to have application in the psychochemical and "K" fields. During the past year importan progress has been made in the area related to stressor compounds and the relationship of these materials to the physiological pathways through which both stress and the reaction to it are mediated in human beings. As is indicated in the attached proposal, the work of the past year has progressed to the point where more definitive experiments on the streas reaction can be carried out. Primarily this was brought about by the characterization of several new materials which produce stress reaction in humans and the application of somne new clinical methods of measuring the extent of the disturbance produced. During the next year proportionally more effort will be expended on the problem of the development of new

DosaSraded to: CONFRENTIAL by authority of:' 187475 data: June 1977

É2 JiPDET; CL BY 187475

29 December 1959

MEMORANDUM FOR: THE RECORD

SUBJECT

[PAGE 286]
"knock-out" types of agents since progress has been slower than is desirable in this direction and because a new approach to the problem has been worked out.

2. also serves as a general consultant to the Agency, provides services of a sensitive nature on an ad hoc basis, and serves as a cut-out in procurement probleme.

3. The total cost of this project for a period of one year 40,50.0 will not exceed \$71, 500.00. Charges should be made against Allotment 0525-1009-4902.

4. has been requeated to submit a summary accounting or a copy of the Fund's annual audit report for the sponsor's inspection. Also, it has been requested that any unexpend funds shall be returned to the Agency.

5. Title to any permanent equipment purchased by funda B granted s shall be retained b , in lieu of higher overhead rates.

6. It was mutually agreed that documentation and accounting B for travel expenses which are normally reimbursable by1 B shall conform with the accepted practices of the

Fuad.

Domsraded to: CONFDENTIAL by authozity of: 187475 datc: June 1977

Doea :d to: CRFDETne by auprority of:- 187475 date: Jue 1977

E2 IMPDET; CL BY 187475

E2 IXFDET; CL BY 187475

[PAGE 287]
TNTE ments of the Memorandum of Agreement.

Chief TSS/Chemical Division

APPROVED FOR OBLIGATION OF FUNDS:

Attachment: Proposal

Distribution: Original only

Downeraded to: CONFIDENTIAL by authority of: 187475 date: Juns 1977

ED IFDET; CL BY 187475

Dovnsraded to: CÉHFOENTAL by authority of: 187475 dato: Juno 1977

E2 IHPDET: CL BY 187475

[PAGE 288]
The research to be undertaken during the twelve month period for whtch finanotal support ts requested will be devoted to the continued analysts of the neural and endocrtne mechantsm of stress and the chemical agents that influence tt. The screening procedures are based largely upon a further analysis of phases of stress and the tnfluences of this physiologic behavior complex upon both body and skin temperatures as detatled in the accompanying report.

The chemtcal syntheste of new compounds will be conttnued
B at the under the supervtston of and at the under the superotston
2of These chemical agents will be soreened for thetr capaotty to provoke stress or to suppress the strees reactton in its acute or chronic phases. Animal testing will inolude pharmacologic soreening and proper toxictty studies.of these compounds as heretofore.

Chemical agents that have been found active and wtthin a suttable toxicity range wtll be subjected to olintoal screening on approprtate patients, the inittal screentng betng carried out on advanced cancer pattents. Ihe amount of money devoted to chemtoal synthesis, however, has been further reduced. Chemtcal compounds available from biologtc sources as well as those synthesised in the project will be screened, partioularly those that are aotive in either raising or lowering body temperature.

As heretofore any agents whtch prove to be of interest in cancer wlll be sublected to Jurther evaluation both on transplanted

WARNING NOTICE

RESEAROH PROPOSAL

1960

[PAGE 289]
animal tumors and on concer patients. This cancer phase of the project will be considered a by-product of the major objective, which wtll bedirscted to the problem of stress.

WARNING NOTICE

SEASNVEMNTEIEIGENCE CORCES AND METHODS INVOLVED

[PAGE 290]
1- PHARMACOLOGY AND TOXICOLOGY

Pharmacologist and technictan toxtcology

Antmal caretaker, animals and animal maintenance

2- CLINICAL SCREENING Clinical assistants Clerical help and supplies

Chemical supplies TOTAL

WARNING NOTICE SENSITIVE INTELLIGENCE SOURCES AND METHODS INVOLVED

\$12,000.00
10,000.00
12,000.00
\$1,500.00
5,000.00
10.000.00
4,000.00

[PAGE 292]
MEMORANDUL FOR: COMPTROLLER

SUBJECT

MKULTRA. Subproject 45, Additional Anthorisation No. 9

Uader the authority granted in the memorandum dated

13 April 1953, ¿rom the DCI to the DD/A end the extensloa of this authority ia subsequeat memoranda, Subproject 45 was previoasly appreved. Uader the same authority an additienal sua ol \$71, 5o0. 00 bas bean sutborised to covor tbe subproject's expenses, to be charged to Allotment

Chief TSS/Chemieal Division

APPROVED FOR OBLIGATION Or FUNDS:

Origiral signed by

1 CERTIFY THAT FUNDS ARE AVAILABLE OHIGATTON RSENCE No CHARGE TO ALLOTIEE N.

Research Director

Date: 3 0 DEC 1959

Distributioa: Orig k 2 - Addressee

1-TSS/OC 1TSS/FASB 2-TSS/CD

[PAGE 293]
21 August 1959

MEMORANDUM FOR: CHIEF, FINANCE DIVISION

: TSS/Badget Officer

SUBJECT

: MKULTRA, Subproject 45, Invoice No. 15 Allotment 9-2502-75-902

L. Invoice No. 15 covering the abov? subproject la attached. Payment nhould be made as follows:

Casbier's check la the amount of \$3,760. 00.
drawu on a bank.

The check should be made payable to the

2. Plozse forward the check to Chief, TSS/Chemical Divieion, through TSS. Budget Oflcer, no latar than 3 September 1959.

3. Thla is & fnal invoice. Howover, since it ie anticipated that additional iunde will be obligated for this project the files abould aot be cloeed.

Attachment: Involce & Certifications

Distribation: Orig & 2 - Addr2see

1 - TSS/FASB TSS/CD

TSS/CD/A

Chief TSS/Chemical Division

SEGRET

[PAGE 294]
CERTIFICATIONS

(1) It is hereby certified that this is Invoice Ngeapplying to Subproject 45of MKULTRA, that performance Rsfactory, that services are being accompllished in accordancowith mutual agreements. that a detalled agenda of the payments  reccipts le on file in TSS/ CD. that this bill is just and correct and tha Eyment thereof bas not yet been made.

(2) It ie heraby certified that this invoice appliee to Subprojoct 45 of MKULTRA which was duly approved, and that the project is being carried out in accordance with the memorandum dated 13 April 1953- from the DCI to the DD/A, and the extension of this authority in subsequent memoranda.

Research Director

SEGRET

[PAGE 295]
Acknowledged herewith receipt of the following check: Treasurer'a Check No., dated 3 Septamber 1959, in the amount of \$3, 760.00, drawn on B , payable to B

DATE 10 Sp159.

[PAGE 298]
SECRET

[PAGE 299]
E2 IMPDET; CL BY 187475

MEMORARDUM FOR THE RECORD

SUBJECT: Supplement to Project HKULIRA, Subproject 45

1. Ope of the activities that the engage in on behalf of the Agency is the procurezent of rare cheaical substances required for the various chemical and physiological research programa being carried on in TSS/CD. Some of these materials are derived frca direct synthetic programs under the direetion of the Fund and others are purchased as such froa domestic or foreign sources vhen the opportunity to do so appears.

2. The purpose of this supplement to Subproject 45 is to ada the sums of \$376o.00 to allow the expansion of the above portion of the actiritias during the renainder of this Jear. This additional work has been made necessary because of developments which have taken place in otber parts or the rescarch program being carried out by TSS/cD which have occurred since the origiral allotment for the vasade. 3

3. All provisions of the original memorandua csteblishing the present grant to the evill apply to thie supplement. The original allotment for Subproject 45 approved on 4 February 1959 was \$71,500.00. The amount of \$3760.00 (charges should be made against A11otment 9-2502-75-902) should be added to this to bring the totel for this year to a total of \$75,260.00.

Chief TSS/Chemical Division

APPROVED FOR OBLIGATION OF FUNDS

Researdh Director Date6)8159

Attachment: Orig. Memo. Only Budget

Dotberadee to: CONFIDENTIAL by authority of: l87475 date: June 1977

Dorzgraded to: CONADENTIAL by authority of: l87475 cate: JEne 1977

E2 INPDET; CL BY 187475

[PAGE 300]
PROPOSED BUDGET

It is proposed to obtain certain substituted Indole compounds of types designated by the Sponsorfrom various ayntbetic programs beiag carried out in industrial facilities and to characterize these materials for the Sponsor's use in various physiological prograns. It is estimated thst the following budget vill be required for six months:

500.00

260.00

\$3,760.00

WARNING NOTICE

SENSITIVE INTELLIGENCE SOURCES AND METHODS INVOLVED

[PAGE 302]
MEMORANDUM FOR: CHIEF, FINANCE DIVISION

: TSS/Budget Officer

SUBJECT

MKULTRA, Subproject 45, Involce No. 14
All0mment 9-2502\~75-902

1. Invoice No. 14 covering the above subproject le atiached. Payraent should be made as foliows:

Cashier's check in the amount of \$35, 750. 00, dzawn ou a

The check aboald be made payable to thes

2. Plsase forward ths check to Chief, TSS/Chemical Divisloa. through TSS Badget Olficer, no later than 22 June 1959. Other invoices will follow.

Chiel TSs/Chemical Division

Attachments: Invoice & Certifications

Distribation: Orig L 2 - Addressea 1 - TSS/FASB 2-TSS/CD TSS/CD 1Jue59) A

[PAGE 303]
(1) It is hereby certifled that thte is Iavoice No. lt appiying to Subproject 45 of MAULTRA, that periormaece is satlslactory. that services ars being accomplished la accordance with mutuai agreenents that a datalled agenda of the payments and recslptis on flle is TSS/CD. that this bill is juet and correct and that payent thereof has aot yet been mads.

C/TSS/Chamical Division

Date:

(2) it is hereby certified thst tale iavoice appliss to Subproject 45 of MKULTRA which was dely approved, and that the project is being carried out ia accordance with the memorandam dated 13 April 1953 from the DCI te the DD/A. and the extanslon of thie authority in subuequeat memoranda.

Date:

Research Dizector

[PAGE 304]
eo e   e  d Das     1   e5

Aa t d  t o ck

[PAGE 306]
MMORANIAOM TOR: CRLLEF, FLNACE DIVISION

, Subproject 45, Invoice No. 13
Allotaoat 9-2502-75-902

l. Involes Se. 13 covering the above subproject is attached. Payment should be ande as follous:

Cashier's ahest in the amount of \$35,750, drewa co a

2. Plense forward the obock to Chiel, Tas/Chouical Divisioa, through ras Bulgat Orticar, no latar than 12 Pabrwary 1959. Other involoes ill follow.

Chiaf Tas/Cheaical Division

Attachaonts: Iuvoice & Certifications

Distributiont
Orig & 2 - Addressee TBS/FASB 2 -TSS/CD
TSS/CD (5reb59)

ORUGATION RETRINCE NO.2 CERTY THAT FUNA 99
CUARGETO ALLOTHENT HO. 9.2542-15.902

AUTHORIZING OFFICER

CHECKRUTIN THE AMOUNT OF \$Z RECEIVED,

[PAGE 307]
CERFIFICATIONS

(1) It is hareby cartiried that this 1s Invoice No. 13 applying to Subproject 45 of MaULrRA, that perfoumanca is satiafactory, that services are being accoaplished in accordance vith mutual agreesents, that a dotalled agenda of the payments and receipt is on file in ms/cD, that this bill is just and correct and that paymont thereaf has not yot beon made.

