Privileged & Confidential April 6, 1994 Attorney Work Produc t

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCPHILIP MORRIS RESEARCH ON NICOTINE

PHARMACOLOGY AND HUMAN SMOKING BEHAVIOR

1. IntroductioPhilip Morris has been interested since the 1960s in thebenefits of smoking andwhy people smoke. Consequently,PhilipMorris conductedandsponsoredresearchrelatedtothese areas. PhilipMorris apparently wantedtosupport itsviewthat smoking provided certain benefits to smokersPhilipMorris alsoconductedresearchtoattempt todetermnewhether smoke deliveries affected howpeople smokedcigarettesBeginning in about 1974 the research programs stated goalswere tolearnmore about why people smoke; to learn more abouthowpeople smoke; and to identify what people want to smokePhilip Morris has continued to investigate these areas. Arecently as 1988, PhilipMorris sponsored researchinvestigating the benefits of smoking and the historical usesof tobacco

II. Philip Morris Research: HumanSmoking BehaviorA . Why conducted

Dr . Wakehamina presentationtothe PhilipMorris Boardof Drectors on November 26 1969 indicated that therewere twoaims for the smoker psychology program. Thesewere "to learn more about the psychology of smoking,hopefully to discover ways to exploit the benefits ofsmoking to the advantage and profitability of our majorcompany business." (Dnn Dposition Exhibit 7(1000273741-3441PT inCpollone; p. 82, lines 6-11,16-21) [Simlar language foundat 1000046538-6546PTDr . Dunn indicated that his charter was to investigatewhy people smokedcigarettes. One of the hypotheses thatthey considered was that nicotine mght be a reinforcingagent. He also indicated that it was his job "to provideinformation knowedge about the consumer of the productwhich Philip Morris made, such that Philip Morris canmake a cigarette that would be more acceptable to thatsmoker andcause himtobuy PhilipMorris cigarettes overa competitor's cigarettes." (pp41, 75, 76-79; DunnDeposition in Cpollone

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCB . What Was Done, When Was It Done/Results

1. Compensation Studies, 1966 - 198Puff volume, puff duration, puff interval, lengthof rodsmokedwere measuredinresponse tovaryingtar andor nicoine levels. It was generallyconcluded that smokers try to maintain constantintake of tar and nicotine levelsAccording toD. Dunn, this was a hypothesis thatPhilip Morris investigated. He would not agreethat Philip Morris research concluded that peoplecompensate. In fact, other Philip Morris studieswere conducted in which they found that theseresults on maintenance for constant intake were notconfirmed. (See pp23-26; Dunn Deposition inCpollone )

2 . Eectrophysiological Sudies, 1969- 1983Currently EEGStudies Are Done A INBIFO(date?)Measured changes in brain activity in response tocigarette smoking in an effort to determne howandwhere nicotine affects CNS.Data indicatedthat cigarette smoking has specificrather thangeneralizedeffects onthe CNS. Theeffects appeared to depend upon the degree ofdeprivation, nicotine delivery, as well as thelocationof electrode placement.

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Present EEGstudies conductedby INBIFOfocus onassessingthe sensoral impact aspect of newproducts3 . Motivation/Quitting, 1964 - 198Goals were to measure psychological andphysiological events preceeding, during, andaftersmoking, particularly concernedwthmotivationssustaining the smoking habit. Concerned wthmarketing the ultimate cigarette

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCThe conclusions were that most smokers can beconsiderednicotine seekers, however, psychosocialandcultural factors are involved

4. Benefits/Smoker Psychology, 1962-198Studied relationships between anxiety, stress,attention performance, aggression mood change,etc. and smoking behavior. Concerned wth whypeople smoke to shed light on smoking rates, stylesandbrandchoices.Conclusions were mxed but generally indicate thatsmoker smokes more whenunder stress

5 . Human Smoker Simulation Studies, 1956 - 198Goal of this research was to determne whetheractual smoker intake of tar paralleledFTCvaluesResults indicated that standard smoke testconditions are not indicitive of howpeople smokeThis researchgeneratednopublicationsC . Connection Wth Addiction

Dr . Dunn authored a document which stated that thecigarette shouldnot be conceivedas a product but ratheras a package and that the real product was nicotineAccording to D. Dunn, [t]his was a hypotheticalpresentationthat I was proposing as a way of thinkingthat mght generate goodresearch." (p72 lines 4-9Dunn Deposition in Cipollone)Whenaskedwhy people smoke, D. Dunn stated: "I couldlist a half dozen motives that would be involved and Ihave no real feel for which is relatively more importantor less important of those motives. (p125, lines 11-19; Dnn Dposition in Cpollone) DDunn alsoacknowedged that tar and/or nicotine may be deleteriousto human beings. (pp102-103; Dunn Deposition inCpollone

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCD . PhilipMorris SponsoredResearch[Conductedby outsideinvestigators

From1972to 1981 Philip Morris supported research byDr. Gary Berntson, first at Rockefeller University andthen at Ohio State University. DBerntson studied theeffects of nicotine on aggression in cats and. laterexended his work to the effect of smoking on learningand stress behaviors in humansFrom1969 to 1972 Philip Morris supported research byDr. Ronald Hutchinson at the Foundation for BehavioralResearch concerning aggressionandsmoking inhumans andinmonkeys. Apart of this research was subsequentlyfundedby CTRgrantsIn 1972 Philip Morris provided funds for research byAlan S . Meyer, Lucy N . FriedmanandPaul F. Lazarsfeld atColumbia University. The purpose of the study was todetermne responses of a sampling of Americans to thecontinuing anti-smoking campaignFrom1974through1976 PhilipMorris fundedresearchbyDr. Robert Waldbillig at Rockefeller University; thisresearch concerned the effect of nicotine on shock-induced aggression and predatory behavior in rats.From1972through1975, PhilipMorris contributedfundingfor support of research by D. Stanley Schachter andseveral of his graduate students at Columbia UniversityHs researchconcernedthe behavior of humansmokers andthe factors that affected it, including nicotineDuring 1976 PhilipMorris providedfunds for researchbyDr . LynnKozlowski at WesleyanUniversity. This researchcontinued some of his studies done under the direction ofDr. Stanley Schachter and also funded in part by PhilipMorris. The studies concerned the effects of variousfactors oncigarette smoking andhumansmokers.

