CENTER FOR HEALTH COMMUNICATIONI· ....,... bnsrd School ol Publle HlslU1 -- Jrl A, Wlnrlen, PI,D,, Dinctor June 19, 1986 Research Status Reoort Nicotine Oependency and Co~Pulsftr~ Tobacco Oae Accumulated evidence is now overwhelming that nicotine, whether inhaled in cigarettes or ingested as snuff or chewing tobacco, II a powerful habll·for~ing drug which may.lead to compulsive use and a greatly diminished capacity to exercise free will over tobacco uael Leading national and international orqanlzations~ including the American Psychiatric Association, world Bealth Drganizatfon, National Institute on Drug Abuse, and the O,S, ~ublic Bealth Servlca,l tave declared that chronic tobacco use constitutes a drug dependence or addiction,' noie people are dependent upon tobacco than on any other drugr and cigarette amol(ing is the leading preventable cause of disease and pteiature death, Drug dependence in a copplex pattern of eampulsiv; oubatance-sccking behavior that is determined by the The terP 'addiction' lacks scientific precision and will not be used in the remainder of this paper, There 18 a growing tendency to substltlrre the term ~deptndenee,' - --- ~C 511 nw~lm~bn Avenue, Barton, MluachuJls 02115 Tel. (611) TJ21038 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 eZ- constituent drug's central nervous system activity, In 1985, seniot'sclenttsts at the National Institute on Drug Abuse reviewed extensive recent evidence and reaffirmed that nicotine is a 'drug with considerable potential to control the behavior or people who use tnbacea.'2 Recidiviss, or relapse, along ex-smokers is as high as among former heroin usera, Indeed, many parallels can be drawn between tobacco and opium (from which heroin is derived) which' are stunning and should alert us to the reality of the situationi tobacco, used by 51 million adult cigarette smokers and over 10 million users of smokeless tobacco in this countryl ahares many critical features with the prototypic dependence-producing substancer opium, At the same time, tobacco is legal, heavily advertised, widely availablei relatively inexpensive, and the cause of more than 3501000 3 than ten tfpeg the numbet of deaths deatha/year ~~ more caused by all hard dtugs~ including opiates, balbtturates, cocpincl and bsllucina~tns, tb~ln topether.l h comparison of tobacco and opium is presented below to highlight the parallels between their constituent drugal nicotine and heroin, Can substance use Etcate_Ehyalala~feal dependence7 Opium yes, Tobacco yes. Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 As defined by the American psychiatric Association (APA), dependence refers to an abnormal phyeinlo(Jic condition resulting from chronic d~ug administration that is revealed by tolerance (a need for increased amounts of the drug to achieve the same response) or by withdrawal (a oubstance- specific set of signs and symptoms manifest upon reduction or cessation of drug use), As discussed later in this document, tolerance develops to many of the effects of nicotine andl since a tobacco withdrawal syndrome is recognized by the APRI tobacco qualifies as a dcpcndencelprodueing substance, Can cessation of substance use cause withdrawal7 ~--- Opium: yes -- charaeteristfe and veil-defined features, Following prolonged use of an optate, abrupt cessation in its use tot administration of a drug which reverses or prevents the opiate's action) leads to a with~raval syndrome which may be severely discomforting, It may be diagnosed, according to the APA, by finding at least four of thess symptoms: lacrimation (teacinq) yawning rhinorrhea (runny nose) mild hypertension tachycatdia (rapid heart beat) fever piloerection ("goose flesh') insomnia sweating diarrhea, pupillary dilation (enlarqed pupils) Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 The first signs of full-blown withdrawal are usually noted within ~·B hours after the last d06CI reach a peak on the second or third db~, snd'disappear In 'l-lO dlyc,l Tobacco: yes ·- characteristic features may vary among individuals,, overt symptans are less dramatic and rarely life-threatening, although not necessarily less disabling than far other dcptndence~ producing substances. Following tobacco use for at least several weeks, abrupt cessation of use leads to a withdrawal syndrome which may be diagnosed, according to the bPa, by finding at least tour of these symptoms,, craving for tobacco restlessness irritability headache anxiety drowsiness impairment of concentration gastrdintestinal disturbances, Research has shown that these affects are replicable and are due to the administration and withdrawal of nlcatlne.