Chier, 188/Chemical Division

Date:

(2) It is hereby certiried that this invoice applies to Sulproject 45 of MLTRa vhich was duly approred, and that the project is being carried out in accordance vith the memorandum dated 13 April 1953 ffom the DCI to the DD/A, and the axtension of this authority in subsequeat memoranda.

[PAGE 308]
1  Gannary 59 2. Pe  r Seron mtril aenstis

SSCRET

[PAGE 309]
Bistribution: Crig & 2 - Addressee 1-/0 1 - TSS/PASB 2158/CD
TSS/CD:(27Jan59) A

[PAGE 310]
Tolt ie an loveice acalnet previcusly coligate: Snda,

or  27 Jen 1959 Analysis or hypothal-

SECHGT

[PAGE 311]
MEMORANDOM FOR: THE RECORD

SUBJECT : Contimation of MKULTRA, Subproject No. 45

1. The scope of this subroiect incluies all those activitics now engaged in by the B under the direction of TSs/cD with the exception of those cutout functions specifically mentioned in connection with other MKULTRA subprojects. In general, the research efrort umder this subproject will continue along the lines laid down in previous years. These involve the synthesis and pbarmacological and clinical evalustion of coepounds of those chemical families knowm to have application in the psychochemical and "K" fields. During the past year inportant progress has been made in the area related to stressor compounds ani the relationship of these materials to the physiological pathways through which both stress and the reaction to it are mediated in human beings. In our Agency frae of reference, the fast adaptive reacticn (nervcus ccntrol) is of more vital importance than the slower humoral reacticn (pituitary-adrenal axis).Since both of these pathways occur in the same individual, one of the major problems in doing research in this area has been the lack of knovledge of techniques allowing one to distinguish between the various types of observed phenomena. Progress de in this subproject on particular stressor agents and their relationships to knowwhumoral agents for the first time permits the experimentor to make this distinction on a raticnal basis. As indicated in the attached proposal, this advantage vill be pursued during the coming year with the folloving goals in mind:

(1) Development of materials & techniques for the production-of maxims levels of physical and emotional strese in human beings.

(2) Development of materials and techniques which produce a maximu attenuation of stress in huan beings once it has been produced. (3) Development of nev and more reproducible indicators of stress than those now in use in the Agency. The empbasis in this will be on those indicators which can be measured indirectly.

(4) Elucidation of the significant properties of the negative phase or stress in order that psychological techniques may be worked out in other projects to exploit this phase of the human reaction to potent emotional stress.

DoznSraded to: COFIDEHTIAL by cuthority of: l37475 dato: June 1977

E2 IMPDET; CL BY 187475

E2 IMPDET; CL BY 187475.

DowoSadad to: CDHFNEMAL by authority of: 137475 Cate: June 1977

[PAGE 312]
Dorg-aded to: COMFDETIAL by authority of: lS7475 date: June 1977

2 IMPDET; CL BY 187475 2. also serves as e general consultant to the Agency, provides services of a sensitive nature on an ad hoc basis, and serves as a:cut-cut in procurement problems

3. The total cost of this project for a period of one year will not exceed \$71, 500. Charges should be mads against A11otment9-2502-75-902.

4. bas been requested to subait a summery accounting or e copy of the Fund's anmual audit report for the sponsor's inspection. Aloo, it has been requestad that any unexpended funds shall be raturzed to the Ageucy.

5. Title to any peruanent equipment purchased by fupda granted shall be retained by the in lieu of higher overhead rates

6. It was muturlly agreed that documentation and accounting for travel expenses which are normally reiabursable by the 0 shall conform vith the sccepted practices of the Pund.

7. agreed to couply vith the requirements of the Memorandum of Agreemeut.

TS8/Chemical Division

APPROVED FOR OBLIGATION OF FUNDS

Research Directo

Pib. 4.-1959

Attachment: Proposal Original only

Domg-aded to: CONFDENTAL by euthority of; l87475 date: June 1977

E2 IMPDET; CL BY 187475

[PAGE 313]
The research to be undertaken during the next 12 months for which financial support is hereby requested will be devoted to the analysia of the hypothalamic and endocrine mechanism of stress and chemical agent that modify it. The investigations proposed are a direct contfnuation ai outgrowth of those supported in the previous year.

The screening procedures to be used have been markedly widened in scope to embrace a conaideration of both the metabolic and enzymatic effects of stress or of the chemical agents studied.

A novel ecreening procedure which depends upon the survival time of animals maintained without food or water has been devised and has already been put to practical use in demonstrating the role of the hypothalamus in survival. In addition to this over-all surviyal screeniug technic, acreening technics have been devised for investigating separately the role of water and fat metabolismin stress.

It is proposed to continue work on the negative phase of stress which we have previously delineated by study of the egg white response in rats. (See research report for 1957 - 1958)

As an outgrowth of experiments performed in l958 it is now possible to evaluate therapeutic agents at the enzymatic level. See research report enclosed. This technic of uaing a battery of enzyme systems in vitro as a method of evaluating the biological effectiveness of newly systhesized organic compounds opens up a whole new line of investigation and is the most rapid method of evaluation that has been devised to date and pobably the most basic. It is proposed that we exploit this new approach to our utmost in the naxt twelve months.

NINGNOTICE

SENSITIVE INTELLIGENCE OURCES AND METHODS INVOLVED

RESEARCH PROPOSAL 1959-1960

[PAGE 314]
Tha chemlcal synthesis of possibly active compdunfs will b continued at the and the and these chemical agents will be acreened for their capacity to provoke atress or to suppresa the stress reaction in its acute or chronic phases. The tests employed on animals will be used for screening and proper toxicity studies of the compounds will be carried out as herstofore.

SENSITIVE INTELLIGENCE SOURCES AND METHODS INVOLVED

[PAGE 315]
RESEARCH PROPOSAL 1959-1960

PHARMACOLOGY AND TOXICOLOGY

Pharmacologist and technician toxicology

Animal caretaker, anirials and animal maintenance

CLINICAL SCREENING

Clinical assistants

Clarical help and supplies

CHEMICAL SYNTHESIS

Chemical supplies

TOTAL

NING NOTICE

TIVE INTELLIGENCE ND METHODS INVOLVED

\$12,000.00

10,000.00

12,000.00

\$34,000.00

10,000.00

5,000.00

15,000.00

1,500.00

5,000,00

12,000.00

4,000.00

22.500.00

71,500.00

[PAGE 318]
l. Iovoice Bo. 12 covering the above subproject is attached. Payornt should be made as follovst

Cashier's check in the suount of \$21,733.34, dram on

2. Plesse forvmard the check to Chief, as/Checical Diviaion, through TEs/Buigst ürrioer, no later than Monday, 6 Ootober 1958.

3.This Lavoice reprosente the total ssount currently suthorised under Bubproject 45. Zowever, since it is mnticipeted that additionel fonde vill be obligsted for this projeot, the files should not be closed.

Chier THE/Chomical Divisicn
Attachments: CHECK THE AMOUNT OF BO/Z33. 3 Invoios and CertificationsRECElVE-2.00
Distributiont Orig & 2 - Adáressee A

21.733.3

[PAGE 319]
(1) It is beredy certified that this is Invoios No. 12 applying to Bubproject h5 of MiRa, that perforuanoe is satisfactory, that services are being accosplished in scccrdance with mutual agrseoents, that & detailed ageuda of the payments and receipt is on file in TS8/, that this bill ie just end correct and thet payaent thereof hes not yet been made.

(2) It is bereby cartiried that this inroice applies to Sabproject \$5 of Hulraa tiich vos duly approred, and that the project ie being carriod out in accordance vith the meeorandum dsted 13 April 1953 roa the DGI to the DO/A, and the extansion of this anthority in subeequent mttoranda.

[PAGE 321]
1. Znvoice Eo. 11. covering the above mubproject is attachod. Paymot ahould be made as follows:

Cashier'a check in the oont of \$21,733-33, drem on a bbank.

Te eck mouta te de poble to the

2. Pleese forward the check to Chies, Tos/chenical Division, through T88/Budget Orficer, no later then Bednesday, 7 May 1958.

3. This invoioe represents the total amount curently. anthorised uoder Bubprojoet 45. Bowever, since it is anticipated that additiocal funds will be obligated for this projoct, the files ahculd not be alosed. 11†

Chlef ss/Cheaicel Division

Attachuentet Iuvodce and Certifications

DIETRLBUTICH: Ori€ & 2 7Addrcesee Y- TSS/EASB V2 - TSS/CD

ICERTIFY THATTU 1450 8-1502-10-01 ORUGATION REFERENES NO. AUTHORIZING CHRCER

CHEOK#ZAC IN THE AMOUNT OF B2/ZU.33
RECEIVED. 5193

[PAGE 322]
(1) It is hereby certiried that this is Imvodce Ho. ll applying to Subproject 45 of MRa, that performnocis is satisfactory, thet services are baing accoeplisied in accordancevith mutuel agreements, that a detailed agenda of the paymonts and recoipts is on file in TS8/CD, that this bill is just and ocrrect and that paywont thereof has not yet boen mado.

(2) It is bereby certiried that this imvoice applies to Subproject 45 af Mulza which was duly approved, ant that the projeot is being oarried out in accordance with the memorazua dated 13 Aprll 1953 froz the DCI to the Do/, and the extension of this authority in subsequent asmoranda.

[PAGE 323]
CTT OHUCATICNFET: 1/50 CHARCST 8-2501-10-001

Diatrlbutiout Oris à 2 - Addrocees

1-Ss/0 -TSS/PASB 1 - Tss/cD

[PAGE 324]
山 lae    the 一 Chk eo ann       e to a

Achk      ck

TI RI

[PAGE 325]
1. Invoice No. l0 for the abore subproject is attached. Payeent should be medo as follovat

Cashior's chack in the amount of p21,733.33, dam on bank.C

2. Please forward the check to Chiot, Tss/Chenical Division through Ts/Budget Orficer by Tussday,  Jetruary 1958. Other Luvalces vill follov.

Attachentsr Invoice & Certifioations CHECK97E AMOUNT OF 1733 RECEIVED.
Distia 2- Addressee 14. A

0. 128 001450 60:1 2503-10-001 17.131733.33
CERTIFIED FOR PAYMENT OR CRED 491.733.33

AUTHORIZED CERTIFYING OFFICER 4FE

[PAGE 326]
(1) It is hereby exrtiried that this is Invoice Bo. 10 spplring to Subproject No. h5 of Mulmia, that rerformance has been satiafastory, that the sarvices bave been accosplished in accordance vith surtual agreemtnts, that a detailad agenia of the pavments and reoeipts is on fle in Tss/cn, that this bill is just and correet and that peymant thereof has not yot been made.

froa the DCI to the DD/A, and the extenaion of this axthority in sube sequent neaorends.

[PAGE 327]
1. The scope of this subproject includes all those activities now engaged in by under the direction of Tss/cD vith the exception of those cutout functions specifically mentioned in connection with other MKULTRA subprojects. In general, the research effort under this subproject will continue along the lines laia dowm in previous years.These involve the synthesis and pharmacolcgical and clinical evaluation of compoumis of those chemical families known to have application in the psychochemical and "k" fields.// Clinical work in the "natural toxic psychoses" carried out last year indicates that, in general, the useful (reversible) pheses of auch paychoses are related to the preaence of various chemical stressor materials in the cixculation. These materiala arise from faulty metabolic proceases occasioned by the particular disease in question. Materials syntheaised in the project are capable of reproducing the various clinical syndiromes that are observed in the natural disease.

2. Knovledge of the nature of the important stressor compounda indicated above has alloved the design of an animal test which indicates relative potency, mode of action, etc., of these materials without the necessity of expensive ani hezardous clinical teating in this area. During the coming year as indicated in the attached proposal from a limited program of synthetic work and the attendant testing and screening wiil be carried out; but the major effort vill be related to studies directly concerned with the production and control of the streas reaction in human beings. In line with the requested reduction of effort in biochemical research in TSs/cD, the funding of this project during the coming year has been reduced some 34% over last year.

