[Re: July, 1983 Discussed Memorandum]

Anne Landman's Collection

[Re: July, 1983 Discussed Memorandum]

Date: 23 Jul 1983
Length: 12 pages
2046754720-2046754731
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youth 3801

Abstract

This is the legal analysis by Shook Hardy and Bacon (SHB) attorney Patrick Sirridge explaining why the results of internal studies being done at Philip Morris by scientists Victor DeNoble and Paul Mele in the early 1980s on the behavioral effects of nicotine posed a danger to the tobacco industry.

At one point, after noting that DeNoble and Mele's experiments proved that animals develop a tolerance for nicotine (a hallmark of addiction), the SHB attorney warns PM counsel that this is contrary to the industry's position of not portraying nicotine as an addictive substance:

"...The bottom line is that the authors are maintaining that there is tolerance to nicotine, which involves both behavioral and phsyiological factors...It is obvious that such a report has undesirable implications for smoking and health litigation. Tolerance is frequently cited as one of the hallmarks of addiction. It is the industry's position that one of the classic criteria for addiction is tolerance, and that such has not been demonstrated in the case of nicotine."

Another passage by SHB says,

"...Thus, research such as [DeNoble and Mele's] strengthens the adverse case against nicotine as an addictive drug... The addiction view of cigarette smoking posits that cigarette smoking is influenced by circulating levels of blood nicotine. The DeNoble, et al. study is consistent with this notion...As with the previous point, this serves to strengthen the adverse case of cigarette smoking as an addicion."

Philip Morris ultimately fired DeNoble and Mele, destroyed their lab and experimental animals, and prevented them from publishing the findings that resulted from much of their work at PM.

Victor DeNoble now gives talks about his experiences at PM.

Fields

Notes

The document is marked "Confidential - Attorney Work Product"

Quotes

The following comments pertain to several reports (unpublished or in the press) from the Philip Morris Research Center. They are as follows:

1. Unpublished manuscript: Brain Sites Involved in the Mediation of the Behavioral Effects of Intraventricularly Administered (-)- Nicotine.

This paper by DeNoble, et al. reports an attempt to isolate the predominant anatomical brain areas at which nicotine acts. The methodology involved injecting nicotine into various brain structures and measure effects on lever pressing by rats...

The major finding was that the "primary site of central action of nicotine is the vestibular nucleus..." Additional evidence was provided suggesting that the action of nicotine...could be influenced by "blocking" with drugs, a different brain structure...The authors make no speculation regarding cigarette smoking. The only troublesome aspect about the report is (as is typical of all papers in this packet) is that nicotine is treated as a drug, and as as drug affecting the central nervous system. Although nothing is said about this being related to smoking or a motivation for smoking, the fact that Philip Morris is even engaged in such research may be taken by some as indicating a particular view of the importance of nicotine in smoking.

2. Unpublished manuscript: Development of Behavioral Tolerance Following Chronic Nicotine Administration.

As is clear from the title, this Mele and DeNoble paper deals with tolerance to the effects of nicotine...

...The bottom line is that the authors are maintaining that there is tolerance to nicotine, which involves both behavioral and phsyiological factors...It is obvious that such a report has undesirable implications for smoking and health litigation. Tolerance is frequently cited as one of the hallmarks of addiction. It is the industry's position that one of the classic criteria for addiction is tolerance, and that such has not been demonstrated in the case of nicotine. While it is true that the Mele and DeNoble paper does not discuss smoking in particular or attempt to extrapolate their experimental findings beyond the laboratory, there is nevertheless the implication simply by the fact that Philip Morris is doing this research, that it is viewing the research as relevant to smoking behavior.

3. Published abstract: Antagonism of Chronic Nicotine Administration: Effects on Schedule-Controlled Behavior in Rats.

This study by DeNoble, et e. was of the effect of nicotine, and of the effect of the nicotine antagonist mecamylamine on a particular pattern of food reinforced lever pressing in rats...This drug presumably blocks the central nervous system actions of nicotine. The logic is that if nicotine leads to phsyiological dependence, than mecamylamine should precipitate withdrawal and lead to a disruption of behavior in rats chronically exposed to nicotine. This disruption was not found.