( Withdraval syiptoms generally begin uithin 21 hours of cessation or reduction in tobacco use, and decrease in intensity over a period of a few days to several weeks, some ~xlsmokass report craving for tobacco for extended periods of time, even 5 to 9 years after qultring.'l Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 _~ ·51 Oo_es substance use lead to tolerancel ~Eium: yes, ~Tobaeco: yes. Repeated administration typically leads to a pronounced tolerance. like the case for opiates, regular users of to~bcco generally increase their intake until it levels off at a dose fulfilling their necd.l Unlike the case for opiates, tolerance to the euphoria effec:s of nicotine may develop within the first fev hours of intake during a day and be largely last after several hours of depIivation, such as during overnight sleep, Thus the first cigarette of the day, or the first in a series of nicotine injections, has the strongest and most potent effects, Is there a tendency among former uaels to relapscl Opfum: yea, Tobacco: yes, Both opium and tobacco use are associated uith a strong tendency to recidivism, ~n tact, the relapse rates over time are parallel for tobacco and opium, as rhoun in the following graph.9 Il~e heroin users, 7(1\ of smokers who successfully complete smoking cessation programs relapse in the first three tenths, and 751 by the end of the first year, O \O ('O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ~s~the constituent drug pavchobct_ive lalters mood ~gnltion, and behavicr)l Opfum: Yes, Tob~ceor yea, lite the opiates, the nicotine in tobacco produces changes in oood and feeling. Alnost Immed~atcly after each puff of " cigarette, the burst at nicotine that reaches the central nervous system induces feelings of satisfaction, Whether given intra~enouiry or inhaled, nicotine produces a similar profile to heroin and other drugs of abuse on standardized tests of euphorfa,ll i Does the aubatanee serve as a reinfarccr? eiumi yea, Tobaccoi yes, R substance is classified as a rcinforcer when the phariacologic activity of its constituent drug is sufficient to Ialntaln drug-seeking behavior, Tests of the reinforcing potential at nicotine pre useful to distinguish its physfologic effects on the central nervous system from other stimuli associated with sooting, such as the touch and feel of the cigarette or the smell of smoke, In some such teats, volunteare who have abstained from sooting are presented with two levers, which when pressed will deliver through an intravenous line a rneasured dose of Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 : ' lWtett Rls~llw Ulmnvll ~l'l~llnnn ~ locn kbecco, UeonJ, rLoln 100 I HEROIN a fMOHINe 'o A1COnOl ii-i-~-i~ tnlfXJ MON'IHS II~( Icc~ptora bltn idlntlllld tp~ the Eona~!tUtnl dru~l ~pluri Yea ·I Eaceptora (IP8ClfLO CI11Ulllr aiteL 01 action) hsve been Idtntllled lo~ the opl~tio end oplu~ derlv,lives In the cantril nervous ~yitsP, neutoendocrine ~lnten, and ~atiou~ peripheral lyll~lll~ Tobaccoi yea ~· nicotine Erc~pto~; have been found In the central nervous ayetea and tarioue piclpberal locallone, Gyit~mle nicotine ~dalniattallon reaulta In the dlatribullon or nicotine to epecllic binding aitea in the brain and alters cerebral function, Nicotine al.eo alters the telsasd.of a nunber oi neuroregulstora which Q tilter bthtrlol tnd plltollancs.ld ~0 3 C\ U Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 either tht,xpcrlPental drug or an inactive substance. When subjects are given a blind chafee between nicotine and an inactive substance such" as salite, nicotine Is preferred to saline and is injected in a regular pattern,L2 Similar findings are obtained with opiates and nicotine, in both humans and animals, confirming that the biologic effects of the drug Itself can control behavior, Is there a substitution therapy7 Opium: yes -· methadone (a synthetic, wraker·icting natcolie), Tobacco: yes -- nicotine chewing gum, To the extent that tobacco use resembles opiate addiction, with nicotine the critical factor in maintaining the behavior, pharmacologically based treatment strategies may be applied successfully, as in smoking cessation programs, Several large, well-designed studies indicate that a prescription form of nicotine chewing gum can improve long-term quilting rates for some smokers,l3 As is the case with methadone substitution for heroin, substituting nicotine gum for tobacco does not completely block the desire for the normally preferred form of the drug. It does reduce the craving to spoke and relieves some of the symptoms associated with withdrawal, such as irritation, anxiety, and difficulty in concentrating, lowcver, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ·9e nicotine gum If not a complete therapy: administered alone it is often no more effective than placebo; the most successful use of the gum has been in combination ulth hbbit-ehbnge procedutes.ll What behavioral patterns are related to substance use7 Tobacco and opium use share other characteristics: Similar development pattern Both forms of dependence develop rapidly and simple exposure or 'experimentation" generally leads to increased drug consumption and then chronic use, Sociall_y mediated spread Adolescents vha use drugs (includlng tobacco) are likely to have friends, siblings, and/or parents who also do, and such use lay confer status among peers, Association vfth other drug use Those who have problems controlling drug use often abuse or overuse more than one substance, For example, smokers tend to consume more coffee, alcohol, psychotrdpie drugs, marijuana, and aspirin than do nonsmokers, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 110- in sum, nicotine has a profile of behavioral and phyaialogic e[faeta typical of other drugs of abuse and, like the heroin derived from oetua~ meets rigorous experimental criteria as a drug with considerable potential to cause dependence, There is