E. Publications [See Appendix Afor compete list][HELPFUL]The research conducted or sponsored by Philip Morrisconcerning smoking behavior and related topics was notsecret. A least seven publications resulted fromresearch conducted by Philip Morris scientists. I

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCaddition at least eighteenpublishedpapers or abstractsresulted fromresearch funded at least in part, byPhilipMorris. PhilipMorriss support was acknowedgedinmany of these publications.Further, D. WlliamL. Dunn a psychologist whoworkedfor Philip Morris for many years, organized and chaireda conference on smoking behavior in 1971. Scientistsinterested in this field fromthe United States andabroad attended this conference and presented someresults of their own research, whether supported byPhilip Morris or not. The proceedings of this conferencewere published as a book in 1973, and scientists activein the field of smoking behavior have often cited papersin this book. Dr. Jerome Jaffe, plaintiff's "addiction"wtness in the Cpollone case, testified at trial that hewas well aware of the conference proceedings, edited byDr . Dunn .

F. Dscontinued ResearchDr . Dunn testified in his deposition in Cpollone thatparts of his programwere discontinued in 1982or 1983He did no specifically idenify which parts. Heindicated that all the people who were working wth himwere reassigned to other functions. He indicated that hehadnoidea why they hadmade reassignments: "I dontknow. Imnot privy to the decisions, the causes for thedecisions that come back onthe program." (pp125-126DunnDepositioninCpollone

III. Philip Morris Research: PharmacologyA. Why Conducted

In1977 the goal of the Comparative Psychology Programwas to conduct research on the premse that if humansmoking behavior was a function of the pharmacologicaleffects of smoke component(s) of smoke, then themechanismsupporting the behavior could be studiedthrough the observation of the effects of smoke on thebehavior of animals. This programwas headed by VctorJ DeNoble .Specifically, the goals of DeNobles programwere108713885


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April 6 1991 .

PRIVILEGED & CONFIDENTIALATTORNEY WORK PRODUCT

todevelopa better understanding of thereinforcing actions of nicotine andnicotineanalogs .

2 . to gain insight into the neurobehavioralactions of nicotine3 . to develop and use animal behavioral techniquesto screen nicotine analogues for their nicotineeliciting properties. [1003060646-0655 P4 . to developemprical evidence that woulddifferentiate nicotine fromthe classical abusesubstances. [1000085385-5392PIn addition, he was to expand an exsting programinnicotine research, nicotine analog research and tocontinue toexpandthat programintosmoke components andother effects that nicotine may have on the centralnervous system." (p15, lines 23-25; p. 16, lines 1-2DeNoble DepositioninRothgebThe primary objective being: to identify uniquepharmacological actions of nicotine as manifested inlower-ordered mammalian behavior. (p23; DeNobleDeposition in Rothgeb1. Ncotine Analog Program- CAVEAT[This programcould play into advocates position re: recognitionby Philip Morris of importance of nicotine and itsdrug-like effects )

The major objective of the animal behavior studieswas to developbehavioral tests which weresensitive to the effects of nicotine and whichcould be used to screen nicoine analogs forcentral nervous systemactivities. Amajor goalwas to develop nicotine analogs which would have"desirable" effects on the central nervous systemwithout the "undesirable" effects of nicotine onthe peripheral nervous system. Studies conductedby DNble included the use of specificexperimental protocols to determne whether theanimals would differentiate between nicotine andthe nicotine analogs108713886


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCAccording to DeNoble, the original purpose of theprogramwas toevaluate nicotine analogues. "Theseare chemcal modifications of the nicotinestructure. The goal of the programwas to identifya nicotine analogue that possessed the centralnervous systemactivities, that is would go to thebrain and have an effect on the brain and yet nothave an effect on the peripheral system thecardiovascular system specifically. (p24 lines4-22; DeNoble Deposition in Rothgeb) [See also1003289027-9035 P ]

2. More "Desirable" Product - CAVEAT[Note: Thesereasons could play into advocates position thatPhilip Morris recognized the importance of nicotineCNS effects andusedthese toget people tosmoke.]James Charles, in a March 18 1980 memorandumstated that nicotine was a "powerfulpharmacological agent" and had been cited as "areason for smoking." He said that for thesereasons, the nicotine analog programcould lead to"many opportunities for acquiring proprietarycompounds whichcanserve as a firmfoundationfornewand innovative products in the fuure."[1003289974-9975 ]"The potential was possibly making a safer, morerewarding cigarette. (p69, lines 2-25; p70,lines 1-2; DeNoble DepositioninRothgebW discussed the potential gains, that is, tounderstandcigarette smoking froma pharmacologicalpoint of view the advantage of once we understoodthat to enhance the process, to make a betterproduct. (p80, lines 2-25; p. 81, lines 1-16,DeNoble DepositioninRothqeb

B . What was done, whenIt Was Done/ResultsAccording to Dr. DeNoble, they establishedthe model inwhich animals would intravenously self-admnisternicotine. They expanded upon nicotine self-admnistrationby looking at agonists andantagonists,compounds toblock the effect. They evaluated theeffects of chronic admnistrationof acetaldehyde andnicotine to determne whether or not there was a

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physiological dependence. They evaluated supersensitivity; changes inbrainreceptors followng chronicadmnistration of nicotine. They investigated theeffects of different brain sites on the nicotine-inducedprostration syndrome to get an idea of hownicotine wasacting and where it was acting in the brain. They lookedat carbon 14labeled acetaldehyde to determne where itwent in the brain of animals. (See pp28-29 36-37DeNoble DepositioninRothgeb1. CNS Studies, 1971-198Sites of action and magnitude of nicotine,acetaldehyde, andnicotine analogue effects wereevaluatedinorder tounderstandhowandwherenicotines beneficial effects occur inthe CNS.

PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC

2 . Analogues, 1969-198Goals were todevelopnicotine analogues wththedesireable CNS effects of nicotine wthout theundesireable PNS effects. No conclusive resultsare present inthe researchdocuments

3. Reinforcement/Self-admnistration Studies

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a. Ncotine, 197The goal was to showthat nicotine functionsas a positive reinforcer. Ncotine was shownto be a weak reinforcing agent.Since nicotines effects were successfullyblocked wth a centrally acting nicotineantagonist (andnot wtha peripherally actingantagonist), it was determnedthat nicotinesreinforcing effects are centrally mediatedDeNobles researchfoundthat some animalspreferredfoodtoreinforcement wthnicotine(p. 131 ; DeNoble Deposition in Rothgeb )Note that: Dunn indicated that there wereother findings not supportive of thehypothesis that nicotine was a positivereinforcer. (p93; Dunn Deposition inCpollone)

