Tobacco Documents Online

-9- the druK ~:en it is ~tbdrmm. 2. DuE tdd,'ction, tape:tally •sLld £oz~ in ~b~cb v~thdrm~sl does not result i• severe abetiJ~emce symptoms". "Addictim: is • marked psycholoKic add physiologic dependence upon a substance, such ss 81cobol or a d~K, whir.h has llmZe ~ voluntaz7 control". The BEL~ah Hed~cal Dictioua:7 (31), barney•r, records that h~b£tuatiou~8" : "in drug addiction, the psych~cLt p~L~lel tO acqtL{red physlcAZ tolerance". '~)ependence'e Ln thin d£ctionary, which us pub14-hed before the World HeLlth 0:Km~sat£o• mrLtcbed from the ms• o£ "addictiou" to "dependence", is de£1ned as: "Z~. • d~ addict, tJ:mt state o£ body mind vbich J.s ¢cmdittmmed by iniesti~ o£ • ~rtain q~tity of d~s or ~ t~reu~ qu~ti~ of £t. ~y dmcre~e 4n dose g£ve• r£s• to ~)St~e Jy~pt~eeo 0~e can see that there £s l£ttle 8Breast in the area of de££n~tlo=, but one o£ the sets of def£nJ.tious vhich enema to cove= met points of view and which is .£alrly cmscise, is rJ~t in Uhe Horck Han~sl (143). The £ollo~L~fi para&Taph is jives under the hea~Lnj e~)tu8 Dependence". '~q; ad~ction is • state of periodic o= chron£c ~[ntoz~catLon, detrimental to the t.nd4vl.du~l and Co society. Drub abuse 4s 8 beh~our pmttez~ cb~tmctettaed by the repetitive use o£ a drug or dzuzs d~e to m strong emotional or me~tLt •eed to obtain pleasure or to mid discomfort. Psychic dependonce or habituation i8 the repeated use of dz~Ks Ln order tO e~Jxleve • S~bjectlve nziOlr~eln state, l~n~s~c~l dspend~ r.bdt~cter~see name but not all tYl~S o£ dr~K dependence and i8 de£Lnod 88 a state of adapt~tlon co • dru~ as um~L£est by 1) the vLtbdrm~l or abst4ne~ce rTndt:me, the cha:~cterietic ph~sLolosic cheeses Chat occuz vhe~ the dt~S ks discontJ~ued ~bz~ptly, when the e~£ect o£ the drug in counte=~cted BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-10- by 8 specific --telouist, or under CtrtL~U phys£ologlc stresses (e.K. seve=e infections), and 2) tolerance, the need to progressively increase the dose £n orde: to p:oduce the e~£ect origlna1Iy achieved by smaller aaoun=s. Add£ct£on is a tez~ w£th many social as well as umdicaT msan£~s, but £8 usually 8ppl£ed to states ~ere boUh phTs£cal and psTchic dependeuce are present, characte:imed by ma:ked /~olvemsut wLth use of the drug sad the secuz-JJxK of its supply, and a b£sh rAmdency to resman use of the drug a~te: i¢I ~thdratml". Zu most cases an 8uCho: tends to choose the definltion which best su£ts h/s vievpoin:. Host arKumsntJ concez~Ln4 the use of the terms "addlction" and "habituaC£on" in connection ~l~h smoking tend to centre arouDd ~h@ ev£denct for: (a) the pbarmacolog4cal basis for the use of tobacco. (b) tolerance to ciKarette mmk~n8 and/mr n~cotine. (c) tendeacy to increase the dose of ~cot£ue. (d) ~tbd=awal symptom8 m~d vhevhe: these ~m be co~nide~ed to constitute • '~r~thdrawal syndramat'. Zn pracC£ce. ~ tez~ "dopenden=e°' is now used by mm~r wuthoz~ but • dlscussion of the £ssues involved ~n distin4ulsh~nj "sddLctLon" and '~abi~t~on" £s • u:e~ul way o£ :evi'~ s~ne of ~he e~£ects o~ n~cot£ne and smoking, some o~ the ~otivstio~ ~heorie8 proposed for smol~z~ and the processes of smoking initiation and :8ssat~on. BAT Co LTD - MINNESOTA TOBACCO LITIGATION c...m ",,O

-11- 2. EV1~mqCZ FOR THE ROLZ OF ~ICOT~gK AS A DETEi~qANT OF CIC~TTE Throu6houC chess discussions £C is 8ssumed chaC nicoC£ne is the major psycboph,,rmacotoKical!~, active principle in tobacco smoke. It sbouZd be remembe:ed, hol~ve:, ChmC ocher 8moko componmaCs could also be 0£ /~porcance. Most authors ktve disregarded this posstbi14Cy buC it has been mu4~emCed that compounds such as terpenoids could be /mporCmnc Co the smoker (74). The two authors who appear co be most convinced about the t~porcmnce of nlcot/~e in cigarette ~nll and hmve worked @xtmnsively c~ the subject, are Russell end Jarv£k. They have, however, different views &bout the extent to ~hich the central role of nicotin~ has been proved. Russell states Chat: "There Ls 14ccle doubt chac 4£ £t weren't for uicoc£ne in tobacco mnoke, people would be ZicCSe more incl£ned to smoke then they are Co bZow bubbles oz' lishC sparklers*' (171). Jmz~J.k however seems Co be less sure. He has said Chat he believes that peopXe hm~e stumbled on. the most e£££c£ent way to bring high concen~raClons o£ n~coc~ £uCo the brml.u (104). Re IIso ch~nks (105) that £t wouZd be • remarkable co£nc£denc~ /~ the ~ects o£ Ch£s powerful pharmacolo~c~l • Zent had noch/~K to do w~Ch the reasons for mmok4nK, but this does re~ai~ a poes~b£1i~y. IC is also amazlus chat ohm retn~orcinK properties of nicotine have not yet bean demonstrated unmqn4vocaZly. Authors di.cues~ mmkiq as an addiction tmually usa Chat smok~ns has • strou8 p~log£cal basis with n~coC4ne as the active • Kent. Some o£ the ev£dence for, and 8Keener, Ch£8 £8 rev£ewed in ¢hLe section. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-12- ~storlce.1 Tobacco see~s to have been used first by Jwnericmn Indians in the form of ciKars and in pipes. It is used in most societies in the world today. In some pr~u~tive societies other oral compulsive behaviour may predmninate such u bate1 nut charon8 or teeth clicklnB (160). In fact 8 umber of societies sen to use the betel nut is: a sd--41a: pux-pose co n£cotlne, and it "contains arecoline, a psychophaz:RcoLosica£1y active alkaloid. Russell points out that some form of elaborate non-nutritive hand-mouth activity associated with taking a stiamlatiz~ alkaloid has been part of the humRn bekuavlour repertoire for nearly 500 years (168). lqo population has been knowD to $ive up tobacco L~ter being introduced to it. The use of tobacco has survived various forms of official disfavour and penalties ranking from decapitation to uccmaanicatiou. Since ie was brousbt to Zurope in the 16~h Century, tobacco has been used £or chewin$, snug££nK and smok£ns. In 18tb Century Britain snt~£1n8 predated (171). C~Kerettes appear not to have been introduced into this country untll soldiers returned fro: the Crimean Waz (1854- 56). At first cigarette smokiuK gas • luxury confined to ~he upper classes but since that time it has spread to all social classes (115). Cilarette smokini has also tended to displace -11 other forms of tobacco use. The possible reasons for this are mentioned in section 2.&. The fact rJ~t tobacco mmklzt8 has continued in the £ane of so ma~y penalties and in recent years, health ~mrninKs and h~Kh taxation, is l~aken by itusstll to t=~dLcate that it produca8 • very stremK dependence (171). Jsrvik &leo mentions the fact that in Eu:ope in World Her IZ people would Ks to incredlble 1emErge to obtain ciKarettes, collect£nK e~um~ %O BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-13- butte from the gutter, resortlnS to prostitution and barterLnK meagre food supplies (104). The common factor in all forms of tobacco use is nicotine. Tobacco ingestion has never been vLdespread. Kussell believes that chls is because £nses~ion leads to metabolism o£ nicotine in the liver to form cotinine which is psy~opharmacologlcally inert. Tobacco is only used in rays allou,~aK nicotine to bypass .the llver a~d enter the brLin in its active £orm. This mens it mJst Senerally be absorbed throu~.h the buccal or nasal mucosa or in the lungs (171). Accordins to Jarvik, purely psycholoilcal theories og motivation £all to cake account of the use o£ tobacco 4n non-smoked forms such as snuff or chevlng tobacco. This is not entirely corcect, however, since these theories often meek only to explain cJ~cette smokLns as it is che most widespread £o~m of tobacco use at present, mad they do not consider the 8eneral came. e ~t should also be noted that herbal end other non-tobacco cigarettes and smokln8 mixtures for pipes, which contain no n£cotium, have never becoam ~dmly popular, although that have been available for many y~mrs. These non-tobacco blends, however ogten seem to have smoke which has a very unpIeuant taste and smell. Their lack of success in terms of sales :nay not be entirely accounted for by the absence of nlcotIJxe but this probably plays the da~Lnant role since even tobacco masks may be considered to be unpleasant by the novice mnoker. On balance the historical e~rLdence favours the interpretation that nicotine i8 of importance in tobacco use. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-14- Zvide~ce from F.xperiments Usluqi; ~im,,ls, Kussm11 often quotas the results of experIJnmnt• in which monkJys and rats learn to self-/~ject n~cotine, as e~dence for the /~portsmce of z~cotine as a dru8 of depend•nee. He has maid that mzL/Jnmls mast be either re~mrded vlth someth/~K pleasdmt or threatened with so•stALing u=pL•asant, bafore ~he7 can be t~a£ned to do anyth:[~g. Nonkey• •elf- inject nicotine for its oqm sake so it must be 4~¢z-~ssicall7 ~wazd~ni in some mty. The quality of actLn~ as s pt/matT, "unnatural', :eLu~orce: of behs~iou: is shazed with other dependence-producing drug• (171). The wRys in wh~c3~ the dependance potemtlal of druKs may be determined by an/aml expe=imentst£on are coy•red vez7 thoroushly in • recent World Kealth Orfju~sst£on publication (227). "Results o£ experJ~entj on animals are, however, not particularly easy to /~terpret. The study on self-lnjection of t~eotiut by monkeys which is most ~r~daly reftr:ad to, is that of Dmn~au m~d ~:oki (52). They used seven rhesus monkeys with /ndwell/~K catheta=s which ~ere connected to /~jecCors activated by • lever in the4= cases. The m~J~eys would press the lever out of cuz~osi~y and obt~n a dose of nlcot/J:e. ~f they did not self-admLulster the drug at • Kivon dose level, uicotlne was auc~stlcally injected once an hour for several weeks or unt41 self- administration started. I£ this was not sucessful the dose was raised. The authors mention that a raisin on the Imr was o£tan ~ee4e4 to ~nduce press/rig, so it appears that monkeys did not •1rays self-/niece nicotine readily. &t 25 ~q~/~4~ two mon~eys aalf-ad~Ln~stsrad spontaneously and the others did -Fte: two to ten days automatic injection. They ~ve=a~ed BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-15- £rom 0.7-1.7 mgfkg per day but the dosing patterns were very variable and sometimes changed by IOOZ on eonsecut£ve days. Days on which a large total dose yes taken were often £ollowed by reduced dosage the next day. Then, 8C one month £ntervals, she dose was raised (to $0, 100, 200, 500, 1000 and 2000 ug/kg per dose). Ac each dose the lever was pressed less £requenCly and ac 8 g£van dose the monkeys refused to self-admiz~scer nicotine. 0£ the six monkeys in this part of the experiment one refused at 50 ~g/kg, one •t 100, own at 500, one at 10OO and one still injected 7000 ug/ks aver•SlnS 9.6 mg/kK per day with • maximum of 14 u~/ka. The monkeys d~d not self-administer nicotine between midnight and eight a.m. (when the cages were in darkness). Jarvik has done m number o£ exper£mencs using monkeys Cra£ned co smoke (105). He maya, however, ChaC althouah they will smoke they don~t inhale. Honkeys trained co smoke cigarettes •1so show • hLgh day to day variac~on in 8~okiD~ ~ poor extL~ccion of r~e boh~r~our (104). Gl£ck, Jarvik and Nakmnura (76) persuaded :onkeys co puff smoke by makdng them take 30 puffs co get one drink of water. They then ~nsCed four rhesus monkeys ~ch drugs co see i~ cbJir smoke/air preference was altered. Smoke was usually pre£erred under noraal circumsr~ances. 14ecmayl~ne, which blocks peripheral and central actions of nicotine, depressed ~he smoke/air preference and produced • mll decrease in puffLu6. This may iud£caCe that smoke is avers£ve if not accompmLLod by rev&rdinS phTslolos£cal effsccs. KexasmChonlum, which blocks per£pheral actions of ~LcotLne, also reversed the smoke/air p=eference and decreased pu~£ rate, sulWeet£ng r~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-16- that peripheral actlous may act as an incentive. Pentobarbital, a Several sedative hypnotic, merely decreased pu~finK rave but did not reverse smoke/air preference. Nicot4~e tartrate in dri~k£n~ water could lover 8moke/a£r preference if a suitable dose level was chosen. These experiments have been covered in some dotaLZ as they serve to illustrate several points. F~stly monkeys do not leiL-n to smoke easily and do not smoke in the sa~e way as humans, Smok~ behav£our is vet7 vsrlable, as is sel£-injectlou when it is induced. Js~Tik has pointed out (IOA) thac this indicates that monkeys do not have a fine degree o£ control for n£cotlne. £nimals will, however, resulate the intake of addicti~ druKs such as opiates, alcohol, cocaine and mnphotamlne and keep the dose :ore or less constane once dependence is established. H~tch£~son and Emley (97) have stated that the d££ficulty in induc~nK s£&~L££cant tobacco or ~cotine usa6e in anlmals may be 4us to incomplete co~slderatlon of the dual ~scure of the reinforcement p:ocess. There are c~o classes of reinforcers: positive reinforcers which senerally