now no question that tobacco use leads to a state of dependence in most regular users, Surveys indicate that 901 of smokers would like to qu~t,l5 bet only a smell minority succeed because o[ the difficulty of overcoming dependence on nlcotlne~ Likewise, ~08 of junior and senior high school users of smokeless tobacco sap that they have tried to quit, often many.tlmes, yet most fail and cite "addiction' or "ctaving" as the main reason why tncy cannot kick the hablt.l6 00 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 References i. Oiagnostie and Statistical Manual of Rental Disorders, fd edition, ~maricin Psychiatric Aseoeiatlon, washington, D,C,I 1980f Intc~n~~ionll clasllification of Diseasct, Oth revilion. world lealth Organization, 1978, Cigarette Smoking as a Dependence Process, National Institute on Drug Abuse Research Monograph 23, 1979, Pollin W, Why People Smoke cigarettes, Public Iealth Service, U,S~ Department of Bealth and Buman Services, 1983, 2, lennfngfield Se, London ED, and JB Jaffe, Nicotine Reward: Studies of Abuse Liability and Physical Dependence Poiential, Presented at the Berzelius Symposium YII: Brain Reward Systens and Abuser in Cothenburg, Sweden, October 1885. 3, The health Consequences of smoking: Chronic Obstructive Lung Discasi~ h Report of the Surgeon General, Public Bealrh Servfeer 01S, Department of Bealth and Bu~an Services, 1984, 4, Ravenholt RT, Addiction Mortality in the united States, 1980: Tobacco, Alcohol, and Other Substances, Population and Development Review, December 1984, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 112- 5, American Oeyehiatric Aeeoeiat~onr op, cit, bl Report of the surgeon eeneral'a Advisory Committee on the Health Consequencee of Using smokeless Tobacco, 1986, 7, American Psychiatric ~ssoeiation, op, ct:, 8, Health Implications of Smokeless Tobacco Use, National Institutes of Health Coneeneus Development Conference Statement, 1986, 9, aenningffeld JE, Pharmacologic Basis and Treatment of Cigarette Smoking, J Clin Psych (45112126,1984, 10, Pomerleau 09 and CS Pomerleau, Neurotegulators and the Rtinforcement of Smoking: Towards a Biobehavioral Explanation, Neuroacf a Bfobehav Rev (81503-513,1981, Nemcth·Coslett R and JE Henningfield, Rational Basis for Chemotherapy of Tobacco Dependenccl National Institute an Drug Abuse Research Monograph 53, 1985, 12, Drug Abuse and Drug Abuse Research, Report to Congress from the Secretary, Department of Health and Human Services, 1984, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ·13· 131 Hughes JR and SA Hiller, Nicotine Gum to Help 51op Smoking, JAHA (252)20:2855·2858,1981, II, Schneider NC et al, Nicotine eum in Smoking Cessation: a Plseeboeeonttollcd, Double-Blind Trial, Addictive Behaviors (81253-26111983, 151 Pollin W,, Director of National Institute on Drug Abuse, Testimony before the Committee on labor and Human Resources, United States Senate, Addictive Properties of Tobacco Smoking, 1982, 16, Youth Use of Smokeless Tobacco: note Than a Pinch of Trouble, Offices of Inspector General, and Analysis and Inspections, Department of Bealth and Human Services, 1986, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 -C-~~ I, ~~Ck Ct~diL·uii Comments on "Re~eatch Status Report : Nicotine Ic~endency and compulsive tobacco usa butho~: Dr, F,JIC, Roe Gate I 2i;th PcSuuar~, 1957 i, This paper begins with the conclusion "hccumulated evidence is now overwhelming that nicotine, wliuther Inhaled in cigarettes or ingested as snuif or chering tobacco, Is a powerful habit-forming drug Which may lead to compulsive use and a greatly diminished capacity to exercise free will over tobacco use" which it r~e~ s~c~s to justify by comparing tobacco with opium in t~e context of the following 9 questions:· (01) Can substance use create Fhysiolo)ical da~cn~ence7 (92) Can cessation of substance use 6ause ~ithdrivaa~ (03) Does substance use lead to lolcrancel (Q4) Is there a tendency among for~~r u~~rs to rclapse~ (05) Have rec~ptors been iil~ntili~ii for t!~r c~nsti~ucilt drupl (Q6) Is the constituent drug psychca~ti~e (aiters mood, cognition, and bch;vior)7 (97) Does the substance serve as a rcinEorccr:l (08) Is there a substitution tbcrapyl (Q9) what behavioral patterns are related to substance usel Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Several of these comparisons are nisleadiny to the point of frank dishonesty or roligious-typa fanjticlsm and, in any case, coinmon srnse leads overuhelmiiiSllr to Fhe conclusion that hard drugs such as heroin ~re very considerably more dangerous than nicotine, In the followin? 3 sections i consider briefly (i) why the answers to the questions are misleading, (ii) other questions which should have been asked and which are not considered, and (iil) what would happen if one compared opium with something rise such as coElee drinking or sexual intercourse, 2, Comparison at cpium and tobacco 01 1~3 Because of increasing tolerance, rith Che passage of time opium addicts need more and more of the drug to satisfy their needs, This in petently not true oI smokers who settle down to a It·vcl of smoking e,(], 10 cigatettesldny or 2C cigarettes/day And remain loyal t~ tilat level over years, Q, 2 That smokers may suffer wit~drsuzl s~~;itcns on stopping smoking cannot be denied, i!