3. also serves as a general consultant to the Agency, provides services of a aensitive nature on an ad hoc basis, and serves as a cut-out in procurement problems.

4. The total cost of this project for a period of one year will not exceed \$65,200.00. Charges shouId be made againat Allotment 8-2502-10.001. 9.2502-95-902

E2 IL2DET: CL BY 187475

MOMORANDUM FOR: THE RECORD

[PAGE 328]
5. haa been requested to aubmit a summary accounting or a copy of the Fund's annual audit report for the sponsor'a inapection. Alao, it has been requegted that any unexpendet funds shall-be returned to the Agency.

6. Title to any permanent equipment purchased by funds granted shsll be retained by in lieu of higher overhead rates.

, 7. It was mutually agreed that documentation and accounting for travel expenses which are normally reimbursable by shall conform with the accepted practices of the Fund.

8. agreed to couply with the requfrerents of the Memorandum of Agreement.

Chief TSS/Chemical Division

Attachment: Proposal Original only

raded toy CANFDENTIA Authoit of :18742 Ete:Ji 1977 E2 IIPDET; CL BY 187475

E2 INPDET; CL B 187475

[PAGE 329]
RESEARCH PROPOSAL 1958-1959

The research to be undertaken during the 12 months period for which financial\_support is requested will be devoted to an analysis of the neural and endocrine mechanism of stress and the chemical agents that influence it. The screening procedures are based largely upon the analysis of the General Adaptation Syndrome that has been workad out in rats during the past year an outline of which is appended.

The chemical synthesis of poscibly active compounds will

and these chemical agents will be screened for their capacity to provoke stress or to auppress the stress reaction in ita acute or chronic phases. The tests employed on animals will be used for screening and proper toxicity studies of tha compounds will be carried out as heretofore.

Chemical agents that have been.found active and within a suitable toxicity range will be subjected to clinical screening on appropriate patients, the initial screening being carried out as heretofore on advanced cancer patients. The amount of money devoted to chemical synthesis will be much reduced and chemical compounds available from various sources as well as those synthesized in the project will be screened.

As heretofore any agents which prove of interest in cancer

will be subjected to further evaluation both on transpianted animal tumors and on cancer patients. This cancer phase of the project.

AND METRODS INVOLED

[PAGE 330]
will be considered a by-product of the major objective, wbi will be directed to the problem of stress

ARNING NOTICE ? SENAITH INTE LO NCE

[PAGE 331]
PROPOSED BUDGET 1958-1959

1 - PHARMACOLOGY AND TOXICOLOGY

Pharmacologist and technician

toxicology

\- Special screening procedures

Aniaml caretaker, animals and animal maintenance

2 - CLINICAL SCREENING

Clinical assistants

Clerical help and supplies

3 - CHEMCAL SYNTHESIS

consultant

Chemical Supplies

TOTAL

12,000.00

8,000.00

1,200.00

12,000.00

9,500.00

5,000.00

14,500.00

1.500.00

5,000.00

7,000.00

4,000.00

17,500.00

\$ 65,200.00

WATNING NOTICE SENSITIINTELLIGENZE SOURCES AND METHODS INVOLVED

[PAGE 332]
id st o o tdtr o Aeled

[PAGE 334]
2. Please forward the check to Acting Chief, TSS/ Chemical Divlsion through TSs/Budget Officer by Thuraday, 31 October 1957. Other invoices will follow.

Digtribution: Órig & & - Addreasee 1 - Comptroller

1.600.1- 587-2202-15-81-142-5 Cs ()  22.331.22 1321 CC1S5-6N:T3

BECCERTTED CR CREDIT -A AUTHORE OFFICER

[PAGE 335]
(1) It is hareby certified shat this is Invoice No. 9 applying to Subproject No. 45 oi MKULTRA, that performance bas been satisfactory. that the services have been accomplishod in accordance with mutual agreements, that a detailed agenda of the payments and recoipts is on filo in TSS/CD, that this bill is just and correct aad that paymont thereof has not yet been made.

(2) It is horeby certified that thia invoice appliea to Subproject 45 of MKULTRA which was duly approved, and that the project has been carried out in accordance with the memorandum dated 13 April 1953 from the DCI to-the DD/A. and the extension of this authority in subeequent memoranda.

Research Director

[PAGE 337]
MEMORANDUM FOR: CHIEF. FINANCE DIVISION

MKULTA Súbproject 15, lavoice No. 8
Allotment 7-2502-10-001

L. Invotce No. 8 for the above subprojeet is attached. Paymeat should be made us follows:

Cashier's check in the amount of \$33, 333.33, drawn on a Phank.

2. Please forward the cheek to Chief, TSS/Chemical Divisioa through Tss/Budgot Oficer by Friday. 17 May 1957. Other invoices will follow.

SIDNEY GOTTLIEB Chief, TSS/Chemical Division

Distribution: Orig & 2 - Addressee 1 - Comptroller

M1. 600.1- 187-2502-10 -01- 17.9-k 33, 333.33
C1. -  33, 353.33

CIAY CERTIFIEDFCR PAYMENT CR CREDIT 1821 OFFICER AUTHORZE

[PAGE 338]
(1) It is hereby certified that this is Invoice No. 8 applying to Subproject 45 of MKULTBA, that performance has been satisfactory. that the services have bees accomplished in accordance with mutual agreements, that a detailed agenda of tus payments and receipts is on file in TSS/CD. that this bill is just and correct and that payment thereof has not yet been made.

4 Chief, TSS/Chemical Division

(2) It is hereby certified that this invoice applies to Subproject 45 of MKULTRA which was duly approved. and that the project has been carried out in accordance with the memorandum dated 13 April 1953 from the DCI to the DD/A, and the extension of this authority in subsequent memoranda.

Hesearch Director

[PAGE 339]
Receipt is hereby acknowledged of the following check:

Cashier's check No. 400840, dated February 12, 1957 drawn on E in the amount of \$33, 333, 34, payable to 8

Dete: 2-26-567

[PAGE 340]
in the mount o a3, 33, 34, peyable to

[PAGE 341]
3. Please forward the check to Chief, TSS/Chemical Dtvislon throagh TSs/Budget Officer by Friday. \$ Febrnary l957. Other invoices will follow.

1.600.1.887-2502-10-001-12.1533333.54
C1.Cae18 33ss3.34

CERTIFIED FCR FAYMENT OR CREDIT 1/29/57 AUTRORL OFTCER

[PAGE 342]
ERTIFICATIONS

(1) It is bereby certifled that tais Ls Iavoice No. 7 applying to Sub project 45 of MKULTRA, that performance has been satisfactory. that the services have beeu accomplished in accordance with mutual agreements, that a detailed agenda of the payments and receipts is o flle in TSS/CD. that this bill is just and correct and that payment thereof has not yet bean made.

Chief. TSS/Chemical Division

(2) It is hereby certifled that thls Lavoice applles to Subproject 45 of MKUL.TRA. which was duly approved, and that the project bas been carried out in accordance with the maemorandum dated l3 April 1953 from the DCi to the DD/A. and the exteasion of this authority in subsequent memoranda

Research Director

[PAGE 343]
APPROVED FOR OBLIGATION OF FUNDS:

Research Director

Date:

Orig & 2 - Addressee 1 - TSS/OC 1-TSS/SRB 1 - TSS/FASB 2 - TSS/CD

TSS/CD (17 January 1957)

[PAGE 344]
Project MKULTRA, Subproject 45

l. The scope of this subproject includes all those activities now engaged in by the under the direction of TSS/CD with the exception of those cutout functions specifically mentioned in connection with other MKULTRA subprojects. In general, the research effort under this subproject will continue along the lines laid down in previous years.These involve the synthesis and pharmacological and clinical evaluation of compounds of those chemical families known to have application in the psychochemical and "K" fields// Also, last year, research in the field of so-called "natural foxic' psychoses" was undertaken and will be continued during the coming year.

The attached proposal from because of C its unclassified status, is couched in therapeutic terms; therefore, a certain amount of translation of its substance is warranted, Very briefiy, the study on "toxic psychoses" has permitted the possible sources of reversible psychotic and/or comatose conditions to be narrowed down to a workable maximum number about which critical experiments can be des'gned to test various hypothetical chemical mediators. The chemical synthetic and screening program (some 100 new compounds during the year) has turned up three compounds of different families which are of fundamental importance with relation to the goals of this project. These three compounds include an orally active material which reduces blood glucose; another which acts by all routes, including percutaneous, and which appears to be the chemical mediator of "stress", and finally, a compound which is also orally active and which is a very potent new type of barbiturate and possibly alcohol antidote. It is now proposed to reduce the volume of the synthetic chemical effort in order to work out the pharmacological and clinical aspects of these and closely related substances.

3. also serves as a general consultant to the C Agency, provides services of a sensitive nature on an ad hoc basis, and serves as a cut-out in procurement problems.

4. The total cost of this project for a period'of cne year will not exceed \$t00, 000.00. Charges should be made against Allotment 7-2502-10-001.45,00.

饰

MEMORANDUM FOR: THE RECORD

SUBJECT:

[PAGE 345]
5. has been requested to submit a summary accounting or a copy of the annual audit report be made avail-5 able for the sponsor's inspection. Also, it has been requested that any unexpended funds shall be returned to the Agency

6. Title to any perrpanent equipment purchased by funds granted shall be retained by the h lieu of higher overhead rates.

7. It was mutually agreed that documentation and accounting for travel expenses which are normally reimbursable by t shall conform with the accepted practices of the Fund.

8. agreed to comply with the requirements of the Memorandum of Agreement.

APPROVED FOR OBLIGATION OF FUNDS:

Research Director

Date: 23. ta 1957.

Attachment: Proposal

Chief, Branch TSS/Chemical Division

Original only

APPROVED:

Chief, TSS/Chemical Division

[PAGE 346]
Four lines of investigation are proposed for the year l957-58. The frst lins of investigation is the continuatlon of the toxic psychic states as illustrated by uremia, which was begun under the last grant. In the present proposal it is plamned to study various phases of the uremic state along twe major lines. One of these is the blochemical and pathological investigation of patients admitted to B

The other line of investigation will be

pursued on experimental animals. Kidneys have either been removed or have been rendered nonfunctional by the ligation of the ureters. The major aspects of these two investigations are discussed in the appended report.

novel giucose metabolic blocking agents. We are currently investigating a series of diglycolate derivatives which we have shown to block glucose metabolism with resulting storage of glycogen in the various organs, liver and kidney. The details of this are also appended.

The third proposal has to do with the study of some cyclic diamino compounds which we have shown produce the stress of phenomonen and asaociated rheumatold states. The details of this proposal are also appended.

The fourth proposal concerns the continuation of chemical synthesis of a variety of piperazine compounds whisà will be linked with sarcosine. Thia report is also appended.

A similar line of chemical synthesis is also being carried out on nitrogen-containing bis phenols. These two parallel lines of chemical synthesis are a coutinuation of the investigations of

PROPOSED RESEARCH PROGRAM

[PAGE 347]
Investigations that have been just completed on 138 autopsles of lafients

that died in uremia have shown that there are three aspects of uremic polsoning as demonstrated by correlation of the pathologic changes in the heart with the blood chemistry prior to death. In one group of cases the toxic effects are caused by acidosis and these effects are not dependent upon the level of the nouprotein nitrogen or potassium levels in the blood. In a second group of patienta with elevated serum potassium definite focal damage with death of myocardial tissue is found in the heart and these patlents died of potassium poisoning. In the third group of patients, who presunably died of the accumulatlou of toxic nitrogenous substances in the blood or related compounds, the cardiac damage is associated with umusually high nonprotein nitrogon levels in the blood and the heart shows a definite inflammatory reaction with the appearance of Anitschkow's c We have reason to believe from the histologic study of the pathologio changes that these toxic nitrogenous compounds are diamino derivatives of aromatio nuclef.

The work on uremic toxic statea is being pursued by the analysis of the

cerebral spinal fiuid of patlents with uremia, and by the production of uremia in experimental animals by three methods: (a) Nephrectomy; (b) ligation of the ureters; (c) poisoning of the kidneys with derivatives of naphthalic anhydride.