It should be noted that in this particular abstract, the authors did not state the implication of their research for physiological dependence involving nicotine. Nevertheless, in a subsequent paper they refer to this abstract and do make that implication explicit.

4. Published article: Behavioral Effects of Intraventricularly Administered (-)- Nicotine on Fixed Ration Schedules of Food Presentation in Rats.

This was a study by DeNoble, et al of the response suppressing effects of nicotine, and their elimination by administration of mecamylamine...According to the authors [the study] indicated that nicotine was having its response suppressing effect due to its action in the central nervous system...

There was no speculation made by the authors as to relevance of their results to human smoking behavior. Nevertheless, the authors do use drug terminology (e.g., dose, antagonism, site of action, etc.) This, in the context of research supported by a cigarette manufacturer, could leave implicit to some that the cigarette manufacturer views the research as relevant to cigarette smoking behavior. If so, then the emphasis of this study on central nervous system pharmacological actions is clearly at variance with postitions which the industry takes in regards to nicotine and smoking.

5. "In press" manuscript: Nicotine as a Positive Reinforcer in Rats: Effects of Infusion Dose and Fixed Ratio Size.

This was a study by DeNoble, et al. of lever pressing in rats, such that presses led to contingent nicotine infusion. This is the classical nicotine self-administraion in animal paradigm....

At any rate, the authors of this report claim to have shown the reinforcing properties of nicotine--a believable claim based on their data. They state that their results "unequivocally" demonstrate that contingent nicotine infusions will maintain behavior....

... Despite the authors' position regarding the apparent lack of physiological dependence, their overall results are extremely unfavorable. The major reasons are (1) Few people, if any, accept that demonstration of reinforcement capacities of a drug is sufficient to label that drug as addictive. However, many people do use that as a primary criterion for assessing the "abuse liability" of a drug. Even more people accept demonstration of reinforcement capacities in animals as at least one of several criteria for an addictive drug. Thus, research such as this strengthens the adverse case against nicotine as an addictive drug. (2) The addiction view of cigarette smoking posits that cigarette smoking is influenced by circulating levels of blood nicotine. The DeNoble, et al. study is consistent with this notion, since apparently the reinforcing capacity of nicotine injections was influenced by an experimentally manipulated blood nicotine level....As with the previous point, this serves to strengthen the adverse case of cigarette smoking as an addicion. (3) ...In sum, there are at least two major reasons why this research is detrimental to the industry, and the one reason for shich the research might be considered helpful is subject to strong challenge.

Company

Philip Morris Cos., Inc.

Author

Shook, Hardy and Bacon

Sirridge, Patrick M. (Attorney, Shook, Hardy and Bacon)

Recipient

Newman, Fredrick S. Esq. (Philip Morris)

Region

United States

Type

Legal- Other

Letter

Operation/Project

Behavioral Research Lab

Subject

addiction

Legal Briefs

nicotine

Research Studies

Document Images

Page 1: 3801

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(u~puhliehed, published or in press) fr~ the Philip Mcrrl8 Rese&rch Center, They are as foll~s~ {-)- Nicotine. The research :epcrted in this DeNoble, et A~. menu-