~u~ver, tl~cse can not fairly be equated either qualitatively or quantitatively with those suffered ~~ h?roin addicts, 01 4 The rapidly increasing Fetcciital;e ot: tile population who are non·sn~~kers beaa ~trony witness to the fact that smoking is r~lativ~l~ easy to give up, and that many smokers have successfully done it, The graph on page 6 of \o Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 the Report obviously does not reflect the true position, It heroin was as easy to give up as smoking then hard drugs would not constitute the serious problem that they do in our society, C~ 5 All vorthvhile slkaloid-type drugs havr recepeors, it is ridiculous to suggest that the fact that there exist receptors for both opiates and nicotine means that the two have something special in common, QI 6 It 16 similarly ridiculous to liken nicotine to opium simply because both affect mood and behaviourl - A glass of water given to a rliitsty man, food given to a hungry man, cofft:e given to a soporific man are all capable of E~l;ctin~ mood and behaviour, Q, 7 Yet again to suggest that there is sopechine special in common between opium anJ nicotine in 50 far as they can both serve as reiniorccrs is absurd, The whole art of advertising is to u~e visual and verbal images as re I nf ore c rs, Whuu does not fancy a cup of coffee if Ii~/s~e smells it brewlngl The olfactory sense is perh3ps the most susceptible to reinlorcers, 01 a The argument seems to have become circular at this point. the title of the Report concerns "8icotine dependency" and yet this question suggests that nicotine is a substitute for itselfl the correct answer to this question in the case of nicotine should have been "No", That is to say "thure is at present no known substitute for nicotine", O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 01 9 There are no yroundn for singling out ol,iun and nicotine as peculiar examples of expericlclntationn leading to use, or of socially~meuiJ~e~ sprea(l of a bebitl All fashions are socially nLIJiatud, The process~s of growinglup is one of experimentation leading to chronic use (e,gl caviar, oysters, snails are tastes acquired after experimentation), 3, Comparisons with opium that are not considcrea in tli~ Report Serious crime including mugging, violence to the person, murder, robbery, burglary etc, are associated with hard~drug use but not with smoking, Deaths of teenages are common in ~·ieroin addicts nut not in adolescent smokers, Families are broken up and dustroyed by hard-dru~ addicition and even by alcohol ad~ictton but not bll smoking, Aids spreads among hard drugs addicts ~ut is not associated witli smoking, Hard drug addicts become 'pusilors' in order ~I, ~L~ ;Il!il, to finance their own habit, Tliis does not ilsppcn witl~ smokers, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 C. comparison of opium. with (a) coffee drlnkinll (b) sexual intercourse 01/03 opium : Yes Coffee Yes Sexual intercourse Yes As with smoking and unlike opium most people settle down to a certain level of coffee and sexual intercourse, Increasing tolerance does not 10Pd to 1 requirement iar more and more, 92 Deprivation of coffee can lead to ~awningr craving, irritability, anxiety, impairment of concentration, restlessness and other symptoms, Deprivation of sexual intercourse is a major source of psychosomatic disease In the middle-aged persons of both sexes - as any psycl~i~trist will testifyl P4 Opium Yes Coffee Yes Sexual intercourse Yes Common sense dictates that there is no need for me to enlarge on these answers, 05 There are receptors for caffeirie (tSouyht to be adenosine receptors) just as there are for nicotine, Sexual intercourse entails a galaxy of neuropharmacolopfcal phenomena with neuropeptides binding to specific receptors all over the placet Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 06 Opium Yes Coffee Yc~s Sexual intercourse Yes Again common sense dictates that tliese simple answers suffice, 07 Opium Yes Coffee Yes Sexual intercourse Yes That is why coffee houses became so popular in the 1Bth century and why sex shops and whore houses colexistl 08 Opium I methadone Coffee I tea Sexual intercourse a colC bath (so say some!) or masturbation 09 The taking of coffee is associated In some circles with the taking of port or brandy, in others with excessive gossip or the eating of Uanlsh pastries, In France, coffee is associated witli the dunking of biscuits, Sexual intercourse is ass~ciate~ with incr~~~~~ expenditure on clothes, jewelry, I,er~ua~r cosmetics, docderants, aftet-shavo lotion and hair Cares Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 4, Conclusion The Research Status Report from the Harvard School of Public Health is selective and not founded on any common sense appraisal of the comparison of nicotine and hard drugs, The ha nf ulness/harmlessnsss of smok ing is closer to that of coffee drinking or indulgence in sexual intercourse than it is to heroin addiction, C O CS, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Sc~· ~* CONTENTS Page No, I ~ll~AOOUCTION I ii NICO'rlNE PHhk.Y~.