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCb. Acetaldehyde, 198

The goal was to better understand possiblereinforcingeffects of acetaldehydeAcetaldehyde was shown to be a positivereinforcerThey were interested in acetaldehyde becauseof its large concentration within cigarettesmoke. (p34; DeNoble DepositioninRothaeb)DeNoble reported the following effect ofacetaldehyde in the animal: "Dopamne is aneurotransmtter in the brain whoseresponsibility is to mediate reward. It letsthe organismknowwhen things are good andwhen things are bad." It was DNblesexperience wthacetaldehyde that it condensedinthe braintoformDopamne-like compoundsandmade the animal somewhat "euphoric." (p66 lines 1-7; DeNoble DepositioninRothgeb

c. Ncotine/Acetaldehyde, 1982[CAVEAT: Thisresearch has never been published. There isnothingin the literature regardingthesynergistic effects of nicotine andacetaldehyde. In addition, see descripionbelowre: Frank Ryan data on predictingsales ]Uponlearning that acetaldehyde functions as apositive reinforcer, they endeavoredtostudythe combined effects of nicotine andacetaldehyde onself-admnistration. Resultsindicated that reinforcing effects of theseagents are additiveResearchdone by Frank Ryanindicatedthatacetaldehyde andnicotine data couldbe usedtopredict cigarette sales at a 96%accuracyAccording toDeNoble, the hypothesis that theywere working under at the time was basedonthe data fromthe animals. They hypothesizedthat they could predict the best sellingcigarette by looking at the concentrationnotof nicotine alone, but by looking at thecombination of nicotine and acetaldehyde108713889


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PRVLEGED&CONFDENTALApl 6 1994ATTORNEYWORKPRODUC

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Frank Ryan ran a programand was able topredict blindly which cigarettes would sellandwhichwouldnt basedonthe combinationofnicotine and acetaldehyde delivery. They wereable to predict sales of 96 percent accuracybased upon the ratios of nicotine andacetaldehyde. They were further able topredict the best selling cigarettes as havingthe higher combination ratio of each one(pp. 56-60; DeNoble DepositioninRothgeb)[1003582081/2082]Nte that DNble claim effect wassynergistic. However, majority of documentsall claimeffect was additive. DNbleindicated that they evaluated the effects ofnicotine and acetaldehyde and found themtoact synergistically together. They found thatthe combination of nicotine and acetaldehydeto be much more reinforcing than either onecompoundalone.(pp37-39DeNobleDepositioninRothgebDeNoble testified that Philip Morris couldadjust the levels of nicotine and acetaldehydein a given cigarette. However, to hisknowedge this was not something that wasdone. (p72 lines 3-21; DeNoble DepositioninRothgeb

d. Tolerance/Wthdrawal Studies, 1979-1983Tolerance to the effects of nicotine was shownto develop probably due to behavioraladaptation. Nte that tolerance in thiscontex is not the same concept whichappearedin, among other places, the 1964 and 1988SurgeonGenerals ReportsDeNoble found that nicotine does produce atolerance, behavioral tolerance as well as ametabolic tolerance. He found that there isno behavioral super sensitivity followingchronic admnistration of nicotine; that is,that the brain didnt up regulate the numberof receptors. (pp37-39; DeNoble DepositioninRothgeb)

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCBehavioral factors appear to be predomnantlyresponsible for tolerance to nicotineDeNoble indicated that there was a mnormetabolic component to tolerance."Bupredomnanly in our animals the majorcontributing factor was a learned tolerance."(p. 137; DeNoble DepositioninRothgebDeNoble concludedthat termnationof chronicnicotine admnistration did not produce aphysical dependence. Termnation did notresult in wthdrawal symptoms. Rsearchshowng that blocking nicotine central nervoussystemactions followng chronic treatmentdoes not result in a disruption of scheduled-controlledperformance. This indicates thatthere is no withdrawal effects to nicotineit also indicates that there is nophysiological dependence to nicotine

C . Connection Wth AddictionDeNoble believed that "cigarette smoking didnt fit thecriteria that was being set forth for addiction. Whetherthat criteria is accurate isnt the question. I dontbelieve that it is a correct statement to say thatnicotine is addicting. I dont believe that; no." (p173, lines 21-25; p. 174 line 1; DeNoble DepositioninRothgeb)DeNoble agrees that there is a difference betweenphysiological dependence andpsychological dependenceHe believes there is a psychological dependence tocigarette smoking. "You canbe psychologically dependentto many substances as well as many things. You can bepsychologically dependent on running, for example. Youcan [be] psychologically dependent on saccharin whichdoesnt produce a physical dependence, nor does cocaineThe degree to which cocaine produces a physiologicaldependence is exremely mnor." DeNoble believes that apersoncanbe addictedtococaine eventhoughthere is nophysiological dependence. (p176, lines 9-25; p. 177lines 1-18; DeNoble DepositioninRothgeb1087138811


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC1. Ncotin

a. As a Positive Reinforcer

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Athough nicotine is self-admnistered, itdoes not produce disruptions in on-goingbehavior, nor does a physical dependenceresult.DeNoble indicated that "many people equatephysiological dependence wth addiction. Andthat's not necessarily true. You dont, justbecause you are physiologically dependentdoesnt mean you are addicted. Conversely,just because you are physiologically dependentdoesnt mean that you are addicted either. Sophysical dependence is a pharmacologicalprinciple that is independent of addiction perse." (See pp132-134 164 170; DeNobleDeposition in Rot~b"We believe that primarily the disturbancesthat you see ina humanare not baseduponaphysiological dependence but more one of apsychological dependence. (p170; DeNobleDeposition in Rothgeb)Many chemcal compounds andphysical stimuliincluding water, saccharin food heat, etc.,can be self-admnistered and are thereforereinforcers. Addictive chemcals are self-admnistered but because self-admnistrationmerely defines reinforcing qualities, thereare other criteria which establish thedefinition of addiction. In DNblesopinion addictive drugs produce disruptionsin ongoingbehavior when they are self-admnistered. Upon termnation of drugaccess, there is a disrupion in ongoingbehavioral patterns. Adictive drugs arepreferred to more conventional reinforcers,for example, food, water, heat, saccharin,etc.(pp100-101; DeNoble Deposition inRothgeb)DeNoble indicated that removal of otherpositive reinforcers such as money, water,