Sinoe it has now been demonstrated that there are at least three components

to the uremic. state (1) acidosis which changes the blood pH, (2) elevated potassium levels, and (3) elevated nonprotein nitrogen levels, it is possible to go back in the histories of thege patients and correlate the depth of uremic coma and its duration with the dominant component in the blood changes in each individual case whether it be potassium, pH or nitrogenous.

WORK ON TOXIC PSYCHOSES

[PAGE 348]
On the living patients it ls possible by placing them on the artificial kidneg and by adjusting the fluid bath which controls the dialysis, to differentially modify each of these three components in individual cases and to determine its effect on comatose states in patients. It is also possible to check this with spinal fluid determinations.

In the experiments that have been set up on animals we have living for periods of two to four days uremic rats and rabbits whose kidneys have been removed or whose kidneys are non-excreting because of ligation of the ureters. In the initial experiment on these animals we have been interested in simple fluid redistribution in the uremic state. It has been known for some time that patients dying of uremia may show increased fluid accumulation in any or all of the serons cavities. In other words, they show an accumulated transudate in the peritoneal cavity, in the pericardial cavity, in the pleural cavity or in the meningeal cavity of the subarachnoid space. In the control animals and in many patients, death from uremia occurs before this change in fluid distribution has occurred. In our experiments, by giving cortisone we can markedly increase the transudating fluid in all of these cavities and therefore produce at will cerebral edema along with increased fluld in the other serous cavities while the animal is still alive. Thls change in the distribution of fluid is important since in all the textbooks on uremia prior to recent potassium studies,t the uremic state as exempllfied by psychoses and coma, was thought to be due to cerebral edema or simple wet brain. One of the most striking bits of ignorxance that were confronted in these studies is the fact that although it has been knowu for hundreds of years that there is such redistribution of fluld in the serous cavities, no one has ever raised the question whether it is due to increased rate of effusion or delayed rate of absorption, or both.

It is becoming increasingly evident in the study of abnormal fluid distribution in the body that there are two major controlling factors. One of these is the chemical WARNING NOTIGE

[PAGE 349]
constltution of the fluid to be exchanged which may alter diffuaion constants by its lonfe or osmotic components, or alter the diffusion rate by coutaining constituents which damag or otherwise alter the diffusion membrane. The second factor is the biological compositio of the diffusion membrane with ita Living structure and collagenous matrix. In the pest geveral hundred years the tanning industry has been working with the biocbemical properties of collagen aince leather is 90 to 95% coliagen. The workers in this induatry have accumulated a large amount of information on two different agents. Those that wet or render more pliable collagen matrix and therefore make it more porous, and those that harden or toughen the collagen matrix and therefore render it less permeable. The first class of agents is termed lyotropic and its classical member is dilute acetic acid. The other group of agents is called tannin and the classical agent is tannic acid or the pyrogallic aèids. This group of agents can be applied to the diffusion membranes to alter theix reaction. Since many of the induced cerebral states can be attributed directly to hydration or dehydration of the cerebral substance, this investigation of the diffusion rates into and out of the serous cavities of the meninges offers a fumdamental approach to study of one aspect of cerebral function.

WARNING NOTICE

SERSINEIECSCRUCS

[PAGE 350]
It is well known that the brain in its metabolic fmction relies beavlly on
glucose and oxygen. The importance, of the relation of glucose to cerebral function was
frst emphasized by the introduction of insulin shock therapyinto the treatment of
schizophrenia. This form of shock therapy was subsequently replaced by electric shock, C
but recently 8

has shown that in diabeties the psychotic state can be induced by low blood sugar in the brain from sensitivity to insulin and can be reversed to normal by the intravenous administration of glucose. The author has been interested in substituting orally active and nontoxic chemical compouds as a substitute for insulin with the hope that more simple methods can be devised for modifying cerebral metabolism. A series of alkyl and alkylamino esters of oxy-diacetic acid have been prepared which block some phase of the Kreb's cycle of glucose metabolism. The exact point of blockcage remains to be determinec The phenomena of blockage by these compounds, however, have been demonstrated in animals by showing that they produce glycogen storage in the liver, heart, and kidneys by preventing the conversion of glycogen to glucose. For the first time it has been possible to produce experimentally von Gierke's disease, which is characterized by glycogen storage in the above-mentioned organs..

The phenomenon of glycogen storage was first produced by both the dlmethyl and diethyl derivatives of the diglycolate compounds. The initial experiments consisted of giving groups of six rats each doses of 5, 10, aņd 25 mg. per rat daily for periods of 6 weeks to 2 montha. The glycogen storage was most marked early in the course of the administration, as demonstrated by sacrificing some rats at the end of 2 to 4 days. The experiments were subsequently modified to include rabbits, so that the blood and urine studies could be more easily made. It was shown in rabbits that the compounds initially

[PAGE 351]
produced glycosuria, which disappeared in 48 hours. The fasting blood sugar of the animals is lowered; no acetone bodies appear in the urine.
In the next experiment the compounds were administered orally, intramuscularly or intravenously to canèer patlents and were found effective in coutrolling for a perlod of 3 months (to-date) diseases in the lymphoms and leukemic class. These patients have been able to tolerate the compound, and although it initially produced lowering of the blood sugar, if the dose is not increased, there is acquired tolerance to the hypoglycemic effect of the drug.

In the next experiment, the drug was administered to four diabetic patients. The blood sugar can be reduced in fresh diabetics. not previously subjected to inaulin from a level of 350 mg% to 250 mg%by the administratlon of 250 mg. of the compound. Diethyl is more potent than dimethyl derivatives. In other diabetics the blood sugar levels can be satisfactorily controlled for a perlod of 3 to 4 wseks on small doses but after that time tolerance develops, and the dosage must be raised. The compound lowers blood sugar by glycogen storage, but does not increase the capacity to burn sugar. Insulin must therefore be added.

In another group of experiments about to be undertaken, it is planned to administer these drugs to hospitalized diabetics and study the effect on mental function of large doses of the compound.

Several of the cancer patients on the compound have complainel of mental fogging, which is accompanied by compiete relief from paln on high dosage. This mental fogging, of course, is not experienced by díabetics and must be a fumction of the glucose level in the brain.

It is planned to synethsize a group of allied compounds and to broaden this Line of investigation. It is also planned to utilize a Warburg apparatus and electrophoresis in order to elucidate the exact phase of glucose metabolism that is inhibited by these comvounds.

WMR!

[PAGE 352]
bacteria or similar injurious substances gain socess to living tissues the local caplllary bed responds and permits the sscape of fluid and lexcocytes into the sone of injury. Nost of the extravasated Iluid returne to the circnlation by the lymphatics beoause the inflanmatory edeme compresses capillaries and venules but distends she lymphatics. which are anchored by numorous septa to the interstitial fluid compartment.

The modified intarstitial fluid from the injured area whieh returns via lyephatics traverses lymphoid tissue in the lyaph nodes. The lymphoid tissus, within 3 to 7 dars, responda by liberatins antibodies which enter the circulation and return to the injured site where thay sorve to zoutralise the injurious agent by uniting antibody vith satigenicusabatances.

It is customary to describe the immne response which follows the inflazmatory reaction to locai injury as a co-defensive mechaniss, which is highly specifio and mearly l00 per cent efficient in its end results. à study of the allorgic diseases such as hay fever, asthma. urticaria and scsemm and the occurrence of such dramatic rsactions as fatal anaphylaxis or exten= sive necrosis in the Arthns'e phenomenon indicates that antibody-antigen reaction is not as accurate and efficient as immumologists lead us to believe.

[PAGE 353]
Noreover, the modern tenlency to olass the diffuss collagen diseeses, such as aouto rheumatic faver, rheumatoid arthritis, disseosinated lupas arythematosus polyarteritis. capillary platelet thrombosis, and soleroderma, as modified forns of Arthus's phenonenon indicates that there ars alditional characteristic ar functions of the antigan-antibody Teaction that have not yet besn elucidatod For a mber of years the author has bean comvinced that one of the functions of the antigen-antibody roection is to prolong the inflammatory process by liberating irritating axines, vhich for want of a better tern have been desoribod in the literature as "union bodies.\* It appears that Sature's oldest and nost reliablo means to combat infury and infection is the inflammatory process, and although the ixmune process is more modern snd efficient, it nonetheless is still mistruatad and provision is made for antigon-antibody union to prolong inflamation under special circumstances. The fact that the combination of antigen and antibody union can itself initiate an inflammatory responcs is only too vell demonstrated in oases of ecrena, urticaria and hay fever. It is only vith the greatest attention to details that an incipient cass of hay faver can be differentiated from a conmon cold.

Experinentation with saveral irritating amines has finally permitted tho characterisation of a substance, which vs havs tarned "alarwine," which we believe is an essantial part of antigen-antibody reactions. The ltberation or such an anine subetance during the antigen-antibody reaction haa three soparate functions: l. The irritant amine or alarnine prolongs the local inflammtory reaction. Thin it does by alteration of the capillary wall of tha affected locality in a more marked famhion than histamine or ay" substance. 2. It triggers the general adaptation ayndrome in the adranals, releasing cortigone. which increases the amount of inmune globulin liberated through the boeak-up of lymphoid tissue. If repetitive injury does not occur. the

[PAGE 354]
tendeooy for alarmine to furthar prolong the inflasmstory renction is ishibited by adrenal cortical hormons. vhich reaches the inflaned tissues via the circalation. This cortisone meutralises the local alarmine effeat and further inflaamatory response is not provoked. 3. If the amount of astigen is umsually great or if ropeated exposure to the antigen occurs alarmine is not neutralized but prolongs the seneral adaptation syndroze and at the saze tine provokes an eren more marked vascular change, which bas been erroncously termed collagenous nsorosis, but is instesd a misguided form of incipient fibrous repair.

It is the purpose of the presant communication to deecribe the actions of amine irritants of ths alarnine class. and to show their role in triggerine the alarn reaction in the adrenal and also their role in the production of so-called diffuse collagen discase. have been able to produce for the first tise experinentally rhouzatio ryocarditis with Aschoff bodies, rheumatoid arthritis vith rheumatoid nodules, and a variety of vascalar lesions knovn as diffuse collagen discase, by irritant anines of relative sixple chemical structure. (Figs I).

Experinental Results of Painting Rats with Alaraine. In the original experiment 24 rats vere painted twico daily with a  per cent solntion of dimethyl dianaline. The solution in sesame oil vas applied to a shaved area of skin on the thigh approzimataly 2 x 3 om. in eiss. The rodents died within 36 to 72 hours. Vesicles or nleerations of the skin appeared in all rate living more than 48 hours. The effect on the epidermis was similar to that of nitrogen-mustard, with destruction of the basal cells of the epidermis and vesiculation of mclei. In some of those rats at autopey the adrenals vere slightly enlarged and hemorrhagic. It was, therefore, decidod to undertako chronic toxicity studies and to study in detail the effect of the compound on the systemig organs, instead of restricting the etudy to the akin.

[PAGE 355]
From the knowledgs of the forzala ad the effects on the skin and adrsnal, 1t vas assumed that one of two things might explain the resulte. The toxicity of the compound might lave destroyed tissuss and in this war caused adrenal hyperfunction through an alarm reaction; cr the cozpound coald be akin to that studied by Landsteiner, in which phenylaminss aoting as haptones combined with proteins to prodnce antibody reactions, tims producing an alars reaction vith firat hypertrophy and then azhaustion of the adrenals through an allergic response. The resulte vere pussling. but interssting.