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scr£p~ has no clear implications re;ardin; smok£n9 ~o~vst!on. The authors make no sperulat£on re~ardin9 clgare~te smoking. The only tro~lesoms aspect about the report (as is t1~icel of a~l no~hing is said about th~s b~ing ~elated to enokin~ or a tion got s~oking~ the ~a~ that Philip Ho~r~s is even engaged in such research ~ b~ ~aken 2. Unpublished ~anueoript: Development of Behavioral Tolerance Following Chronic N~co~Ine Administration. AS is cle~.T from the title, ~hls Msle ~nd De~ohle paper deals with ~olsrance to the e~ects o~ nicotine. It b~ins with the s~a~emsnt ~h&t it is "well documented that tolerance develops ~o many of the effects of nicotine following its repeated a~n~n- istration." The question for this study is to whet exten~ the developmen~ of tolerance is mediated by behavloral/envlronmental factors versus physiological factors. The ~ethodology is what is known as the "beZore/aftar" method. In this method, a behavloral task is e~ployed -- in this specific case, a fo~ relnforcemen~ schedule in rats. ~ver a series of experln~ntal essslon8, one group receives nicotine i~.jeotions before the ex~rlmental sessions (performance of the behavioral task). The other group receives the drug after the ex~'..Timen~al sessions. The logic is that both groups receive equal exposure to the drug, therefore ~oth have -2-

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e~ual oppo~-'.~it~ CO experience phys£olog£ca~ tolerance to dru~. Hoveve=~ the "before" group experiences exposure to the task under ~he conditions of the drug, and should or could also shOW a behavioral/environmental ~oleran=e -- i.e., leaz-ning of groups nlco~ine before ~he e~er~enEal session. If the "before" ~ha~ a ~havioEal ~ole=ance Is involve~. A phya~olo;ical tolerance on pe~fo~nce In a hasellne test before ~he chEonlc ~he "before" group showed less disruption of responding in the tes~ for tolerance ~han the .'after" group, thereby indicating ~ehavioral ~olerance. Also, ths~ reported tha~ the "after" g=oup showed less disruption of responding then during an initial baseline test, thereby indicating some physiological tolerance. The ~ottom line is that the authors ~re malntaLuing that there is tolerance to nicotine, which involves both heh~vloral and physlologicel factors. ~t iS obvious ~at such a repor~ has ~ndesira~le implica- tions for smoking and health litigation. Tolerance is fre~ontly cited as one of the hallmazke of addiction. Z~ is ~e indus~°s -).

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pos£tion ~h&~ one of ~he classic cri=eria got addiction ks tolerance, While At is tr~e ~hst the Hele end DeNoble paper does not discuss smoking in particular or attempt to extrapolate their e~perimental findings beyond the la~ra~or~, ~hl~e is nevertheless ~he ~p~ica- tio~: Effmo~s on Schedule-Controlled Behavior in ~£ts. This study by DeNoble, et el. was of the mffect of nicotine, end of the effect of the nlcoclne a~tagonlst mecamylamlne, on • particular pattern of food reinforced lever pressing in rats. RaUs were given ch~onlo nicotine in~ectlone during ~helr period of chronic a~nls~ti~n o~ nicotine, the rats vaEe challenge~ vi~h ~e d~g mec~l~ne. This ~g pres~ly ~p~i~n was no~ fo~d. the authors did not state the implication of ~helr research for -4-

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physiological dependence involving nlco=ine. Nevertheless, in a subsequen= paper ~hey refer to =hie a~snrace and do make Chau impllc&~iOn explicit. P~liehe~ a~clclez Behavioral Effects of Zncravencricul~cly Achninletered (-)- Niootlne on Fixed Ratio Schedules of Foo~ This w&e • study by DeNoble, e~ el. of the response suppressing effecce of nicotine, and their elimination by a~mln- le~ration of mec~mylamlne. The authors eetabllshe~ s pattern of lever pressing in rats using foo~ reinforcement, ~hen n~cotlne into the ventricles of the brain. This resulte~ in suppression of respo~ing, which was ellmlna~e~ if the central ner~o~s syetem nicotine antagoni•t mec~mylamlne was also a~min- istered. The ~esponee suppressing effects of nicotine were not blocked by the peripheral nervous system nicotine antagonist hexamethoni~m. According to the authors this in~Icate~ that nicotine was having its reeponee suppressing effect due to its action in the central nervous less, the a~l;h~rl do use ~TUg ~e~olo~ (e.~., dolt, &nt&~oniem, site of action, etc.). This, in the context of rose,oh supporte~ -5-