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCfood, sex, can produce physiologicaldisturbances. The behavioral changes thataccompany the cessation of smoking are notdifferen fromthat observed when oherreinforcers such as food water, sex money,heat, light, sugar are withheld. (See pp105-107; DeNoble DepositioninRothgebDeNoble agreed that 1) self-admnistrationtechniques establish reinforcing properties ofa stimulus not its dependence producingcapabilities; 2) animals wll self-admnisternicotine, however it does not appear to be aparticularly powerful reinforcer compared toother drugs; 3) nicotine self-admnistrationcannot be viewedas a formof drug abuse or asan addiction because there is strong evidencethat nicotine does not fit the accepedcriteria for drug dependence; 4 theres noevidence that smokingresults in anoverwhelmng involvement wththe use of smokesuch that it interferes with normal socialactivities. (pp110-111; DeNoble DepositioninRothgeb; and also pp. 114-121 for simlarstatements by DeNoble

b. WthdrawalTrmnation of nicoine access does noproduce a wthdrawal syndrome

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C . ToleranceDeNoble contendedthat tolerance canandoftendoes develop to many stimuli (such as light,noise, temperature, etc.) Therefore, tolerancealone is no a definingcharacteristic ofaddiction[10030606670668PAccording to DeNoble, development of atolerance to nicotine is a two-componentprocess: the major component involves thebehavior adaptationof the organism the mnorcomponent may involve traditionalpharmacological mechanics. DeNoble believesthat animals and people can becomebehaviorally adapted to many chemcals

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCincluding saccharinandcaffeine. (p165DeNoble Deposition in Rothgeb)

d. ConclusionNcotine is a reinforcer in a classof"nonaddictive" chemcal compounds such assaccharin or water. [1003060621] (See pp101-104; specifically p. 103, lines 15-25 andp. 104 lines 13DeNoble Deposition inRothgeb)2 . Acetaldehyde

Acetaldehyde was foundtobe a positive reinforcerwthout wthdrawal effects.3. Ncotine/acetaldehyde [CAVEAT: This research hasnever been published. There is nothingin theliterature regardingthe synergistic effects ofnicotine and acetaldehyde. DeNoble believed thatadditional research on nicotine/acetaldehydesynergismmay have shown that cigarettes were infact addictive. See belowfor DeNoble depositionexcerpts ]

DeNoble position regarding addiction: "I thinkthat we have been discussingis the role ofnicotine, and whether nicotine is addicting, and wehave to realize that there are thousands of thingsin cigarette smoke. One of themis acetaldehydeAd I think when you combine nicoine andacetaldehyde you are talking about a very differentcombination. Talkingabout somethingthatsprobably muchmore dangerous thaneither one aloneSo that has led me to believe that its verypossible that there are things that could lead toaddiction; yes." (emphasis added) (p. 144, lines20-25; p145, lines 17; DeNoble Deposition inRo hgeb) I wll go on record as sayingacombination of nicotine and acetaldehyde, thereinforcingproperties of that substance, thatcombination are very, very powerful." (p145,lines 12-14 17-22; DeNoble DepositioninRothgeb)DeNoble: "I think by and large fromthe previoustestimony they made nicotine in and of itself as

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April 6 1994 PRIVILEGED & CONFIDENTIALATTORNEY WORK PRODUCTprobably not a very dangerous substance andacetaldehyde has a little more of a liability toit. But if you put the two together, you aretalking about something thats synergistic and thatwas something that we have never experiencedbeforeand we never observed before. It was a ratherunique andunprecedentedfinding. We never reallygot to the end of it. So I cant tell you what itmeans for addiction. But if you put the twotogether, it is clearly much more reinforcing thaneither one alone. Ad that makes me verysuspicious that combination as well as other thingscould have potential for danger." (p159, lines3-7 22-25; p. 160, lines 1-10; DeNoble DepositioninRothgeba. Rsult

Experiments conductedwthacetaldehyde werevery simlar to those that were done withnicotine. As with nicotine, they found nowthdrawal symptoms whenusing acetaldehydeTermnation of chronic exposure tocombinations of nicotine and acetaldehyde didnot result in a wthdrawal symptom. He gaverats chronic admnistration of nicotine andacetaldehyde and never found physiologicaldependence. (pp135-136; DeNoble DepositioninRothgebResearch comparing the results of nicotinealone versus acetaldehyde alone versus severalcombinations of each. They foundthat if youcombine nicotine and acetaldehyde, you can getself-admnistrationrates, that is, the animalwll work 500-600percent more thaneithercompound alone. (p154 ; DeNoble Depositionin Rothgeb)

b. ConclusionDeNoble statedthat the followng conclusionswere reachedregarding researchonthe effectsof nicotine andacetaldehyde onthe centralnervous system: "Primarily that nicotine andacetaldehyde were probably acting throughdifferent biogenetic systems. They act o1087138815


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCdifferent brain systems but, nevertheless,they interacted. Ncoine primarily in themuscriaric (sp?) nicotinic side of the brainand acetaldehyde probably -- most probablythrough condensation reactions wth a knownneurotransmtter, Dopamne, in the brain."(p. 64 lines 18-25; p. 65, line 1DeNobleDepositioninRothaebNcotine and acetaldehyde function as positivereinforcers in rats. Combinations of nicotineand acetaldehyde are more reinforcing thaneither compoundpresentedalone. The opiatereward systemdid not appear to mediate thereinforcingeffects of nicotine oracetaldehyde. Since structurally acetaldehydeand nicotine have the potential to interactwth the opiate system they did prelimnarywork whichinvolvedblocking the opiate rewardsystemwthmaloxone andit failedtohave anyeffect. This initial result suggested that atleast blocking one kind of opiate receptor,the newreceptor, would not effect nicotine oracetaldehyde. They needed to do other workwith other receptors to exclusively rule itout. Experimentation indicated that nicotineand acetaldehyde did not effect these opiatesystems. Ncotine and acetaldehydeinteracting alone were a reinforcer. Togetherthey can act as a reinforcer. Specifically,they synergize to act as a reinforcerChronic studies usingnicotine andacetaldehyde indicated that if you took itaway there was nowthdrawal. (pp166-168170-171 and 173; DeNoble Deposition inRothgeb)

D . Why Was Research Stopped1. Sensitivity [CAVEAT: Sgnificance is self-evident. ]

According toDeNoble, "we were the only tobaccocompany that I knewof, or that anybody else knewof, doing work wth whole animals, live, wholeanimals, andbecause of the nature of the researchthat is, looking at self-admnistration looking at1087138816


