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ONR 441:FHQ:0p NR 113-149 Ser, 31540

21 1anvary 1952

DROMORANPROJECT

Declassified by187475 date 4-FED 7

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The recrultment and dcamiagef-personnel began In July. The training of: personnel was completed in late September and an additioaal research ward was opened In October l95l. The work on the human pharmacology and toxlclty of 3-methoxy-a-. methylmorphinan, as well as the work on the detectlon of euphorls, wos completed during the summer. Work on the rellef of abstlnence and substitutton of this compound for morphine was completed in December 1951.

The results to date can be summarized as follows: Doses i of less than 30 mg. dl-methoxy-a-methylmorphlnan produced no untoward toxic effects In former morphine addlcts. Doses of 20 to 30 mg-, elfher hypodermlcally or orally, Induced euphorla similar to and equal ln,intensity to that seen after the admiaistration af 30 mg- morphine. Other morphine-like effects, such as nousea, vomiting, miosis and resptratory depresslon, were observed with the larger doses. The compound was found to Induce its effects more quickly when administered orally as compared wlth hypodermic administratlon. It relizved abstinence from morphine and could be substituted for morphtne In addlsted persons. Substltution was comglete as contrasted with codelne,which will not support physicaldependence. on morphine completzly. Following withdrawal of 3-methoxy-a-methyImorphinan after substitutlon for morphine, a typlcai morphine-llke abstinence syadrome appeared. For further detalls oi these studtes see the reports 'to the Drug Addiction Committee, National Research Council, which are attached.

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BACKGROUND INFORMATION

In late June of. 1951 \$30,000 was mode avallable by the Department of Defense for determinlng the addictlon Iiability of dl-3-methoxy-a-methyImorphinan {methoxy-dromoran) In the hope that this drug mlght represent an adequate synthetic substitute for codelne. This grant was made.following the submission of a project descrlptlon entitled "The Determinatlon of the Addiction Llabflity of Synthetlc.Analgesies of the The project was supported for the foliowleg reasons: -4

Due to the curreatly disturbed lateraational sltuation, It was possible that the United States mlght be cut off from all lts usual sources of oplum. Synthetle analgesies dre avallablz which are entirely adequate for the replacement of morphine. However, none of the avallabie synthetis analgeslcs are as safe for general use as is codelne. More than sO per cent of the Armed Forces requirements for narcoties is for codelae rather than for morphine.Finding a synthetie substitute for codelne Is, therefors, of considerable importance and It was hoped that methylation of 3-hydroxy-a-methylmorphiaan, a synthetic drug of morphlae-fike structure, would produce such a compound. The facilitlzs of the Addiction Research Center were not sufficlent to carry out thz work unless additional funds could be obtalned.

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ADDICTICNE3CUAB SYNTHETIC ANALGESICS WHICH MIGHT SERVE AS SUBSTITUTES FOR CODEINE.

Declassified by187475 date — 4 FEB 1977

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It Is obvlous that di-methoxy-n-methyimorphinaa has addictlon Ilability equlvalent to that of morphiae, and for this reason, cannot be regarded os belag as safe as codelne for general use. We, therefore, have not carrled oyt Pert Flve of our original. experimental procedure which deals wlth direct former eddiction of/morphine addicts to the new drug. It was felt that the tIme would be better spent 1n screeniag & Aumber of other compouads In the hope of flnding a drug which gave promtse of belag more codetne-like thaa is dl-3-methoxy-n-methylmorphlnan. Work along these llaes Is aow going on wlth the dextrorotatory ad levorotatory Isomers of methoxy-dromoran and with some vilerates in the methadone series. The Isomers of 3-methoxy-. R-methyImorphinan are being studled because the dextrorotatory Isomer is sald to be an exczllent antitussive egent In dogs las judged by a newly developed technle) and probably will have very low addictioa liablllty. Later, It Is hoped that addiflonal derlvatives of dromoraa with substitueats other than methyl in posltlon Number 3 will be studled. The reason for Investigating these additlonal drugs in the dromoran serles is that the astivity of dromoran was alfered in the proper dlrection by methylatfon, but the addiction liabillty of the derivative was not reduced sufficiently for it to be redarded as being Innocuous as codelne.. Substitution of ethyl, propyi or other groups in position 3 might yleld a xam drug w3th sufficient reductlon in addiction Ilabillty.