A second series of experinonts were andortaken in which three groups of
rats were painted daily on the surface of the shaved skin of the thigh
aver an area of approxinately 2 x 3 cm. These were Wistar rats weighing l20 Gm. Group I, consisting of eight rats, was painted with a 3 per cent solution
in sesame oil daily except Sunday. Four untreated rats served as controls. Group II. consisting of eight rats, vas painted with a l per cent solution
in sesame oil daily axcept Sunday. Four untreatedrats served as controls. Group III. consisting of eight rats, vas painted vith a 0.5 per cent
solution in sesaze oil daily except Sunday. Four untreated rats served as contro Groun I. Flsh Dosage. The rats died between l0 and 15 days, on the
avarage of l2 dayi, They shoved stationary weight. Ths skin showed some
alceration and vesiclesp but not as severe as vith the 5 per cent solution.
Grossly. tho adrenals did not appear to be markedly enlarged. The spleen and
lyaphoid tiasues shoved slight atrophy. The lungs showed iacreased secrotion
in the bronchi. and these rats seemed to die of pulmonary edema and congestion.
The heart was dilated. Hioroscopicallr, the pulmonary edema waa due to exadatio
of plasma (so-called lymphorrhagia) about the smallar blood vessels in the lung.
The basement membrane of these smaller vessels ahoved smudging and dissolution
and the endothelial lining cells projected into the lumen and some were
detached. In the heart there vas an accumulation of spindle cells bamegs (endothel-

ial cells liberated by dissolution of adjacent capillaries) lying between

[PAGE 356]
the wyocardial fibers, whare thay had been separated by edema flnid fros leakir vessels sinilar to those found in the lnngs, Soms of the sections shoved typical Asohoff bodies (Figs. 2 ani 3). There were mumerons dilated vascular spaces lined by a single layer of endotholiun and many extravasated erythrocytes. In the synovial zombranes of the knes joint the capillaries vere dilatod and filled with red cells, some of which wore undergoing lysis. There vas smudging of the ground substancs inmediately benoath the mesothelial lining layer. In the bone marroy the capillarlss vere similarly dilated and there vere areas of coagulated extravasated flnid. The bone marrow elements vere intact. The splaen shoved almoat complete disappearance of lymphoid pulp. The surviving gerninal centers shoved evidence of necrosis.Other. Organs were negative. Gronp IL. Mialle Dosage. These rats lired a maximum period of 2 months,

and they died betvaen the 3oth and 60th day. They showed failure to piz weight. At autopsy, grosely, the lungs were congested and shoved pulmonary adema and incrcased sooration in tho tronchi. Thore was some thickoning of the arteries in the lungs, but not the veins. Histologically. there was some "onion poeling" of small arteries and arterioles, but some of the controla shoved similar changes. The heart was dilated and the adrenale vere enlarged. Microscopically, the adranals shoved hypertrophr and hyperplasia confined to the cortex. The splsen and lyophoid tissues were similar to. Group I. Microscopically. the spleen ehowed reduotion of lymphoid tissue and necrosis of the gerninal oenters. There was increased munber of macrophages in the pulp with mueroos bimuclaated forms. (Figure-L)a: . The heart showed focal fibrosis vith Aaitschkow's cells and some Aschodf bodies, and about this there vore areas or fibrinoid degenuration. The joint changes ln animals that died early ware similar to Group I.Other organs were negative.

Group Ill. Low Dosage. Some of the rats in thia group died 6 weeks after the beginning of the axperimante, but some were still living 3 months

[PAGE 357]
later. At autopsy, the outatening Finding wns eniothelial proliferatiin of the lining of saall puloonary vessels, so that their lumon was practically occlnded Sone of the vessels looked liks thay were being recanalisod and sone looked alnost like golmeruli. The andothelial proliferation in places extanded out into the sdjacent septs of the lung. This was fand in only two rats, who apperently inhals the alarnine while licking their wounds. (Fig. 5). The spleen was practicnlly devoid o lymphoid tissue and noarly double in sise. The pulp coutained many zacrophages with mnerous foam cell types ani there ware sone granulocytes but practically no lymphocytes. A few germinal centers were intact. The heart showed areas of fibrinoid degeneration and typical Aschofr bodies with Anitachkow's calls. In other rassels, the walls or the capillaries were disintegrating and the liberatad endothelial cells accumlsted about arteriolos to fors typical Ascboff bodies. The atjacent mvofibrils were netrotic and hyalinised. Thase changee were not as widespread as in the rsts on higher dosage.

The kes joints on microecopic exanination showod rheumatoid arthritis with the formation of rhoumatoid nodulee in the synovial mombrane. (Fig. 6). The boue zarrow was not remarkablo. The brains and kidneys were normal in appearance. In tbe region or the kidneya and pancreas saall to pediur-eized vessela showed thrarbcoecrcsis or marked endothelial proliferation similar to that found in the lunga. (Fig. 7).

The skin showed epideranl hoperplasia in the paintod areas In the-subcutaneons tissue af those rats there was marked edema simulating a stage in scleroderma, except that the location was nct in the derma and wae unaccompanied by strophy of the hair follicles. In the voluntary muacles beneath the painted sreas thore were also colloctions of plasma colls and Lytaphocytes and damage to blood vessels simulating the lesions of dermatayositis. (Fis. 9).

In the liver there were increased numbers of cells with acidophilic

[PAGE 358]
cytoplasn and binucleated forns. Sone of the vessels showed endothelial proliferation as in the lungs. There seenod to beacidophilic incluoions resembling Councilman's bodies. Some or the liver cells were vacuolated; others showed hralin droplet dogenoration, and the muclei were af verying size and density. (Fig. l0). The control rats showed no significant changes. Krfect of Alarmine on the Cement and Ground Subetances. Ths prinary Krfect of Alarmine on the Cenent ani Ground Subetances. Ths prinary erfect of alarnine is to produce hydration of the mucopolysaccharide struoture of basement nembranes and ground substance in mesenchynal tissues. The rost sensitive tissue coaponant is the cement subetance in the andotbelial wall of capillarisss perhaps because this is the site of the initial contact in the tissue. The sarliest change is softening which allous the capillary wall to stretch and fors aneuryamal dilatations. (Fig. ll). In the basement membrane behind the endotheliwa in precapillary artories and in arterioles, this bydration can bo seen histologically as a chain of saall bubbles, which we have terned beading. (Fig. 12). In the next stage the capillary wall disintegrates and the viabla endothelial cells and intact erythrocytes apill into the tissue spaces. (Fie. 13). In the heart the liberated endothelial cells from ths coronary capillaries nigrate toward damaged arterioles and fora perivascular Aachof? bodies. In subsequent- stages there is zore widespread damege to the connective tissue components. This results in fusion of erythrocytes, condensation of grounud substance to fora ibrinoid degeneration and liquefaction a otber portions of the ground subatance probably due to its infiltration by plasma leaking Trom the ruptured capillaries, and shredding of the collagen fibers with subsequent necrosis of these structur and adjacent muscle cells. Depolymerisation and hydrolysis affects the nonviable cement and

WARNING NOTICE

[PAGE 359]
ground substance and fibers of vessels and connective tiesue. ilaraine dacomposes these nonviable components of stromal tissue, which are techpicaily known as mucopolysaccharidcs and scleroproteins. Tais target tissue is the identical structure dasegeá by vitania O deficianay and by hyaluronidases and it is the sams atructurs which is strsngthened and rendored mors Fssistant to this effect by cortisone. Alermine is, therefore, an antagonist of vitamin C and cortisone and tha artifieiel tamning sobetances, such as the quinolizes.

If ve analyre this pathologio ssries of responsss into its major components, ve find that intense injury by alaruine is an exaggeration of the pathologic process found in the sizple healing of wounds, which has beon termed organisation. Here the injured tissue releases ainimal amounts of alarnine vhich produces matrix bydrolysis and capillary aneurysmal dilatation of the capillaries dus to the flaccid state of their walls. Bacause of the chemotaxis of the capillary endotheliun for the hydrated matriz in the injured area, so-ca capillary aproats are dragged into the wound. The histologio picture that results is known as granulation tissus.

The ptizary effect of alarzine in prodacing the changes of rhoumatoid carditis, rhennatoid arthritiz and polyarteritis is on the basement membrane of blood vessols and not primarily on the collagea fibers of connactive tissue. According to the latest cheaical.studies of collagen, the fibrinoid degeneration where 1t occurs in connective tissue does not involve the collagen bundles of well-formed connective tissae fibers. In ordar to emphasise the exact sequence of ovents it is important to raview the histological and biochemical composition of connectire tiseue.

Robb-Smith² haa defined connactive tissue aa a continuous natrix varying in consistency from the lixpidnsss of Wharton's Jelly of the umbilical cord to the hardness of bone in which lies an interlacing fabrio of fibers of different and is bathing iaolated or closely set cells.. sorts/ This continuoas matrix pervades the spacos between organs and major

[PAGE 360]
reasels and supplies tho capaule for these mejor structures, as woll as their supporting strcma. This definition does not emphasise the moat important cells fibroblaats, which show various stages of davelopaent from the reticulum cells to tha adult fibrocytes and also a parallel line of development (usually under pathologic conditions) from reticulu cells to histiocytes The definition also does not amphasise an additional specialised component of commective tlasue. the basement nenbrane. The matrix of cannective tissue contains a zariety of mucopolysaccharides, such as lyaluronic acid and chondroitin sulfate in combination with proteins. In this matrix are embedded fibers of collagen, reticulin and elastica, which are dafined as precipitated scleroproteins. Ths elastica does not concern us here, but the reticnlin and collagen fibers do. The collagen fibers are polymerized polypeptides, which are oriented in linear fashion and contain a amall mmount or mcopolysacchardde. Theereticullnuftbers are really nonorientod ecleroproteina with more abundant micopolysaccharide. They may be termed precollagenous fibrils with a less difrerentiated structure. The important point is that both are precipitated ef formed fron the mat rix. The third noncellular structure, besides fibers and ground substance, is the basement menbrane, which is formed from reticulin fibers and condensed matrix, which stains more intensively for mucopolysaccharidee than the ground substance. This condensed matrix at the basement membrane is usually termed cementin and also forms a binding substance betwoen the endothelial cells in the capillary wall.

Histogenesis of the Aachoff Body

In pathologic reaponse, depolymerization of the reticulin fibers and the condensed ground substance, both o which fora the basenent membrane of amall vessols, permits hydratiou of the matrix, mhich is hydrophilic and retains water ani abaorbs electrolytes. At tbe same time the cement substance of the capillary wall is similarly affected. The initial stage, therefore, in the

[PAGE 361]
rhedaatoid and collacea dissases that ve are disoxssing is s depolyserisation of cenentun vith loakage and hydration of ths ground sobstance with secoadery loss of collagen fibrils. \_In rosponse to the hydration of the groumd eubetane the coonectivs tisaua calls proliferste and contrlbute to the Aschoff bodies (which at firet contain only liberated endotheliai cells fros destroyed capillarios) and form rhoumatoid nodules, vhich are so charaoteristio of the rheumatoid state. Since the basement senbrane is the primarily affocted structure and this is composed of condensed ground sabstance and reticulin fibers and not of the more highly differentiated collagen fibers. the ters collagen disease does not describe the prinary process. The fibrinoid degeneratic obserred is a coagulum of the cround sabstance and cement sabstance. The endothelial aggregates, which proviously have been neglected, are previded by separation of the endothelial cells from altered or disaolved capillaries. Eadothelial proliferation and fibrocytio proliferation both contribute to the formation of tho Aschafr body and are both secondary to the freeing of these fized cells vhich coms to lie fres in a fluid matrix. vhioh is zoetly blood plasma and partly hydrated cenent substance and matrix.

Role of Adrenal in, tho General Adaptation Syndrome

There is good reason to beliave that tha general adaptation syndrome of 3 Selye, in vhich the adrenel cortax plays ths dominant role, serves as a co-defansive nechanism both in local tissuo damage and in the iranological responses of the reticaloendotholial systen. Sajers\* balievee that products of tissua dansge following severe injury coxbine vith cortical hornones in the peripheral tissuos, and vith the resultent fall in thair concontration ia the rencus blood, this normal check on the adenohrpopbyeis ie reloased and the pituitary responds by incressed secretion of ACty. This remultant increase in the output of ACTy depletes the adrenal cortex of its hormones and stimulates additional hormone production.