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCthe effects of nicotine on the brain function, theresearch was held restricted to upper managementuse only." (p48 lines 17-23; DeNoble DepositioninRothaebDeNoble discussed the effect of his research on thecompany wthD. Charles, D. Osdene, D. Pages,Mr . MDow MxHausermann M. Pollock and JimRemington. "The potential was possibly making asafer, more rewarding cigarette. The downside wasthat we were doing whole animal research whichlooked to themlike we were doing Federal DugAdmnistration research." (p69, lines 2-25; p70, lines 1-2; DeNoble DepositioninRothaebDeNoble understood that the research he was doingcould undermne the public posture Philip Morriswas taking wth outsiders. (p149DeNoble discussedwthJimCharles andTomOsdenethe potential damage to the company of continuinganimal research. He indicated this was alsodiscussed with Dr. Abood D. Wolf and withMr . McDow. In fact a meeting was held wth AboodWolf, DeNoble andMcDowtodiscuss why they shouldcontinue the researchandwhat impact it may or maynot have on Philip Morris. (p80, lines 2-12DeNoble DepositioninRothgebDeNoble stated: "In discussions wth management atPhilip Morris, specifically D. Charles, BobPagesand D. [Osdene], Max[Hausermann], the VcePresident, we discussed the potential gains, thatis, to understand cigarette smokingfromapharmacological point of view the advantage ofonce we understood that to enhance the process, tomake a better product. The downside of the wholeaspect is we were doing whole animal research. Wewere the only ones in the field doing that. Andwewere discovering things that could be viewed aspotentially dangerous froma biomedical point ofview . . we were developing nicotines effects ina way in which the compound was viewed as areinforcer, in the same way other substances areviewed as reinforcers, not only food and water andsexbut also perhaps drugs. Andwe were using FD1087138817


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCapprovedmethods at the time." (p80, lines 2-25p. 81, lines 1-16

2 . Laboratory Shutdown [CAVEAT: Sgnificance isself-evident. ]DeNoble, "We were offered an exit contract,termnation, which consisted of a salary forseveral months and our job during that time ofemployment was tofindanother job . Our labwas termnated on April 5th at 3 oclock in theafternoon. We were called -- I was called into JimCharles office. Present was Max[Hausermann], theVce President of Research. They proceeded to tellme what a wonderful job the laboratory was doing,and then proceeded to say that we no longer didthis research and that we had an option to leavethe company, immediately wtha cashsettlement, tostay wth the company at a severely reducedemployment rate, as well as a reduction in grade,or we could opt to find another job while employedat Philip Morris, but our actual physical beingswould be moved out of the research area into aprivate office." DNble stated that he wasallowed back into the laboratory the followng dayon Friday, April 6 and was brought back anothertime in the preceding weeks to open up a safe inthe lab. He was no permtted to go ino thelaboratory after those two occasions. He was notallowed to remove results of his tests, personalnotebooks, data which he indicated would havesupported the conclusions his research had reached(p. 67, lines 10-25; p68, lines 125; DeNobleDeposition in Cpollone"The official line given to us was that ourresearch efforts were no longer compatible wth thegoals of the Research Center. And for that reasonour laboratory was termnatedinone day." DeNobleindicates that up until the day of the termnationno one had indicated to himthat his research wasnot in the best interest of the company. (p70,lines 12-16; DeNoble DepositioninRothgeb

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCE. Publication Issues [HELPFUL

DeNoble statedthat he was allowedtopublishsome of hisresearch projects. He indicated that he believed he hadpublished two papers resulting fromPhilip Morrisresearch. (p73, lines 11-17; DeNoble Deposition inRothaeb)1. What DeNoble Has Published

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DeNoble has published two full papers and fiveabstracts reporting on research he and his co-workers conducted at Philip Morris. One paper andits correspondingabstract of a meetingpresentation were published while DeNoble wasemployed by Philip Morris. The rest were allpublished in 1986 after DNble left PhilipMorris. [See AppendixBfor complete list andcopies of publications ]DeNoble indicated that he sought publication of anarticle he had previously published in abstractformin the 1983Society for NuroscienceHowever, Philip Morris had told himthat this wasproprietary and he could not publish thisinformation. DNble did no abide by PhilipMorris instructions and published the research infull inPsychopharmacoloay in1983 or 1984. Aterthis was published, he received a call indicatingthat permssion had not been granted and he shouldnot do anything like that in the future. (pp81-8 4In1986 DeNoble andMele submttedanabstract tothe Federation of Experimental Bologists.Theabstract was submtted and published. When PhilipMorris learned of this, they remnded himof theagreement whichhe hadsignedrequiring himtokeephis information confidential. DeNoble reportedthat he called Tussigand expained that theinformation he was publishing could in no way hurtPhilipMorris because it was basic scienceresearch. However, DeNoble was told that anyfurther breach of his contract would result inlegal action against him. (pp85-86; DeNobleDepositioninRothgeb)19C


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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCAmerican Psychological Association Convention inSeptember of 1986. DeNoble reported that FrankRyan was there to inerviewhimand to takepictures of his presentation. Frank Ryan admttedto DeNoble that he was there at the request ofPhilip Morris to find out what DeNoble was doingDeNoble was contacted by Taussig concerning theDeNoble andMele presentations made at the AmericanPsychological AssociationConvention. According toDeNoble, "I spoke wth M. Taussigafter thisletter and assured himafter discussing wth himthe potential damage that could occur or potentialproblem that could occur wth divulginginformation and assured himthat that would nothappen in the fuure."(pp87-90; DeNobleDepositioninRothgeb

2 . ConclusionsNone of DeNobles publications contains anystatement about nicotine dependence or addictionThe reported research certainly suggests, however,that the effects of nicotine on the behavior ofrats are mediated in the central nervous systemIn fact, in one publication DeNoble reports thatspecific brain sites have been located for theaction of nicotineDeNoble also reports that his results showthatrats may developa behavioral tolerance tonicotine. O the other hand, Henningfieldsapparent interpretation, in a 1984 reviewarticle,of one of DeNobles abstracts, is that it showsthat there is no wthdrawal syndrome aftercessation of nicotine admnistration

3 . So-called "Suppressed" ManuscriptsHe statedspecifically that he was not allowedtopublish the research regarding the effects ofnicotine andacetaldehyde. (p73, lines 19-23DeNoble Deposition in Rothgeb)According to DeNoble, he has never revealed thefindings of his research concerning the combinedeffect of nicotine and acetaldehyde in cigarettes.(pp. 90-91; DeNoble DepositioninCpollone

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCa. "Positive Reinforcer"