~\I`OI[1~J~:TICS 3 I\. j a. Distribution 6 C, Metabolism and Excretion 8 I D, C~nclus_ion g E: ill NICOTIIIE CDI~1'ROI , 10 I k, Preferred Cioarette Brands 10 8, loii~laticn 12 i' I C. Sm~ting Fattcm 12 F n aicolins-ri:ration · 13 1 I t I IV NICOI'I#E v'l!!l~l·:!COD~Ck~~lCS 30 .j A, NeuroChemj cal Action of Ni cotine jO ; I B, sauroph~sioloaieal Action of Nicotine jii C. Ni~orinp Ind I(unan IrychoghyrlPlagy II /I j/l ( ( 0· 51 i I; ill j I j.] Ct] ~O I · i : ~3 M I O j' CI I~B~-·\:Il ?I::~f~isiiai-o la ~L?% e I, ~C: ' ·:,C ·--- ·i. :- C P ~o Page IL "' r I II~1L ISE n PERSPElTIVf a ~L· II ~CZUDI16 CO~~~S re IA~ICS 93·112 I ~ " i I II O O r CllbP~F -~?-~J~~3i~'--~--~-- -- , ~·5: 1'6: IIII c- -" ~ - I, IW~I~~~ S~~iap has bean indicted bg health authorities around the world as I praetles which 14~ir~ haslth and shortens life, I~~lnp to ~: epidtdalogiltl, s~~ip( causes ill health lad prelatpre death through coronary heart disease, lung cancer, chronic bIone~itit, elDphysepa and cancers of the upper respiratory tract and even if it does not always cause death or disablement, there is h~era~idl~ for these diseases among aklra. Joseph Califano, forrr secretary of the 05 Dlprtlmt of health, Education lad welfare described sllaking as 'Pretentable PJlle health Bnt4 l~sr Op(l which has been Convicted,'erond I,aloPBlo doubt, of cri~~ against the p~lic hsal~" (Qlifano, 1980), 1 ~··: in this elllate of political and mdlfll opinion, it is not sqrfsibg C. ~tl beneficial in any way, and yet coaP sense argues that it oust he, 8P~lrl that researchers are reluctant 0 state publicly that smakin9 can he Ire exposed to considerable publicity about the health risks and so every saker must have made some judsrncnt about the Iddltbnl risk to health ct.. ~ I *u· continuing to sake. since cigarettes continue to he purchased, we can only conclude that EaktrJ consider that the risks are outweighed by soaking's benaiitr. This belief of soakers about the beneficial effects of soaking is sPbsbPtiatod b thip sll,eti~, b~t bal4nesd rlrir of ~a lit~ratPn on a~~doc and tbs slIX]king hahit. it shows that Pit soakers absorb nicotine into their bloodstream during the act of cigarette satlpg~ lhe nicotine aP acts on the priparal nervous system, releasing brans, which reduce f~tiac ma on the central nervous systeo to provide Dte srtidiant I processing of information. lhis efficiency of function, after nlatial I il~ intake, enables people (smckers and non-sakers) to prmn better in work l!i : I i ' db~bs. ~ addilion, ~m~a h~l~~U* ~dh~ ndrir ude~ jl; and anger, smokers titrate their nicotine intake according to their view jl of the situation so that they obtain the appropriate dose of nicotine Ior I ijl iII : ' i i: stlmul~tion or Jedatio~ In this usy, nicotine helps them cope with ) ) i i situational dewnds, lad Iqroval the quality of their lives. i ; /O CO n C I I b pQ ~~1-~.~~rst~~~~lllm~l~*··l·ll~n~rr~- - tt~ ·;Y, · 2. ~1· The pharrrscokinetfe properties of nicotine make sm3king doses remarkably safe for normal healthy adults In ccn~parison vith other stirmlant and sedative substances. Consequently there Is a high benefit-risk ratio for nicotine versus other comparable agents. In my view, the unique pharmacological properties of nicotine make it an ideal substance for self-medication by inhalatfon if the sroke can be made less dangerous. It follows that the less hazardous cigarette will not be a product with low tar, low carbon nnnoxide and law nicotine but one with the reduction of some sake constituents but sufficient nicotine (Ivld commensurate taste) to satisfy the saker, and so prevent are intensive smoking, This type of product would provide the benefits of sm31:ing with minimum risk. Ine idea is not new; on the contrary, it was proposed allP3st 10 years ago (Russell, Wilson, Patel, cole and Feyerabend, 19?3), However, at that tina, rritLr rechmlo~y oI pnvalanf UlinXini vat rcady ior ruth 1Movahon. hr and nimline l~agot tl~i had only jole b,m iltlodund, lad tL ~iaiLbtianr I oi ]OY deliYOTI CiglRttel YPR not yet apparent. indeed, it ii Imeertain that all factions would accept such counsel even pow, current opinion Is to reduce tar and nicotine conjointly, but such 'across-the-board' reduction in sake deliverll ignores the smoker's needs. Examination of the evidence (US Surgeon General, 19'19 a 1981) suggests that any health problems that may he associated with smsking are are likely to be related to the vehicle by which nicotine is carried (viz, the tar) than Ij to nicotine itself. A are sensible approach to the less hazardous cigarette i : ia~i is thus to provide the saker with the level of nicotine required, whiost minimising the uptake of unwanted sake components. The reduction of aany `iiil·t· other constituents muld be lolerdted by E~o~en as long as rutfieient nicotine rc~lins: the continuous removal of nicotine, however, may prove i I i ill-advised. ji i I ''~·~ I~ c 't ~O I \S I· I~ ·'I Clil;P`DF -~ijTil 3, rl, r~cwIn II~COK~S~ r· robaeoo Isavel have 1 aicotin~ ontsPt bstwssn 0.2\ and 56 of the d~ )I ·dqht. In a cigarette there is about 10 to 20 og of nicotine and I~ to ]O\ is transferred into the eaiasttsal 6m311l so" 35 "i puff on 1 1,2 q Ilnrctte will giva a mouth level ol IS0~50 ~g of nIFIItlne (I~tagl, 16131, 'pbacco gnke has about 2000 other glpu"d' in it aII co~plax lirtp~a of lasss, uncondensed conpcunds and liguid droplets as an (erDsol, The pH of :he mainstrealP smoke ranpsl babrn 515 and 6,2 