[PAGE 362]
If the period of stress is proloncet or continued. stisalation produces cortical hyperplasia and enlargenent of the adremals. This cortical kyperfunction results in, alteration of carbohydratef. protein and fat metaboliss. Thare is also an elavation of sódiam cloctrolytes in the serus, vhich increase the resistance of the animl by expending the metabohic pool and the volmme of tissue fluids. At tho sana time, there is increased excrotion of such tozio products as potassiue, histaminss and urio acid. Simaltaneously, the immune mechanisms are reinforced by destruction of lymphocytes resalting in lyaphoeytopenia, eosinopeata and leucocytonis, Since lymcbocytes store immmne globulins, their disintagration leads to a rapid rise in antibody titar.

If expoeure to stress continuea, the adaptation syndrose fails and is folloved by exhaustion. Salys balisved that the excessive drain on the anterior pituitary and adrenal cortical hormones incident to protracted or Fepeated trauma may rosult in cardiovascular renal and joint diaease. and he lists such entities as aephroaclerosise polyartaritis, carditis and arthrit! as adsptation diseases. Hovever, the consensus of present day opinion holds that these are forns of dirfuse collaga dispase resulting from hyperimmunity. Talbott and Ferrandis beliave that the etiology of these conditions is sttll unknown and that no investigation has succsssfully reproduced thea in anisala except for pelyartaritis in rabbits and the occurrance of disseminated lupus erythomatosus in humans following the adzinistration of the antibypertensive drog, hydralaxine (Apresaline).

Is the authors: ocinion, it is now poasible to domonstrate that similar irritating aminos are released in tissue danageptwhere thoy bave been custorarily rererred ào as "y" subetances, and in the union of antigen and antibody, whero they have been termed Bunion substances." These irritating

[PAGE 363]
aninee. hich we heve termed alaruines, neutralise adrenal corticel borucoes in the tissues ani tins release ACTB and stimulate the genaral adaptation syndrcoe. They are in turn neutralized by inoreased axcretion of adrenal cortical bormcnes if bodily roaistanos is adegnate (the resistance phase of Selye). Bowever, ir tissue daaage is ovorahelning the body passes rapidly through the pheses af alars and rosistance to exhaustion. Such acute exhanstion is oynonymous with irreversible shouk ar peripheral vascular failare (so-callod forward cardiac failure). Ir ovarwholaing scute stroos involves the iimune mechaniam. tha high concentration of unneutralized alarmins provokeo the irthus's phenomenon with its characteristic vascular throrbosis and resultant tissue Decrcsis. If stress is undnly prolonged by ropeated exposure to infectiony or sinilar antigens, the continned and increasirg release unneutralised alaraine exhmste the adrenals or exceeds their protective capacity (even in the presence of cortical bopertrophy), end collagen disease recults.

The Streas Aspocte of Alareine

In the experiments reportod sbove the adrennl ocrtical enlargement observed my be coneidered a indireot effect  alarmine, which neutralises ccrtisone in the tissues and tha stizulates the adenohypophysis, which relsases ACTH to bring about the cortical hyperplasie. Another interpretation, hosever, is posaible. The alarnine nay act directly on the adrenal medulla, which in turn relenses adrenalin to stimulata the adenohypopbysis to secrete increased ACTH. This second interpratation is auggeated by the deganerative changes in tho adrenal pedulla, which were observed. in a. further group of experiments deacribed balow. Whather sither or both mechanisms spply, the faot remains the adrenals un go enlarge:ent in some aninals to four times their normal weight). The changes in the lymphoid tissue, particolarly mared in the sploon, are the result df. the adrenal cortical hyperplasia. The alarmino in any event initiatee the WRNNG NOTICE adaptation syndrome.

TVEINTELLCRNCOIN

[PAGE 364]
the atrese phenomenon, which Selye has termed ths general adaptstion syndross a third group of axperinants was perforned. Therats used were males of the Wistar strain, weighing l00 (m. each, and-were injected intrsmuacularly six days weekly for 25 days and then sacrificed. The tissnes of all major organs mere examined.

Group I consisted of six control rats, receiring 1/2 cc. of nommal saline. No significant changes were obeerved in this group. One aninal had murine puoumonitis, and one had some increase in the connective tissue cells between the myocardial fibers.

Group II consisted of ó rats, receiving O.1 oc. each of spirits of tur pentine. These rats were sacrificed on the ninth day. They ahored mild perivascular edena and seperation of connective tissue fibers about small reasels, but none o the striking changes observed with alaraine. There was no lrenal hypertrophy.

Group III consistod of 6 rats, receiving 2 mg. daily of an amine compound in which zethyl piperasins was liaked with propenol to dimethyl piparazine. No significant changes were obseried in these rats, when sacrificed on the 2óth day.

Group Iv consisted of 6 rats, raceiving 2.5 ng. daily of an amine compouns in which pethyl piperádine was linked with another molecule of piperidine by propanol. No significant changes were observed in these rats when süerificed on the 26th day.

Group V consisted of 6 rats, recaiving 0.1 mg. daily of alarmine. These rats were aacrificed on the 2óth day.. They showed changes in the lungs, heart, joints, spleen and adrenals similar to those reported above in the rats painted with 0.5 per cent solution of alaraine in sesams oll.

Group VI consisted of 6 rata, receiving O.l mg. of alarmine daily, plus 2.5 mg. daily of procaine H0l. These rata were sacrificed on the 2óth day. WARNING NOTO

[PAGE 365]
They ahowed chatgo sisilar to those in Croup V, but the changes were slightly more pronounced. The resson for this, in our opinion, is that the procaine inhibited pain and irritatioa fros tho alaraine inthe local tissues, and thus did not provoke such a pronounced cortical response in the adronals. In other words, there was lesa stress phonccenon.provoked in the adrsnal.

Group vII consisted of 6 rata, receiving O.1 ag. of alarmins daily, plu 1 es. daily of cortisons. These rata wers sacrificed on the 2óth day. No signiricant change was obserred in any organ. The cortisone had complétely inhibited the response to alarmine.

Conelusion

It may be concluded frcm the above experinents and observatione that a dianino benzene derivative, which.ws have terned alarnine, is a relatively specific irritant axine, which is capable of hydrolysing the cement and groand subatancea of commective tisate and of producing the so-called collagen diseases. it the same time it provokes the generaladaptation synirono, but if given in sufficient anounts or concentration it is cspable of overriding the protective response of the general adaptation syndrome, which it provokes. This irritant amine can be neutralised in its pathologio affects by the simultenocus administration of anfficient emounta of cortisone.

The collagen discases which we beliave to be reproducible with this sub
stance are: rheumatic carditis, rheumatoid arthritis, scleroderma and dermato
myositis, and polyarteritis. In the experiments recorded above glomerulonophriti
and membranecus gloerulitis with wire-looping in the capillary loops of the neph
characteristic of disseninated lupus erythematosua were not observed. Since this
is undoubtedly a collagen disease, an atteapt to produce such changes was made
in a final group of experiments. Six Wistar male rats, wighing 60 to 80 Om.,
were painted dally with a 2 per cent solution of alarmine to a ahaved area of
the thigh 2 x 3 ca. The smaller rats were chosen in praference to raising the WARNING NOTICE.

[PAGE 366]
alarnine dosage. These rats died after three dys and c caplote sntopeies were performed. They showed chenges in ths heart and joints charscteristic of early rheunatic carditis and rheumatoid arthritis,aasgreviously described. Iu adiition all of the rats showed mosbraneous glomsrulonephritis, with wiro-loops character istic of dissaninated lupus erythomatosus. There were also vascular lesions in the brain, such as are seen in collagen diseases, and azall focal accumulations of gitter cells, resembling typius nodules, a reection to vascular darage. The type of collagen disease observed, therafore, is dependent upon the concentration of alarmine released in the tissues.

[PAGE 367]
BIBLIOGRAPHY

L. Landstoiner, Karl: The Specificity of Serological Reactions, Earvard University Press, Cambridge, Mass., 1o15.

2. Robb-Snith, &. H. T.t The Punctioning Signiricance f Commective Tisate. Lectures on the Sciontific Basis d Kedicine, Vol. 2, 1952-l953, Univ. or London, The Athlone Prsss, 19h.

3. Selye, Hanst Stress, Acta., Inc., Ued, Publishers, Montreal, Canada, 1950.

l. Sayera, 0.1 Adrenal Corter and Homeostasis. Piysiol. Re. 3012ll, 1950.

5. Talbott, J. H. and Ferrandis, R. H.; CollagonDiseases, Grune & Stratton, New York, 19564

[PAGE 368]
Figare 2.  Changa in Vessels in Lang

Figare 3. Aschoff Bodies in Reart

Pigure L.Changes in Adrenal

Pigare 5. Changes in Spleee

Figure 6. Rheuzatoid Arthritis of Knee Joint

Figurs 7. Thrombonecrosis of irtery in Henal Fat

Figure 8.Subcutancous Scleroderms

Figaro 9. Dernatomyositis

Figuro 10. Liver Changes

Figure ll. Capillary Aneurysne

Figure 12. Beading of the Basenont Mombrane

Figure l3. Capillary Dissolution with Liberation of Endothelial Cells

WARNINO NOTICE

SOURCES AND METHORG INVOLVED:

[PAGE 369]
This syuthetic work relates to compounds of the structure

and the halohydrins

B P-H AcN N CH2H-CH2X B

which may be used in the synthesis of I, where AC is a member of the group made up of acyl, aryl sulfonyl and alkyl sulfonyl, and B is a member chosen from the group made up of H and CH3 and X is a member of the group made up of chloride, bromide and fodine.

Typical compouads to be included:

CH2CH2 HCO.N N-CH2CH-OH2 CH2CH2

CH2CH2 C6H5SO2NCH2CH2 N-CH2CH-CH2

1. Code: Ac.7.

WARNNONOTCE

ENCEIOTTRLIO SQURCES-M

[PAGE 370]
This synthetic work relates to compounds of the structure

A CH-CH2 EIN N-22- CH2CH

their acid addition salts and quaternary ammonium salts,

and the formyl derivatives,

AR-CH2HCON N-CH2CHOCH2-BCE2CH

which may be used in the synthesis of I where A. ia a member chosen from the group made up of E and CHg and B is a monovalent amino radical which is a member taken from the group made up of the following:

(1) a radioal of the structure RNH- where R is an alkyl radical from 1 to 4 carbons Rt
(2) a radical of the structurè -N R"

where R' and R' are alkyl radicals, the total carbon content of which is between 2 and 8

(3) a heteocyclic radical which is à member of the group made up of

pyrrolidino, piperidino and morpholino

(4) 1-(1, 2, 3, 4-tetrahydroquinolino), 1-(decahydroquinolino),

1-(6-methoxy-1, 2, 3, 4-tetrahydroquinolino) and-

2-(1, 2, 3, 4-tetrahydroisoquinolino).

CH2CH2 Typical compounds: CH3NHCH2CHOC2N NH CH2CH2

2. Code: Ax7 Cx7

[PAGE 371]
This synthetic work relates to compounds of the structure

CH-CH2 B-NCH2CH 2H-H2

and the halohydrins

CH-CH2 R-N - 2 CHCH A

which may be used in the synthesis of I

vhere R is a member chosen from the group made up of an alkyì

adical of from 1 to 6 carbons, benzyl and benzhydryl, and

A is a member chosen from the group made up of H and CH3 and X is a member chosen from the group made up of chloride, bromide and iodide.