Achronology of events concerning DeNoblesmanuscript is giveninAppendixC. In brief,the manuscript was approvedby the ManuscriptReviewBoard for publication in Science,although DeNoble had originally indicated hepanned to publish it in Nture.Themanuscript was also approved for publicationby the Philip Morris Legal Department inJanuary 1983, at whichtime DeNoble apparentlysubmtted it for publication inPsychopharmacology. Subsequently, after aletter fromShook, Hardy to the Philip MorrisLegal Department anddiscussions betweenAexHoltzmanandJimCharles, DeNoble wrote totheeditor of Psychopharmacology, Herbert Barry,withdrawing his manuscript due to factorsbeyond his control.DeNoble, et al. (unpublished manuscript wassubmttedtoPsychopharmacoloay) [See AppendixD reported that rats could learn howtoperforma simple task (pressing a lever) whenthey were rewarded by a small amount ofinjected nicotine. This suggests thatnicotine mght be mldly pleasurable to ratsunder certain laboratory conditions. Thesedata do not imply that nicotine is addictive[VERYHELPFUL The manuscript only providedprelimnary data on a small number of rats. Atotal of only 10 rats were used; some datawere based on only three rats.The study was generally well-designed butbecause of its small size, even if publishedwouldhave beena mnor contributiontotheliteratureThe results reported by DeNoble, et al.challenge the addiction hypothesis ofnicotine

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC(a) The data indicate only weakreinforcement, which is notcomparable to otherpharmacologic drugs .(b) The data did not provide anyindication of physiologicaldependence on nicotine .

Several nicotine self-admnistrationstudieswere appearing in the public literature atabout the same time as DeNobles research(a) DeNobles manuscript does notreport any action of nicotinenot previously reported(b) The 1988Surgeon GeneralsReport considers the questionof nicotine reinforcement tohave been"showedconclusively"in 1981 based on governmentsupportedresearch

The DeNoble, et al. manuscript was not secret.Athough unpublished it was cited in 1984byJack Henningfield in a major reviewof theliterature. Henningfields review in turn,was cited in the 1988 Surgeon GeneralsReport.b. "Mecamylamne"" (Central Nervous SystemNcotine Antagonist

There was no manuscript wth the title read byKessler and Waxman, purportedly the 1986manuscript that DeNoble withdrewfrompublication. There were research reports byDeNoble that discussed this research. [SeeAppendix E.] It appears that a abstract ofpart of this research was published inNovember 1986. DeNobles wthdrawal of thismanuscrip frompublication apparenlyoccurred after he had received a letter fromEric Taussig (PhilipMorris Legal Department),sen after DNble had presened yet adifferen paper based on his research at1087138822


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PhilipMorris. M. Taussig reminded DeNobleof the agreement he had signed wth PhilipMorris not todisclose any researchwthoutthe companys permssion. MTaussigapparently didnot specifically tell DeNoblehe couldnot publishthe mecamylamne paper,but DeNoble subsequently told himit would notbe publishedPhilip Morris has not seen the manuscriptreferred to by D. Kessler. It is apparenlybased on a small amount of prelimnary datainvolving an attempt to demonstrate that ifrats find nicoine mldly rewarding it isbecause of some pleasurable effect of nicotinein the brainDNbles data on mecamylamne andreinforcement were only exploratory. WileDeNoble was employedby PhilipMorris, thesedata had never been written up for potentialpublication, much less submtted to thecompany for consideration for poenialpublicationTo the exent that any research by DeNoble onmecamylamne had been prepared forpublication, it was, in fact, publishedThere are tworeports onmecamylamne basedonPhilip Morris research, both of which makeclaims simlar to the manuscript referred toby Dr . Kessler, at least insofar as both claimcentral nervous systemeffects of nicotineUe of nicotine blockers, such asmecamylamne, to evaluate reported centralnervous systemeffects of nicotine, has beenreported for decades, certainly as early as1973 in humans . Numerous studies beginning inthe late 1970s and early 1980s involvinganimals are reported in the literature, andthese are reviewed by the 1988 SurgeonGenerals Report.Mcamylamne is a highly imperfect substanceas a tool to identify central nervous systemeffects of nicotine. It has a wde variety of

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PRIVILEGED & CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCphysiological effects. These effects includeblocking peripheral sensations fromnicotine,which may be important to its actions as areward.In general, whether any reinforcing capacityof nicotine in a laboratory rat can be blockedby mecamylamne does not bear strongly ontheaddiction issue

F. Admssion[CAVEAT: Significance is self-evident]DeNoble was asked if any executive of Philip Morrisexpressed to himwhether or not smoking was addictingAccording to DeNoble, JimRemngton told DeNoble andDr . Mele that cigarette smoking was probably addicting."Mr. Remngton visited our laboratory with D. JimCharles, myself, and Paul Mele to discuss the concept ofaddiction and what we were doing wth our rats. And inthe conversation we were relating to M. Remngtonthatnicotine in and of itself we didnt believe produced aphysical dependence. It was a weak reinforcer. A thatpoint we were both surprised to hear M. Remngtonsaythat as far as he knewthat was not true, and he was --as far as he knew nicotine was addicting, and cigarettesmoke was addicting." (pp144 171-172; DeNobleDepositioninRothaeb

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APPENDI X A


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Aprl 6 1994PRVLEGEDANDCONFDENTALATTORNEY WORK PRODUCTPUBLICATIONS OF RESEARCH ON SMOKING BEHAVIORCONDUCTED OR SPONSORED BY PHILIP MORRIS

Conductedby PhilipMorris1. Dunn WL "Experimental Methods andConceptual Models asAppliedtothe Study of MotivationinCgarette Smoking," In:Smoking Behavior: Motives andIncentives, 93-111(1973) .2.Jchori TR ; "3 .

,Performance,"(1974) .Ryan FJ,Study," In(1975) .

ones, Bw Smoking and Multiple-TaskVrginia Journal of Science, Z3): 147-151"Cold Turkey in Greenfield, Iowa: AFollow-UpSmoking Behavior: Motives and Incentives, 231-241

4. Schori, TR; Jones, BW "Smoking and Work Load" Journal ofMotor Behavior, 7(2): 113-120(1975).5. Schori, TR; Jones, BW "The Effect of Smoking onRsk-Takingin a Simulated Passing Task," Human Factors, 19(l): 37-45(1977) .6. Dunn, WL "Smoking: What Reinforces the Habit?" KargerGazette, 36. 1-2(1978) .7 . Dunn, WL "Smoking as a Possible Inhibitor of Arousal," IntWorkshopBehav Effects of Ncotine, 18-25 (1978) .Sponsoredby PhilipMorris1 . Emey, GS; Hunter, NA; Hutchinson RR "Selective Actions ofMorphine, Chlorpromazine, Chlordiazepoxde, Ncotine, andDAmphetamne on Shock-Produced Aggressive and Oher MotorResponses inthe Squirrel Monkey," FederationProceedings, L0:390(1971) .2. Hutchinson, RR; Emey, GS, "Effects of Ncotine onAvoidance,ConditionedSuppressionandAggressionResponse Measures inAnimals and Man," In: Smoking Behavior: Moives andIncentives, 171-196 (1973) .