for flue EPrsd Cigltlttll ind bcbeen 6.5 and 8.8 fdr cigar Ind pipe snta. mt Idyll of acidity is nrL1 B dc~ddll tht d~ of I~r~l~ l~d ~I Il~t pi dmlbl ;6~ · I I free the acroaol, 1. Rbsolption me first requirement for a ehldcal to probes a biologlesl rssFonss Is absorption, lieotine Irol tobacco slDka is absorbed from the Duth, ~14 and lungs and digestive tract Ind the IDmt absorbed irol~lt sites,.. depan6 on the let~ty of the total I~kl~ I, Oral ~l~tiOD R licotine Bit is readily absorbed b9 th' bPeell membrane from the ~d~dl~ ~uc of sde L4 a b 'D~ Of h* hn hplb a ~· pB, be amount of nicotine absorbed orally depends on pB. ncn the I'lbu, ·I IF~ ph Is 5.35, about 0.1 pr cent pi 61 nicotine is present as ~ ' I1~1 "* ~41~~~~ ~~~b nrll~~i~~~ present as the free base. Beekllt and Trlgbs (19671 found In hu~anJ that troo ].1 lag of nicotine base about 6\ "5 taken up at p6 55 and I ~~ it pi LL hl·1 ~pl~ db nicotine *h~al have b· that Ij I g I j I eamtid nicotine level of WO oqlll cc be achieved It pi 6 II the mouth but this increases to 500 ng/ll at pi 6 (Araitage and hmr, ) i )I f ji 19701. Unp~U~d relcareh 9 sr I I I Im~ll end cr I Wesnerl ( I shawed that bucFal absorption ~0" "Il~llnl tablets Fontaininq IJ q I I nimtine gave venous levels of LO "~~ "t PR 6 and ln,5 nglll at I p 4. Iml d4e bu ~ uDuld bc(xPtctrd ulat ·4 little nicotine i i ;I i I i I I I ii n CI Ib PB~INETf Lv L -- ;----~==- -L- 1. r? :.· j; : would be absorbed orally from cigarette smoke (pH 5.5 to 6.2), perhaps !j as little as 301 (Armitage, 1973), although much more 15 taken up from cigar smoke IpB 6,5 to 8,8), in a bioassay study to compare oral `; · absorption of cigar and cigarette smoke, Armitage and Turner (1970) introduced equal numbers of puffs of cigar smoke at ph 8,5 and of cigarette sloke at pH 5.4 Into the mouth of an anaesthetised eat. The cigar sr,ke produced an increase in blood pressure in the femoral artery but cigarette sm3ke did not, In the same study the oral uptake of radioactively labelled nicotine was compared at ph 7 and pH 8, there was much nv,re taken up when the ph was 8, Thus oral absorption appears to be important for cigar and pipe smokers but much less significant for cigarette smokers, Consequently, a crucial part of the cigarette srmking habit is the further manipulation of slldke by inhaling and then expelling through the nose and ~uth or even lust expelling through the nose, 2. Nasal Absorption rn order to account for the habit of snuff taking, which is found in mini' cultures, and the popularity of snuff taking klu~nq sn~kea working in munitions factories, it has been suggested that nicotine is L.·~ , absorbed by the nasal mucosa (Proosdij, 1960), Evidence for this explanation has cole from two studies, Temple (1976) found that snuff taking resulted in measurable levels of nicotine and its major meta~3lites in urine. Here recently, Russell described the time course of plasroa I ' : : iF~~ nicotine that resulted from snuff taking by an experienced snuff taker (Russell, Jarvis and Feyerabend, 1980), Uptake of nicotine from the j I 1: nasal mucous membrane was extremely rapid and nicotine concentrations al owr 20 rylll uere found in blwd raap]s fml a forPan vein. j : Therefore, it uald seem probable that nicotine Is absorbed from the nose during sm~te manipulation but the absorbed amount is probably small in comparison with the uptake that results from inhalation, i '' /I '·· ·~ 3, Inhalation ·~he major site of nicotine absorption for cigarette smoke land so for i the sjority of srmkcrs) is the lungs. During inhalation, the sm3ke I i t O C13 f j ~I ~C Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill '&~B laroaol pa5aea down the branehi and into the alveoli. Psrtlelal of i~ cigarette smoke are an ideal sire (0,01 - 2 ~~1 for penetration into the alveoli and absorption occurs through the thin alveolar membrane into the pulmonary capillaries, It is estimated that prl than 90\ - 95\ of inhaled nicotine it absorbed (Initags, LllsV, Geor9el Rouscsn, Lcufs and B~eI, 1974; Arlltage lad Turner, 19801 I!tbo and Croh, 1965), When equivalent sized boli of cigar or cigarette smoke were puffed into a cat's 1Pag, changes in femoral artery blood pressure 1(~~1 id mre elficiMt p~ D[ i.~· 1II d~rl~ Ide C than elqar ~mke Ik~t~qc, sail end Morrilon, ]965). Niatiac dlfiusss rapidly E4a de dlvaalll leablaac and dr rbdt d blaed Oar ~Y· · id~i through the capillaries is so slow that ~aPilibri~ is probably reached between alveolar nicotine and capillary nicotine ensuring pr~ spB~I~ P~~· - ~ the taois ol the praviouo a~lmtc~ of ISO to' 250 ~~ Puth level bf nicotine from each puff, over 100 pg would be taken up during ld~ &; inhalation from a medium delivery cigarette (h~bgs, BoPlsn, fP~~r Idlln, ])?