3. Code: R.7.

[PAGE 372]
H-CH2 R-N N-H2CHO2-B CH2CH A

their acid addition salts and quaternary ammonium salts,

where R is a member taken from the group made up of akyl

radicals of from 1 to 6 carbons, benzyl and benzhydryl,

where A is a member chosen from the group made up of H and CH3

and B is monovalent amino radical which is a member taken from ths group

made up of the following:

(1) a radical of the structure R'NH where R' is a member chosen from

the group made up of H and an alkyl radical of from 1 to 4 carbons

(2) a radical of the structure -N

where R" and R'r are alkyl radicals, the totai carbon content of which is between 2 and 8 inclusive

(3) a heterocyclic radical which is a member of the group made up of

pyrrolidino, piperidino and morpholino

(4) 1-(1, 2, 3, 4-tetrahydroquinolino), 1-(decahydroquinolino),

1-(6-methoxy-1,2, 3,4-tetrahydroquinolino) and

2-(1, 2, 3, 4-tetrahydroisoquinolino).

Typical examples:

CECHZ CEBN -2 CH2CH2

CH2CH2 {C6H5} CN N-2 2N3 CH2CH2 B

SOURCES AND MSTHODE RIOWNE

4. Code: R.7xC R. 7xA

This synthetic work relates to compouds of the structare

[PAGE 373]
PROPOSED BUDGET

[PAGE 374]
oc    d re eck

[PAGE 375]
MKULTRA Subprofeet 4\$ Invoice No. 6. Alloteat 6-2502-10-00l

Cashieris check in the amount of \$34, 000.00, drawa on a abane.

2. Please forward the cbeck. te Chief, TSS/Chemical Diviston through Tss/Budget Officer by Friday, 5 Oetober 1958.

J. This 1s a final lavolce, A total of \$133, 000.00 was obligated under this subproject during FY 36. However slnce it is aaticipated that additlonal fuads will be obligeted for this project, the flles should not be closed.

CHECK C IN THE AMOUNT OF S RECEIVED.26,

SIDNEY GOTTLIEB Chfet TSS/Chemlcal Division

CERTIFY THAT FUNS AILASLE OSLIGANON REEENCE CHARGE IC ALLOTMENT

Distribution; Orig & 2 - Addressee 1 - Comptroller 1- TSS/FASB 1 - 2 TSS/CD

0n1 (10 September 1956) 213 a se  2

[PAGE 376]
CERTIFICATIONS

(l) It is hereby certified that thia is Invoice No. 6 applying to Subproject 45 of MKULTRA, that performance is satisfactory, that the services are being accomplished in accordance with mutual agreements. that a detalled agenda of the payments and receipts is on file in TSS/CD, that this bill is just and correct and that payment thereof has not yet been made.

Chief, TSS/Chemical Division

Date:

(2) It is hereby certifled that this invoice applies to Subproject 45 of MKULTRA which was duly approved, and that the project is being carried out in accordance with the memorandum dated 13 April l953 from the DCI to the DD/A, and the extension of this authority in subsequent memoranda.

Research Director

Date:

[PAGE 377]
RECCCIPT

pPae te tahe 00000 Orii    nk nt ea r c

[PAGE 379]
Uoder the antbority granted in the Mancrandus Asted 13 April 1953 from the DCI to the DD/A, and the axtenaion of this nuthority in sabsequent mesoranda, Suproject 45 was previouely approved. Under the sons muthority an additional ss of \$3,760.00 has been suthorized to cover the subproject's exponses and ahoald be chargsd to Allotment 9-2502-75-902.

T38/Chenical Diviaion

APPROVKD POR CELILATIOM OP FUBDS:

I CERTIFY THAT FUNDS ARE AVAILABLE GRUGATIEN RERENT 20 CHAROE TO T6-2502-y02

Distributions Qrig à 2 - Addressne 1 - TSs/∞c -TSS/TASB 2 - TSS/CD

AUTHORUING CMICR

[PAGE 380]
MEMORANDUM FOR: CHIEF, FINANCE DIVISION

TSS/Budget Officer

SUBJECT

: MKULTRA, Subproject 45, Invoice No. 14 Allotment 9-2502-75-902

1. Invoice No. 14 covering the above subproject is attached. Payment should be made as follows:

(ε) Cashier's check lo tho amount of \$35, 750. 00, drawn on Bank.

2. Please forward ths check to Chlef, TS5/Chemical Divislon, through TSS Budget Ofllcer, no later than 22 June 1959. Other favoices will follow.

(A)

Chiel TSS/Chemlcal Division

Attachments: Invoice & Certifications

I CERTIFY THAT FUNDS ARE AVAILABLE ONUGATION REERENCE No SHARGE TO ALLOTNST N -252-S-

Distribution: Orig & 2 - Addressee -TSS/FASB 2- TSS/CD TSS/CD (11June59)

AUTHORIZING CRICER

[PAGE 381]
CERTIFICATIONS

(l) It is hereby cortifled that this im Iavoice No. 14 applying to Subproject 45 of MKULTRA, that performance is satiafactory, that services 2re being accompllshed in accordance with mutaal agreements, that a detalled agenda of the payments and zeceipt is on file in TSS/CD, that thie bill is just and correct and that payment thereof has not yot been made.

C/TSS/Chemical Diviston

Date:

(2) It is hereby ceztified that this invoice spplies to Subproject 45 of MKULTRA which was daly approved, and that the project ls being carried out in accordance with the menorandum dated 13 April 1953 from the DCI to the DD/A, and the extension of this authority in subeequent memoranda.

Origical slgned by

Date: 1 1 JUN 1959

Research Director

[PAGE 382]
RICIPT

ia a t o d e L I

[PAGE 383]
I. Invoice Ko. & for MKULT&A Subproject 45 is attached. Cther invoices will follow later. It is requested that payaent be made by E) eashier's chech ln the zmoant of \$33, 009.00. The check shoald be drawn on a bank and made payable to the 1 B)

HVA 52 5026H.20

[PAGE 384]
CERTIFICATIONS

(1) It is hereby certified that this is Invoice No. 5 applying to Subproject 45 of MKULTRA. that performance is satisfactory. that -the services are being accomplished in accordance with mutual agreements.- that a detailed agenda of the payments and receipts is on file in TSS/CD, that this bill is just and correct and that payment thereof has not yet been made.

Acting Chief, TSS/Chemical Division

(2) It is hereby certified that this invoice applies to Subproject 45 of MKULTRA which was duly approved, and that the project is being carried out in accordance with the memorandum dated l3 April l953 from the DCI to the DD/A, and the extension of this authority in subsequent memoranda.

[PAGE 385]
1. Iavoice fa for loLrsa Susproject 45 is attached. Other inroices vill follov later. It is requested that payment be ande by cuahier's ehock in the amount of \$33,000.00. the check shcuid ba dravn ca a ebank and mnde payablo to the dmer

2. Plaase foruard the check to Chief, TBs/Chemical Diviaicn through s/Budget Otricer by 5 Nairch 1956.

Distribution: 7 Orig & 2 - Addressee 1 - Comptroller

CERTIFIED FOR FAYTENT OR CREOIT 1020 5 \$1.0: CERTEY THAT ALNDS ARE AVARAREE CHUIGATICN REFERNCE 3 A) FFICER AUTHORZED

[PAGE 386]
(2) It is hereby certiried that this invoice applies to Subproject 45 of Muá which was duly approved, and that the project is being carried out in accordance vith the nemorandum dated 13 April 1953 from the DCI to the Du/A, and the extension of this authority in subsequent memoranda.

[PAGE 387]
The purpose of this memorandum is to set forth the mutual administrative responsibilities of-the hereafter known as the the principal investigator, and the sponsor. Therefore, it is mutually agreed that,

A. the principal investigator shall subnit for the sponsor's inapection theannual audit report, certified by a CPA.

B. The bank statements and cancelled checks of the special account, maintained for third party disbursements, shall be submitted- for inspection upon the sponsor's request.

C. It is understood that any travel expenses incurred in the furtherance of the research program will be accounted to the in a manner consistent with its established practices and policies.

D. Upon the request of TSs/CD, the principel investigator shall submit to the sponsor reports of technioal progress in the research covered by these funds.

Doo 2/1/56

MEMORANDUM OF AGREEMENT

[PAGE 388]
Dongradeo: CONFDENIAL by a rity of : 207475 June 10 -1

2 IPD: CL BY 187475

MEHORANDUM FCR: THE RECORD

SUBJECT: Project MULIRA, Subproject 45

1. The scope of this project is intended to encompass all those activities now engaged in by ths. under the direction of TSS/CD. These activities take the form of three lines of biochemical investigation, namely, the Curare-like effect of certain thiols, the preparation of hydrogenated quinolines and indole alkaloids and a program of investigation of toxic cerebral states. This last investigation will include bio-assay and chemicalanalysis of various body fluids of animals in which cerebral toxemias have been produced. It is the aim of this program to endeavor to understand the mechanism of such states as toxic delirium, uremic coma, and cerebral toxicity from poifsoning- In order to continue the established "cover" activities of the and to make available a pool of subjects for testing purposes, the effects of compounds resulting from the above program will be evaluated.

2. The attached proposal from indicates the extent of the investigations that his facilities will allow him to carry out on the materlals developed in the three lines of research referred to in paragraph one, as well as certain other materials of interest to TSS/CD. also serves as a general consultant to this Division and provides cover and cut-out facilities to the Agency.

3. The total cost of this project for a period of one year will not exceed \$100,000. Charges should be made against Allotment 6-2502-10-001.

4. has been requested to submit a summary accounting or a copy of the annual audit report be made available for the sponsor's inspectioa. Also, it has beenrequested that any unexpended funds shall be returned to the Agency.

Title to any permanent equipment purchased by funds granted shall be retained by the in lieu of higher overhead rates.

\* other than its activities as a cut-out

Downgrad  to: COHFDFuTi by awenority of.o/47s dete: June 1a

E2 IT: CL BY 187475

[PAGE 389]
Dowagrade to: Confmpumr by arcnority of o7475 cace: Jone o77

(B) 7. egreed to comply with the requirements of the Memorandum of Agreement.

TSS/Chemical Division

APPROVED:

APPROVED FOR OBLIGATION F FUNDS:

Chief, TSS/Chemical Division

Deto: 2Fnli4oG

Attachment: Proposal

Distribution: Original Only

Do ded to EHIIA by Autho-ity o 187475 cete: Juner977

[PAGE 390]
Bio-assay and Chemical Analysis of Body Fluida in Toxic Cerebral States General Survey of the Problem

There are a varlety of clinical conditions, many of them terminal, in which patiente under clinical obaervation pass from milld disorientatiou into delirium and coma. These conditions of cerebral intoxication are often associated with the failure of some vital organ other than the brain. The most important forms of such cerebral intoxications are

1 - Uremic coma associated with renal failure

2 - Hepatic coma associated with liver fallure

3 - Convulsions and coma of eclampsia aasociated with the pathology of the placenta and involving also the liver and kidneys

4 - Malignant cachexia asaociated with advanced carcinomatosis

5 - Toxic delirium associated with severe bacterial infection, at times with a generalized septicemia or bacteremia

6 - Deliriun, coma and convulsions resulting from chemical poisoning in which the toxic substance.may act directly or indirectly on cerebral tissue.

1 - Uremia. A review of the current texts and contributions to medical journals reveals a remarkable lack of information concerning these forms of cerebral intoxications Thus, in uremia there is a wide difference of opinion in regard to the identity of the urinary constituents retained in the blood which are responsible for the effecta on the central nervous system. Fishberg states that after a hundred years of search for the "uremic prinoiple" its identity still remains a mystery. Homer Smith, in his wor on the kidney, stresses the importance of potassium retention. Others have implicated the magnesium ion. Most authors

[PAGE 391]
on the subject believe that the cerebral effects of uremia are the result of retention of phenolo compounds. A smaller number believe that retained nitrogenous substances such as indfcan and umidentified producta of intermediary protein metabollsm are the respomible agents. The only sphere of agreement is the well-established fact that injection of normal urine Lato laboratory animals in adequate doses will produce coma and death, whereas the urine from pationts in uremia is relatively non-toxic, the toxic substances remaining in the bloodstream of the affected individuals. It is Interestirg to note in the transactions of the Macey Foundaton on Renal Function from 1949 to 1953 that a conference has not been devoted to the subject of uremia. 2 - Hepatic Coma. The cerebral effects of hepatic fallure consisting of high fever 2 - Hepatic Coma. The cerebral effects of hepatic fallure consisting of high fever and progressively deppening coma have been atressed by Heyd, and are often known as the Heyd syndrome. The cause of the coma is generally attributed to the retention of ammonia or ammonium carbonate. However, with the introduetion of the artificial kidney the removal of ammonia by dlalysis, which is readily accomplished, has been shown to have no inluence on the comatose condition of the patient. Some investigators have postulated the retention of bile acids as the cause of the coma. There is even less information available on hepatio coma than on uremia,

3 - Eclampsia. Eclampsia remains "a disease of theory". The convulsions and coma that occur in these patientg are of unexplained origin. The concensus of opinion to date is that the effects are brought about by spasm of the smaller blood vessels but the cause of the vascular spasm remains undetermined.