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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC3 .Myer, ASFriedman, LN; Lazarsfeld, PF, "MotivationalConflicts Engendered by the On-Going Dscussion of CgaretteSmoking," In: Smoking Behavior: Motives and Incentives,243-254(1973) .4 . Lazarsfeld PF, "The Social Sciences and the Smoking Problem"In: Smoking Behavior: Motives andIncentives, 283-286(1973) .5. Kozlowski, LT; Harford, MR "On the Significance of NeverUing a Dug: AnExample fromCgarette Smoking," J. AbnormalPsychology, 85(4): 433-434(1976) .6 . Kozlowski, LT "Effects of Caffeine Consumption on NcotineConsumption" Psychopharmacology, 47: 165-168(1976) .7 . Berntson, GG; Beattie, MS; Walker, JM "Effects of Ncotineand Nuscarinic Compounds on Bting Atack in the Cat,"Pharmacology Bochemstry, andBehavior, 5: 235-239(1976) .8 . Berntson, GG; Sahley, T "Some Effects of Ncotine on PainSensitivity in the Rat," Bulletin of the PsychoneurologicalSociety, 10: 246(1977) .9 . Hutchinson, RR; Pierce, GE; Emey, GS; Proni, TJ; Sauer, RA"The Laboratory Measurement of HumanAnger," BobehavioralReviews, 1(4) : 241-259(1977) .10. Schachter, 8; Slverstein, BKozlowski, LT; Perlick, DHerman, CP; Lebling B "Sudies of the Interaction ofPsycbnlogical andPharmacological Determnants of Smoking,"Jour1 of Experimental Psychology: General, 104(1): 3-4

(19777Y .11. Schachter, 8, "Ncoine Rgulation in Heavy and LghtSmokers," Journal of Experimental Psychology: General, 104(l) :5-12(1977).12. Scharher, 8; Kozlowski, LT; Slverstein, B "Efects ofUirrry pHon Cgarette Smoking," Journal of Experimental

psycYolocgy: General, 104(l): 13-19(1977) .13. SJstein, BKozlowski, LT; Schachter, S, "Social Lfe,Ccmette Smoking, and Uinary pH" Journal of ExperimentalPsychology: General, 104(1): 20-23 (1977) .10871229


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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC14. Schachter, S Slverstein, BKozlowski, LT; Herman PCLebling, B "Effects of Stress on Cgarette Smoking andUinary pH" Journal of Experimental Psychology: General,104(l): 24-30(1977) .15. Schachter, S; Silverstein, B; Perlick, D "Psychological andPharmacological Explanations of Smoking Under Stress," Journalof Experimental Psychology: General, 104(1): 31-40(1977) .16. Kozlowski, LT; Keiman RM "Effects of Oal pHon CgaretteSmoking," Pharmacology Bochemstry &Behavior, 9(4): 477-480(1978) .17. Sahley, TL; Berntson GG "Antinociceptive Effects of Centraland Systemc Amnistrations of Ncoine in the Rt,"Psychopharmacoloay, 65: 279-283 (1979).18. Waldbillig, RJ, "Suppressive Effects of Intraperitoneal andIntraventricular Injections of Ncotine on Muricide and Shock-InducedAtack onConspecifics," Pharmacology, Bochemstry,andBehavior, 12: 619-632(1980) :

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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCTPUBLICATIONS OF RESEARCH ON SMOKING BEHAVIOR

CONDUCTED OR SPONSORED BY PHILIP MORRI S

Conducted by Philip Morris1. Dunn WL "Experimental Methods and Conceptual Models asApplied to the Study of Motivation in Cgarette Smoking," In:Smoking Behavior: Motives and Incentives, 93-111 (1973) .2. Schori, TR; Jones, BW "Smokingand Multipe-TskPerformance," Vrginia Journal of Science, 2_5(3): 147-151(1974) .3 . Ryan, FJ, "Cold Turkey in Greenfield, Iowa: AFollow-UpStudy," In: Smoking Behavior: Motives andIncentives, 231-241(1975) .4. Schori, TR; Jones, BW "Smoking and Work Load" Journal ofMotor Behavior, 7(2): 113-120(1975) .5. Schori, TR; Jones, BW "The Effect of Smoking onRsk-Takingin a Simulated Passing Task," Human Factors, 19(l): 37-45(1977) .6. Dunn, WL "Smoking: What Reinforces the Habit?" iargerGazette, 36: 1-2(1978) .7 . Dunn, WL "Smoking as a Possible Inhibitor of Arousal," IntWorkshopBehav Effects of Ncotine, 18-25 (1978) .Sponsoredby PhilipMorris1. Emey, GS; Hunter, NA; Hutchinson RR "Selective Actions ofMorphine, Chlorpromazine, Chlordiazepoxde, Ncotine, andDAmphetamne on Shock-Produced Aggressive and Oher MotorResponses inthe Squirrel Monkey," FederationProceedings, 30:390(1971) .2. Hutchinson, RR; Emey, GS, "Effects of Ncotine onAvoidance,ConditionedSuppressionandAggressionResponse Measures inAnimals and Man," In: Smoking Behavior: Moives andIncentives, 171-196(1973) .

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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC3 .Myer, ASFriedman, LN; Lazarsfeld, PF, "MotivationalConflicts Engendered by the On-Going Dscussion of CgaretteSmoking," In: Smoking Behavior: Motives and Incentives,243-254(1973) .4 . Lazarsfeld PF, "The Social Sciences and the Smoking Problem"In: Smoking Behavior: Motives andIncentives, 283-286(1973) .5 . Kozlowski, LTHarford, MR "On the Significance of NeverUing a Dug: AnExample fromCgarette Smoking," J. AbnormalPsychology, 85(4): 433-434(1976) .6 . Kozlowski, LT "Effects of Caffeine Consumption on NcotineConsumption" Psychopharmacology, 47: 165-168(1976) .7 . Berntson, GG; Beattie, MS; Walker, JM "Effects of Ncotineand Muscarinic Compounds on Bting Atack in the Cat,"Pharmacology Bochemstry and Behavior, 5: 235-239(1976) .8. Berntson, GG; Sahley, T "Some Effects of Ncotine on PainSensitivity in the Rat," Bulletin of the PsychoneurologicalSociety, 10: 246(1977) .9 . Hutchinson, RRPierce, GE; Emey, GS; Proni, TJ; Sauer, RA"The Laboratory Measurement of HumanAnger," Bobehavioral