() gY~ ovcI 193d dc~~, p. dCsdr I I~ course, the actual intake may not only depend on smoke gsncr~tibg 8:1; Ipllilop patternl lad al3ke lanipulation IpPaltiB 161116 Ifd depth of ~, in~l~ticn) but also perhaps on smoke moisture, PB of mucus membrane, and the contact time with the alrsoli~ t' The time course of nicotine in human plasma has ban studied a~t eXtensiVely by Dr III Russell. Smokers puffed ten times on 1 cigarette and plas· samples were taken every five minutes from In indvallipg needle in 1 forearm vein. nllC was I rapid increase in plasma nicotine with each puff with irregularities in the ~scmt profile from the puff by pufr blulal of nicotine. peak venous nicotine levels of 15,5 to 38.4 nglml won reached at the end of the j (I ~ cigarette and then corresponded to about one fifth or one sixth of the III: camtid artery lavlls. licoti~ dleay ii net lmeoth either, and iij Ruslell 119761 ar~cJ that the i~equl~ritias rcprcJmt nleotine Ijj ~ redistribution and rcgcliPg, lhe estimated overall half-life in ''t huans is arolnd 20 mins after finishing the cigarette and baseline levels of IBlt 1 Dgll1 are reached in 40 dPo. O \O O C? ?3 '0~' CllbPD~~~f~ ~r~~r~t~.~.~.~.~.~.~.~.~.~.~.~.~.~.~~,; C~~· ~3C:r: j 81 s 4. Gastric Absorption ja Gastric absorption only plays a small part in nicotine uptake from cigarette smoking in norn~l circumstances, Nicotine from the smoke i' aerorol will dissolve in the saliva where ph ranges of between 5.6 and 7.6 would give about 6 pet cent to 20 per cent free nicotine base. Traoell (1967) showed that nicotine was rapidly absorbed from a cat's I storrsch when the solution ph was between 1,8 and 8,6 but not when the solution was acidic, with a pH between 1.2 and 4.2. There is evidence Q of active nicotine excretion from the salivary glands. This nicotine passes into the stomach and Russell (1976) has suggested that this "rel:ycle~" nicotine could maintain the plasma levels of nicotine in slplkers. Hovever this seems unlikely; the normal gastric pH is acidic and so nicotine Hill be absorbed very little from the stomach although B absorption from other regions of the digestive tract cannot be ruled out. 5. Sum~n~y I · · The aaating, complicated practice of puffing on burning tobacco leaves, inhaling the spoke and blowing it out through the nose and mouth has ~ simple explanation. This procedure enables the most efficient transfer .i: of nicotine from the tobacco leaves to the smoker's bloodstream and more imcortantly the saDker can control the level of nicotine intake (see Section III). B. Distribution ,After absorption into the pulanaxy capillaries, nicotine does not bind ::I g to plasma protein and so all the nicotine is available for biological activity, 1' 'I'I The nicotine-loaded blood Il!aves the lungs via the pulla~nary veins and passes i I i: g :1. thmuqh the left atrium of the heart inte the left ventricles. From there :: the nicotine is pun~ed out into the aorta frdm uhich the large arteries ?: ilii it branch off. The significant branch, from the point of view of the smoking iiii. habit, is the carotid artery which leads directly to the brain, so that u some absorbed nicotine passes directly unwtabolised fra lung to.brain O 1 within fO sees. About a fifth of the bledd from, the heart ascends in the \O \Q) carotid artery so that a fifth of the absorbed nicotine passes to the brain Q ; · (Otdend3rf, 1977) ie a dose of around 250 ~p from a medium delivery cigarette I on the basis of the previous assumptions, i ct I: p;~,~;""""""""~c"clccl~l' ~~15d C~ rf~c,:,E, St'~i' ·~.! X i- i. Brain In order to act on the brain, a substance must penetrate the bl~od·brain barrier (IMinly the membrane lipid of the brain capillary walls) to the brain extracellular fluid, Nicotine is soluble in lipid !?art!tlon coefficient of 0,i) which suggests that It will freely pass through r: this barrier, Studies in the rat have compared the percentage of I· ~ · nicotine ren~ining in the brain 15 seconds after a rapid inlrsearadd ii..":· I~ Injection with tritiated water as a standard, Ninety pet cent of the trftjated water is taken up by the brain on the first pass through the brain, and uptake of nicotine is 131t that of tritiated water. l0ldendorf, Hyman, Brown and Oldendorf, 1972), Thus virtually all the :$:;::: nicotine that is delivered to the,bratn leaves the blood since the Ic: . '· volume of brain tissue to which it can distributed is so much larger, ;USS·''r':; i~lp·*l1 than the capillary plasma volume. As a result, the am3unt of nicotine entering the brain is proportional to the cardiac output to the brain 1~ ie about 250 ~g nicotine per cigarette, As a consequence of this efficient uptake of nicotine, doses affecting the brain can be obtained i~iii.: with relatively low blood levels which rainimises the risk of toxicity Ii· to other organs in the body, ... Whole b3dy autoradiograms of mice given Intravenous doses of I~bnicotine reveal a high accumulation of nicotine In the grey matter (onmyclinated tissue) with much smaller quantities in the white matter. I : I This distribution occurs because nicotine's partition coefficient ii'· of 0,4 allows good penetration of the blood-brain barrier but does not ii' 14 i I i I.