involve /~take of, or contact with, substances which are =ntritive or essential £or life or health or ~Latc such agents; the other class cause reduction of noxiousness, avarslveness, pain, irritation or stress. Their results 8usgeet that nicotine sez~es to reduce reactions and a££ects caused by noxious aSents and it is not there£ore surpr£sinS that animal expsr/mants, in which stress £s m4ntmal, do not lemd to SiSZL~flCant tobacco usage. Yhe~e are savor81 points wh£ch should be considered in e~n~tction with the experiments on m~4~als. As with a human population it seems llkely r, hat indiv£dual monkeys prohably d££fer in their reactions to BAT Co LTD - MINNESOTA TOBACCO LITIGATION c~

-17- drugs ~ in their propl~i~y go~ se~-I~niitr•¢ion. ~hu,e .o~peri~nt• • sin•.11 n~er of monkeys may not be z'epresentat£ve of 'le.rser sRmp%eSo ~n the Den•an end ~nokl study, d£f£eremces beer•an indivldul8 a:e seen in the ~ nicotine doses that were tolerated. The monkey /nject~ £cse1£ w~ch 2000 t~/k~ dose• was Caking very Large amounts of nicotine, £•r more than the equivalent dosage taken dur£n8 swokins by human subjects. ¢c is also interesting Chat: monkeys cra£ned r.o puJE£ 8moke show e~£ects due to nicot£ne in their drinkinK ~uater. One would expect Chat nicot/.tun ingested in ~his way would have little eJ~£ect since it Would be metebolised in the liver. Considerable caution must almays be applied when results on animals ere extrapolated Co humans but there is ~ indication Chat nlcotine does provide some sort og "¢everd" ¢o monkeys. The posiclon, especially with regard to comparisons w~h dalHnxla~ce produciJ~i druss is not. however, as clear-cut as lussell su4~emts. 2.3 Evidence =ro~ E xpe=~ts on Humans: The E~£ects of Nicotine and o£ Changed Deliver7 o£ Smoke Constituents on Smokins Behaviour As Jerv'J~ has stated: "To prove that: n£cotine is the essential inKredienc in cigarettes it i8 necessary to show I:ha1: cigarettes £rom vhlch nlcocine has been rmnoved are not crooked and. conversely, that n~cotiwe alone can substitute for el•metes" (105). This has been extremely di££1cult to prove in practice. The £irst study published on the e£fects o~ n.'lLco¢:lLum ~t smoking seems to be that o£ Johnston in 19~2 (109). Re ~a~e intrmnous nicotine to smokers and non-smokers. The smokers thouKht that it was pleasent and were disincl£ned ¢o smoke £o: som~ ¢~ne a~ter ~he inject:ion if the BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢,...m,

-18- dose was adeqtmte. Non-smokers termed the sensation after injection "queer". This study lacked r~nCrols and no girm c~nclusim can be drawn fr~ it, but it prompted F~anejan, L~rson and HaaK, in 1945, to izr~estigate further (62). They obtained some low nicotine tobacco and, by 8ddlng u~cot£ne to sa~e of it, made up cigarettes dellverlnK O,3~ mK and 1.96 mK n£cot£ne per cijaretce. Their subjects were 24 mnokers who first kept records of nmnbers smoked lot their own brand, Chert the hiJ~h u~cocine ciKarettes (about two weeks), then the low nlcotine ciKarettes (about one month). The differences in the numbers smoked were small and some subjects were not concerned by the lack of ~4cot/Jae in the low delivez~y c£Karette8. Nine subjects, however, ~4ssed the ~Lcotine, and did not adapt, but they accepted the lov nicotine eiKarettss as better than norJ:Lu8. This e~per~Jnent showe~ that nicotlx~t may be o£ mportance for some mnokars but not for others. SurprisinKly the holt study which is ~u~orr~nt in th~s area ~s not publlshed until 1967 (133). This is the work of Lucchesi, Schuster and ~nley, who remlised the importunes of dolnK an expari~emt in which the subjects were unavare of the purpose of the tests. They ~arried out 8~-hour pqcholoiical tests on subjects who were fitted ~th an tnCra~Inou8 drip deliveri3z8 either SL~JJae o= nicotine (iJx doses ~Hlich produced no subject£ve e~£ect in ~be subjects used). The subjects were allem~d to moke d~£nK the tests If they v~mhed to, and the mmaber of c£sarettas smoked were recorded and the butts were collected. Subjects were infused vith 4 u~ u£cotine per bout as rJais was squtvalmat to the averaKe smokin8 dose at • rate of one to turn ctSarattes per hour. Four imbje~te ~Lven 2m$ n~eot~e in the first hour. than & ~ per hour for five hours BAT Co LTD - MINNESOTA TOBACCO LITIGATION