_Reviews, 1(4) : 241-259(1977) .10. Schachter, S; Slverstein, BKozlowski, LT; Perlick, DHerman CP; Lebling B "Sudies of the Interaction ofPsyctnlogical and Pharmacological Determnants of Smoking,"Jourm of Experimental Psychology: General, 104(1): 3-4

(197?7J .11. Schachter, S, "Ncotine Regulation in Heavy and LghtSmokers," Journal of Experimental Psychology: General, 104(l):5-12 (1977) .12 . Schachter, S; Kozlowski, LT; Silverstein, B "Effects ofUirrry pHonCgarette Smoking," Journal of ExperimentalPsylogy: General, 104(1): 13-19 (1977) .13. Sistein, BKozlowski, LT; Schachter, S, "Social Lfe,Cgmette Smoking, and Uinary pH" Journal of ExperimentalPsy ology: General, 104(1): 20-23 (1977) .10871229


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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC14. Schachter, 8; Slverstein, BKozlowski, LT; Herman PCLebling, B "Effects of Stress on Cgarette Smoking andUinary pH" Journal of Experimental Psychology: General,104(l): 24-30(1977) .15. Schachter, S; Silverstein, B; Perlick, D "Psychological andPharmacological Explanations of Smoking Under Stress, 11Journalof Experimental Psychology: General, 104(1): 31-40(1977) .16. Kozlowski, LT; Keiman RM "Effects of Oal pHon CgaretteSmoking," Pharmacology Bochemstry &Behavior, 9(4) : 477-480

(1978) .17. Sahley, TL; Berntson GG "Antinociceptive Effects of Centraland Systemc Amnistrations of Ncoine in the Rt,"Psychopharmacology, 65: 279-283 (1979) .18. Waldbillig, RJ, "Suppressive Effects of Intraperitoneal andIntraventricular Injections of Ncotine on Muricide and Shock-InducedAtack onConspecifics," Pharmacology. Bochemstry,andBehavior, 12: 619-632(1980).

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APPENDI X B


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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUCPUBLICATIONS BY VICTOR J . DeNOBLE

BASED ON RESEARCH PERFORMED AT PHILIP MORRIS

1. "Behavioral Effects of Intraventricularly Admnistered (-)-Ncotine on Fixed Ratio Schedules of Food Presentation inRats." (VDeNoble, Y. DaganandL. Carron*1981 Presentation of part of this research at meeting ofthe Society for Neuroscience, November 1981*1981 Abstract published (note different title): "Studieson the Effects of Intraventricular Infusions of (-)-Ncotine on Behavior Maintained Under Fixed RatioSchedules," Society for Neuroscience Abstracts 7(1981).*1982 Full paper published: Psychopharmacolocry 77:317-321 (1982) .* AfiliationPhilipMorris ResearchCenter*Experiment wthmecamylamne suggests that the behavioraleffects of nicotine in rats are mediated by centralnervous system(CNS) receptors*A least five previously published studies of the effectsof nicotine on the behavior of rats were cited*This research replicated in part and exended previouspublished research by Abood.

2 . "Antagonismof Chronic Ncotine Admnistration: Effects onSchedule-ControlledBehavior inRats." (VDeNoble, F Ryan,Y . Dagan P. Mele, J. Naworal andRKornfeld* 1982 Pesentation at meetingof the Society forNeuroscience, 1982* 1982 Astract publishedSociety for NeuroscienceAbstracts 8:395 (1982) . [copy of abstract not available*1984 Abstract cited by Jack Henningfield in a publishedreviewarticle: "Behavioral Pharmacology of CgaretteSmoking," Advances inBehavioral Pharmacology 4:131-210(1984) .

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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC*Henningfield cited DeNobles abstract as an example ofresearch that supported the following conclusion"Finally, in animal studies in which high levels oftobacco smoke or nicotine intake are maintained forexended periods, abrupt abstinence is not followed bythe onset of a wthdrawal syndrome." [emphasis added*Henningfields comment is helpful in itself; it is alsosignificant in that Henningfield was aware in 1984thatPhilip Morris was conducting research on nicotine inanimals. (In this reviewarticle, Henningfield alsocitedDeNobles 1983 unpublishedmanuscript releasedtothe press by Waxman. This is addressed in otherresources. )

3 . "Brain Sites Involved in the Mediation of the BehavioralEffects of Intraventricularly Admnistered (-)-Ncotine." (VDeNoble and P. Mle* 1986Pesentation at meetingof the AmericanPsychological Association August 23-26 1986*1986 Abstract published: Pharmacol. BochemBehav25:307(1986) .*1986 Full paper published: Psychopharmacology 90:156-159 (1986) .* AfiliationDepartment of Psychology, VrginiaCommonwealthUniversity, but unquestionably basedonresearchconductedat PhilipMorris* This report exended DNbles previous report onnicotines effect on rat behavior to a second strain ofrats*This research identified specific brain sites at whichnicotine acts.*There is no indication in the publication that theresults shownicotine dependence or addiction

4 . "Chronic Mecamylamne Does Not Produce BehavioralSupersensitivity toNcotine." (PMele and V. DeNoble)* 1986Pesentation at meetingof the Society forNeuroscience, November 9-14 198610869453


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PRIVILEGED AND CONFIDENTIALApl 6 1994ATTORNEYWORKPRODUC* 1986Astract publishedSociety for NeuroscienceAbstracts 12:309(1986) .* Afiliation: Dpartmen of Pychology, VrginiaCommonwealthUniversity, but unquestionably basedonresearch conducted at Philip Morris*The reported research implicitly indicates that nicotineacts on the central nervous system*There is no statement concerning the implications of theresearch for nicotine dependence or addiction

5 . "Development of Behavioral Tolerance Followng ChronicNcotine Admnistration." (PMle andVDeNoble)* 1986Pesenation at meetingof the Federation ofAmericanSocieties for Experimental Bology, April 13-181986 .

*1986 Abstract published: Fed. Proc. 45:431(1986) .* Afiliation: Dpartmen of Pychology, VrginiaCommonwealth University, but unquestionably based onresearch conducted at Philip Morris.*DeNoble concluded that his results "demonstrate thattolerance develops tothe behaviorally disrupting effectsof [nicotine]. "*He also concluded that behavioral factors can enhance thedegree of tolerance developed* There is no indication that the results showed aphysiological tolerance to nicotine*There is no statement in the abstract relating theseresults tonicotine dependence or addiction

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Privileged & Confidential April 6, 1994 Attorney Work Produc t

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