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c~arec:e s~o~in~ behavior. Zf so, 1~en the e~phas£s oE th£s variance wi~h positions which the ~nduetry takes in regard to nicotine and s~oking. 5. "Zn press" manuscript: Nicotine as a Positive Reinforcer in Rats: ~ffects of Znfusion DOse ~ Fixed Re'~o Size. This was a study by DeNcbla, at el. of laver pressing in tans, such that presses lad to contingent nicotine infusion. This is the classical nicotine self-admlnistratlon in animals paradigm. In this particular study, two levers were used, such ~hat if the rat pressed one laver it would result in nicotine Injection| if the rat pressed the other lever there was no effect other than for the response to be counted. Thus, one laver secved as a control for any noncontlngant stimulatory eEfects of nicotine. This p&r¢icular control has bean absent in mos~ past research on nicotine self-a~ministratlon in animals and has been At any rata, the authors of this repo~ claim to h~ve shown the reinforcing properties of nicotine -- a believable claim baeea on ~hai~ data. They state that their results "unequiv- ocally" demonstrate that ¢on~Ingen~ nicotine infusions will maln~aln ~havi~r. -6-

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Fire~, ac one poLnc in ~he£~ s~udy, they delivered, in edd£clon co the ~eepcnea contingent nlco~ine In~ecCions, an add£tional aeriesof spaced nicotine in~ectlona vh£ch were pcogranuned leas of the ~in~Is' behavlo=. They varied the interval ~etween Chess noncontingent in~ectlons a~d sought to deternctne the e~ecCs of ~hese on ~e an~s ~elpon~Ang ~ nico~Ane in~eccA~ns. ~hey ~epocce~ that as ~e Ance~al ~ueen noncoacAngenC nAceclne An~ecCAons Ancreaee~, there yes less of a suppressing e~ecc ~n ~hac the mo~e ~e ~ac ~eceived nLcocAne nonconcingen~ly~ ~he less ~ vaJ ~o~v~ed ~o ~espond ~o obtain nicotine ~co=dAn~ ~o ~he authors, ~mse =esul~s "sugqes~ level." A.eeoond additional aspect of the study is that the inveeniga~ore vlauall~ ohse~-ved the ~ete dieting • control procedure where saline was I~bs~ituted re= nicotine. They visually noted no signs of wlthdEawal. They cle~n tha~ based On this there was no evidence that nicotine injections ~e le~in~ to physiological lack of physlological dependence, their overall results are -7-

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if any, accept that de~onstrac£on of =e£nforce=ent capa=lties of a dxu~ is sufficient ~o label that d~ug as many people do use that as a primary criterion for assessing ~he "&b~se 1£ab£1i~" o~ • d~u;. Zven more people non,on+ s~nce app~en~ly the re~nforc~n~ n~co~£ne level. {See earlier co~en~e ~n regard ~o noncon¢~ng~n~ n~co~lne ~n~us~on~ supe=~poeed on px~a~ response con~gen~ n~co~lne p~cedu=e.) As ~lth the previous point, l~reng~hen ~he adverse ca~e of cigarette smokin~ as ~ addlc~ion. (3) ~ ~y ~ ¢onsideE~ helpful ~hat ~he •hat physiologlcal de~nd~ce to nlco~Ine ~d hoe dsvelo~d. fo~ ph~siolo~ical dependence ~d ~ ~ that ~ au~o=s ~ld -8-

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which ~he research might be considered helpful is subject to A~d to Dr. Oadene in which A~o~xl enclosed apaper by Bozarth Depen~ence-Pro~uoin~ Properties ~f ~hEne.~ the anancmloal brain ~reas rasponslhle ~or the phyaloal dapendence producing aspect of ~o~phine. According to the paper, previous The baa£c procedure was ~o ln~ect morph£ne ~epeatedly into particular brain areas, than challenge the anlmala with the on mo~hine, su=h ~ ~Jec~ion should precipitate withdrawal withdrawal m~ only wh~ ~m rata had ~n previously injected -9-

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