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Declassified by 187475 date 4FEB 1977

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AMace th.caminder of the tineravallable under the current grant from the Derectmeni ci Deiense must be spent in \$creening, It is hoped that an addltional grant can be obtalned for continudt'ton of the work during the fiscal year l953. lf a promislng drug is revealed by the' screenlng.test, Intensive work with it wlll begin as soon as possible during fiscal year 1953. If so such drug Is fouad, screening should coatlaue. 111. EXPERIMENTAL PRCCEDURES

Drugs belag screcned wlll.be subjected to the followlng types of Investlgatlon:

A. Human Pharmacolooy and Toxicity. This involves the administratlon of progressively Increaslig doses of the drug under study to hujan volunteers, chlefly former morphiae addicts. i Observatlons on respiratory minute volume, pupillary size, blood pressure and pulse rate, etc., are:made following tãe administration of the drugs.

B. Administratlon to Human Volunteers of Single Doses of the Druas Being Screeaed for the Detection of Euphoria. This ezperlment Is. conducted in exactly the same way as the studles on humaa pharmacology, except that detalled observations on the physiological effects of the drug are not made, because taking of observations tends to negate the pleasurable effects of the drugs. Two methods are used for gauging the "euphorla" induced by the drugs. These are, l) unobtrustve clinical observatlons for the eppzarance of behevlor rzsembling that seen after the admtaistratlon of morphiae, and 2) the administration of projective psychologlcal tests.

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Under Study to tlents Showing Signs of Moderate to Marked Abstinence from Oplates. Aay drug which, on the basis of the screenlng test, appears to be promising as & potentisl substitute for codelne will be subjected to additional studies: i) substitutlon of the drug for morphlne In strongly addlcted persoas, followed by abruptwithdrawal of the new drug, 2) dlrect addlction of former morphine addict volunteers, under two conditlons, lal very hlgh-dose levels, such as would be expected In "natural" addiction under conditlons of abuse, Ibl condItlons of low-dosage, such as would be expected during long contiaued clinical admlnlstratlon of the drug.

D. Evaluatlon of Data. The drug we are seeking
should have the following characteristicst I) It should be
a weak analgesle, as judged by anlmal experimentatlon;
2) The ratlo'of toxielty to therapeutic effect should be
favorable In both animals and man; 3) lt should be a good
antitussive agent; 4) should relieve abstineace from morphlae
only partlaliy; 51 should not substitute for morphlne completeiy;
á) should laduce onlya mild grade of physical dependence In
directcaddictlan tesfs under conditleas of t gh dosage. Informatlon submitted to the Drug Addictlon Committee

by the pharmaceutical compenles and universitles wtll be sufficient to evaluate the actlons of the drug in animais.

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Studles on addiioa liebilitycwrtt nleld Iaformatlon on the toxlcologyr. phahacology and euphorlc potency of the drug ia man and -on Its abllity to produce and support physical dependence. From these data a satisfactory evaluatlon of fhe addictlon llablllty of the compound can be made.

E. Locatloa of the Project. The experiments described above will be carried out In the Addictlon Research Center, U. S. Public Health Service Hospltai, Lexington, Kentucky. This hospital Is devoted entirely to the treatment and study of drog addiction and is the only place Ia the warid where a study such as those deseribed above can be satisfactorily carrled out. The Institutiop provided the two necessary facilltles for -thls type of work: ll r large pool of patlent volonteers, 21 strict eavlronmental control whlch preyents the Iatroductlon of drugs other than those uader study into the situation.

F. Experimental Personnel. The work will be carrled out uader the directioa of Harrls Isbell, M.D., Director af the Addiction Research Center. Thls investigator has had

almost eight years experlence in nareotic drug addictlon and hasnanyputlicetions:i ieldHe wllr be asslsted by two other experienced Medical Offlcers, Dr. H. F. Fraser and

Dr. Abraham Wikler, both of whom have had extensive experience la research In addiction and have many publtcetions in thls fleld.

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SFCUO In additde to-the"medlcar pertonnel,the part-time services of.a Beochemlst and a Psychologist will he mada aveilable. Sub-professlonal personael Include 5 Psychiatric Aldes, a Medical Technician, Blological Alde, Securlty Aldę and Clerk-Stenographer.

A special ward for conducting these studies has already been set up aad Is In operation-

G. Estimate of Cost.

I'. Personnel

5 Bychiatrlc Aides GS-5
I Clerk-Stenographer GS-4
I. Securlty Alde CPC-S
-I Medtcal Techniclan GS-4
Blological Aide GS-5

2. Reserve for night differential and overtime pay, withinrgrsde ralses, efc

3. Mlscellaneous expenses

It should be noted that personnei cost for the flscal ye r l953 wlll be bigher due to the recent salary Increase granted goverament employees. Item for miscellaneous expenses lacludes money for the purchase of drugs, chemicals, glassware, electroencephatographicand photographic paper, etc

Harris Isbell, M.D. Direetor of Research

Hi:ra Attachments 2 4 January 1952

Declassified by137475 Bate 4 FEB 1977