4 - Cachexia. The disorientation and coma of patients with cachexia resulting from malignaat disease have provoked remarkably littie attention in recent years. Willis believes that the cachectic state is an expression of malnutrition with the reteution of acetone bodies and is therefore related to dlabetic corna. However, there are no adequate studies to subgtatiate this theory and the treatment of such patients with intravenous glucose and injections of insulin has not been carried out to my knowledge.

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5 - Toxic Delirium.Before the davs of penicillin and the antibiotics, disorienta-

tlon and delirium were frequent complications of severe infection. It was common in pneumonia and treated by forcing flulds either intravenously or by mouth. However, the toxic effects on the central nervous system of common infectious organisms received no detailed study. In general, the cause of the delirium was related to the severity of the infection.

In summarizing the known facts about uremia, hepatic coma, eclampsia and toxic delirium we can say that the specific cause of the cerebral depression remains unknown in all of them. The only common pathologlc effect is the lowering of the cerebral uptake of oxygan. This, however, apparently is a consequence of the suppression of cerebral function rather than a causative factor.

6 - Cerebral Toxlcity Associated with Poisoning. The terminal stage of most forms of poisoning is usually described as "Convulsions, coma and death", The localization of the underlylng cerebral effects, bowever, has not been ascertained for the systemic poisons. In an attempt to arrive at a compendium of present day information we have summarized the pathology of varlous forms of poisoning in the tabulations submitted with this proposal.

Plan of Procedure

Analysis of Body Fluids. We propose to eatablish a laboratory for the chemical
analysis of body fluids in the toxic cerebral states. When patients with toxic cerebral mani
festations are under observation in the hospital for uremia, hepatic coma, eclampsia,
malignant cachexia, ete., blood serum, cerebrospinal fluld, intraperitoneal fluld and pleural
fluid will be obtained and fractionated for possible toxic components such as phenol, bile acids,
toxic amines and other components that may be found of interest as the project develops. This
analytical laboratory will employ two hiochemists. One will be associated with the routine (B)
service Iaboratories ai the fand will supervise the collection and

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preservation of these materials and will provide the routine analysls of their constituents which can be determined by known chemical technics such as determination of potassium, sodium and other inorganic constituents, theír organic constituents such as bile acids, urea, non-protein nitrogen, COg combining power, ete. The other biochemist will be engaged in specialized chemical analysis, such as electrophoresis, spectrographic analysis, etc. and will try to devise new methods for the determination of toxic amines, phenols, etc.

Bio-Assay of Body Flulds. Another laboratory will be maintained in the animal house for bio-assay on laboratory animals of the toxic constituents isolated in the chemical laboratory.

Animal Experimentation. While the chief interest in the toxic cerebral state

centers in patients, it is planned nevertheless, to produce these conditions in laboratory animals and to carry out parallel studies on their body fluids. Both uremia and hepatic coma are readily produced in laboratory animals, such as dogs, rabbits, guinea pigs and rats by the surgical removal of the kidneys or liver, or through selective poisoning of these organs. A highly specific form of chemical damage to the liver can be achieved by injecting carbon tetrachloride into the portal vein and a highly selective form of renal damage can be produced by injecting $\tt R e C l _ { 2 }$ into the renal arteries. Laboratory animals also offer the best available means for the analysis of the cerebral effects of neurotoxic chemical compound

WADMING NOTICE SENSITIVESNTELLIGENCE SOURCES AND METHODS INVOLVED

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with the previous leads and accomplishments disclosed by the work carried out during 1954 and 1955. Four separate laboratories are engaged in this work. an cooperation with is continuing the synthesis of sulfur-containing organic compounds. These thiol compounds beside their curare-like effects also are effective agents in influencing the automonic nervous system. During the year 1955 the

cooperated in the pharmacological testing of these compounds.The has found that the isothiouroniums exhibit inhibitory effects on both the sympathetic and parasympathetic ganglia and also potentiate epinephrine

the nitrogen group has been introduced by the Mannich reaction on the pheholic ring so that there is one carbcn between the nitrogen and the ring structure. In 1956 it is proposed to Introduce the nitrogen directly on the ring by nitration. Some of phenolic compounds produce definite auitory hallucinations and disturbance of taste and oral sensations. These effects are transitory and their duration is dependent on the dose of the drug. These compounds are of great clinical intarest because of the acarcity of drugs in this fleld. The most potent compound in this group are derivatives of 4-chloro-3, 5 dimethyl phenol.

has prepared nunerous nitrogen derivatives of the hydrogenated quínolires. He also has succeeded in making similar derivatives of hydrogenated indol. These compoumds prepared by are unique in that they produce pronounced curare action in animals, both by inječtion-

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and oral admiristration without the presence of the methtonium group. These compounds (in suitable doses) have been uged in a series of over 50 patienta by both intramuscular and oral routes. At the low dosage level used they showed specific muscular relaxing effects
on selective organs; some of them relax voluntary muacle while others sbow specific relaxing
effect on the musculature of either the urinary tract or the gastrointestinal tract. The
voluntary muscle relaxants bave been used on patients with paralysis agitans and rheumatold arthritis. Those which relax the smooth muscle of visceral organshave been used on
natients with disturbed bladder functlon. with multple aclerosis and prostatic hypertrophy. B)
has continued to cooperate under a written agreement (previously arrived at) in syntbesizing starting materials for They have supplied bydrogenated
quinolines for and nitrated some of the diphenollc compounds in cooperation with It is proposed to continue this cooperation.

WARNING NOTIC

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Analysis of Body Fluids in Toxic States

Biochemists (2)

Techricians, Laboratory (2)

Special Equipment

Supplies

Clinical Assistant

Chemical Synthesis

Chemical Supplies

Toxicology and Pharmacology Laboratory

Animal caretaker and animala

Pharmacologist and tecbalcian

TOTAL

\$16,000.00

6,000.00

10,000.00

8,000.00

6,000.00

\$46,000.00

2,000.00

4,500.00

6,000.00

12,000.00

12,000.00

5,000.00

\$25,000.00

\$29,000.00

\$100,000.00

WARNING NOTICE

SENSITIVE INTELECSUCE

SOURCES AND METHODS INVOL

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MoR 1433

Distributiont Orig à 2 - idtressse

1 - TSS/0C
1 - TS3/TASB
1 - TSS/SRB
2-TSS/CD

A ss/(31 J 1956)

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Oushisr's chock in the ount of 833,667.00 dro (e) and peyable to the (B)

2. The eheek should de furwardod to Chiat, Tat/Cheaical Division, throngh ISs/Budget Orrioer, no later than 30 Septerber 1955.

. Tae three invoices oovering this mpabproject segrogate \$100.000.00. and mke ues of ths balmmoe of the 71 55 funds pins the FY 56 fuds obligated to date wnder this mibprojeot. Sirce it is erperted that additional FI 56 funds vill bo oblipated wnder this aubproject, the flles on this projeat shoold not be closet.

Attanbmentot Invoice & Certificaticns

Digtributiont Orig & 2 - ddiressoe 1 - Comptroller 1- TSS/FASB 2 - tss/d

(A) r33/cD(13 Septmber 1955)

SIDEEY GOTTLIER Chif TSs/Chemical Division

I CERTIFY THAT FUIDS ARE AVMLAZLE:

OSLGATION REFSAE C N..

CHARGE TO ALOTNE:

223 5.3502.10.81667.0 6. 252-10. 011\$10.N

CHECKNNOPR RECEIVES. 27

THE AMOUNT OF S24

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(1) It is hereby certifiod that thin is Invoice f3 applying to Subprojoct 45 of MKULTRA, that performance is satiafactory, that the parvices are being acooapiished in accordance with mutual agreeaonts, that a detailod agonda of the payments and rocoipta is on fild in Tss/CD, that this bill is just and correct and that peynent thereor has not yet been mado,

Chief. TSS/Chemical Diviaion

(2) It is hereby cortified that this invoice applies to Subproject 45 under ULTRA which was duly approved and that the projeot is being carriod out in accordance with the zemorandum dated 13 April i953 from the DCI to the DD/A, and the extension of thia anthority in aubsequent xemorande.

Research Director

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AP2ROWED FOR OBLIATIOS CF FUDS:

Digtributions Oris & 2 - Adtresnoe 1 - TSS/0C 1 - TSS/TASB 1 - TSS/S8B N2 -TSS/D

[PAGE 406]
(2) It is horoby certiried that this imvoioe appliea to Subproject 45 undar Project MuLTRA which wes duly approved and that the projoot is boing carried out in aceordance with the memorandus datei 13 Apr11 1953 from tho DCI to the DD/4, and the extension of this authority ia subsoquent memoranda.

Rescaroh Director

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: Froject-MKULTRA, Subproject 45

1. The scope of this project is intended to encompass all those activities now engaged in by the , in its own facilities under the direction of TSS, Chemical Division. These activities will take the form of three lines of biochemical investigation; namely, the curare-like effect of certain- thiols, the preparation of hydrogenated quinolines and indole alkaloids, and the continued study of diphenolic compounds. In addition to the above investigations, the present biological testing and assaying techniques will be elaborated and broadened to include cardiovascular and anticarcinogenic effects of compounds·resulting from the above programs.

2. The attached proposal from - indicates the extent of the investigations that his facilities will allow him te carry out on the materials developed in the three lines of research referred to in paragraph l, as well as certain other materials of interest to TSS/CD. also serves as a general consultant to this Division and provides cover and cut-out facilities to the Agency.

3. The total cost of this project for a period of one year will not exceed \$100,000.00. At the present time, the sum of \$40,000,00 is being committed, the balance of the total to be comaitted at a later date.

e has been granted a TOP SECRET clearance by the Agency, and is fully capable of protecting the security of the Government's interest in this matter.

APPROVED FOR OBLIGATION OF FUNDS:

APFROVED:

21 March 1955

MEMORANDUM FOR: THE RECORD

SUBJECT

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APPROVED FOR ADDITIONAL APPROFRIATION OF \$33,O0O.O0:

Date:

AUG 10 1955

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Three lines of biocbemical investigation are proposed for 1955.

These are being pursued with as senior consultant, and the
compounds are being prepared, as in 1954, by (C at the and B
the The chief interest in work for 1955 will

be in the thiol compounds, some of which have carboxy groups, as well as amíne groups, and some of which have either curare or soporic action. will continue his work on the diphenolic compounds.

In this work the nitrogen for the first time will be placed directly on the ring. A wide variety of biological effects is found in these compounds. The work of will center about the hydrogenated quinolines and the indole alkaloids. Not only will the propanol linkage be used in the synthesis of these new compounds but also the methyl propanol linkage and a linkage in which the carboxy group gubstitutes for the hydroxyl in the propanol.

Biologlcal testing of these compounds will be more elaborate than previously and the assay technica will be broadened to include work on the tracheal rings of the guinea pig, hyperthermia in rabbits, blood pressure and cardiovascular effects and anticarcinogenic effects.

RESEARCH PROPOSAL

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Biological and Pharmacological Testing

Pharmacological, technical Research Pharmacologist Anímals and anímal maintenance

Contribution to maintenance of