· · result in depot fat storage, Hicroautoradiograms after C-nicotine and Ijl' i ,III· ti-nicotine show radioactivity in cortical cells, high levels in ii molel:ular and WraPidal cells of the hippocdnpus, the albcular lever of the cerc~Pllun, the nuclei of the hyp3thalarnus and the brain stern iahnit.llbu, Ilmron. I~pl~gnn and bli~, l.li, mis pltlm pi ji: nicotine distribution throughout the brain allows wide scope for phdrmaeodynaolic interaction. O i ' :i I I·~~ a I Ilu i i i Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill ?1~- rh --L- --~-_5-e The time course of nicotine distribution in ao9e brain shows that the rxilul concentration is reached within one minute of an intravenous injection, lhe level then decreases rapidly to about 50 pr cent in five minutes and one Pi Felt after II hour (Stdihandske, 1910) ~ Silflarly tehlit,rldv found a rapid nicotine decrease fat 3.93 ug (pr gram of brain tissue) It five minutes to 0.71 no at 20 minutes and 0.10 pq at ons bur (Sc~llterldv, BlnooP lad Anderslon, 1967), Is these workers and others found, the brain doss not rta~llze nicotine but the dru9 washes out quickly from the brain and so qjYeI 1 short duration of action, mus nicotine is I drop which is rapidly absorbed into the brain, widely distributed and then quickly the ideal specifications for a substance that is required for a short duration of action. 2· The nicotine that is eliminated from the brain is redistributed Is~d 81~ the rest of the body and joins the aiotiac~ introduced via the other,., ~ 61 arteries from the aorta. AO the partition coefficient,fs less ~ao ;b; one very little storlgl in solution in fatty tissues results. Inltrld, vholr body autoradiogaa (Scbritcrlb ct 11 1967) show a pattern of distribution after intravenous injection that corresponds to the blood supplyl with the highest levels of radioactivity in the liver 141 of :hs injected dose), about the same levels in the kidneys as in the brain (2\ of the injected mit) and less In the stomach. In contrast to ha brain, nicotine is metabolised in the liver and ~~4~ 8* s* ~~~~1 ~d ~ml~e L~~ in thl Il~r bll 1~1 6.12 no (pr cram of tissue) It five minutes to 0,76 pg at 20 minutes I jl ~:i Ic ahpur 90\ ii ~ta~lised In 1S ,inut,E. It 20 olnu,l ~( i II n~~ ~~ radioactivity in the liver and kidneys is mainly das to Eotinine and other metabolites of nicotine (bchmitarldw st al 19671, e, act~li~l and Brcntioa I~o Metabolisl and cErctfon have been discussed It length in numerous publicltions. B~rvcr there are two aspects of major importance ~I1 the srmkinp habit, First, It is clear from the tit course that nicotine O I~ ClibPDF - v~~fastio.soni : :.-;C~·ly~LA· ~" d ~·;'". -- ---- L~~· is metabolised very efficiently by the river, this limits nicotine's duration of action in the body, Second, the metabolites appear to be virtually inactive. Metabolic transformation is carried out by the entyme systems of the liver picrosomes and it seems that nicrosomal oxidation systems are protected by a liFDid barrier (8rodie, naickel and Jondorf, 1958) which nicotine is fat-soluble enough to penetrate, The IMjDT metabolic route is probably hydroxylation Ifnsertion of a carbonyl group in the pyrmlidine ring) to form cotinine, in addition, other metabolites, including nicotine I·#-oxide and nornicotine, are formed and excreted. The importance of this metabolic outcome is that no compounds of demonstrated pharmacological action are produced and the pharlMcodynamic P·~.: effects are determined almost completely by the action of nicotine alone. 't· ': ··· D. Conclusion rib:. 3 Studies of nicotine pharmacokinetics have revealed it to be a substance which is absorbed very efficiently from the lungs, readily enters and is quickly eliminated from the brat, and is rapidly metabolised .. to relatively inactive metabolites, This pharmacokinetic pattern allows a brief duration of action and the possibility of central nervous action virh linim~ Bid) eiiletr ii. artirmp PP BL r(lt PI th( tO$· Th( realization of this possibility depends on the ability of the sm,ker to control his exposure to nicotine ie titrate far nicotine. :: j ii: I j ~ i j k fS :ij \c, $ d I 'iI'ii I Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ·~d rrI~ NICOTlNE CONTROL Tile first argument for the relevance of nicotine to the spklnq habit EbneS IIO. evidence that people saoke to obtain nicotine, and many of then appear to regulars nicotine intake to obtain spclIie levels of nicotine in their blwdstreela. me implication of titration is that srdnlrr have need for nicotine and possess a mechanism in the body which is sensitive to nicotine sc enabling them to titrate the dose. Evidence for nicotine need and titration has come from surveys of cigarette preference, studies of inhalJtion, studies of sloking patterns throughout the day, the titration of individual cigarettes. nicotine preloading studies and a nicotine antagonist experiment. k. Preferred Cigarette Brands · In 1951 the Readers' Dlser( egazine published a list of the deliveries of njmline and total particulare atter fmm cigarette handr in the United States. At that time only one per cent of the cigarettes were filter tyX and tha average FigarLft! delivered 2.5 !g oi nimtis and aroi~d 36 mg of prticul:e matter. After the adverse publicity in the United States [wm tie Surgeon General's reEOlt in 1964, and the reprts in 1962 and 1971 of the Royal College of Physicians in Britainl the average levels of nicotine. determined by sloking machine analyses, were 1.3 mg. After 1966, American cigarette ~nu~aeturers cited tar and nicotine levels in their advertiremmrs and coqetirl~n began. between the rmnu[actunrs, to · ;1 Fb9 introduce I~ve~ deliverl cigarettes onto the market. in 1917 just under half oI the United States cigarette Indu~trlls budget for advertising and i: it pro.t;on .I ul,l to ~uour.gl LII purihar. .! :hal prdrli I. suD;;r ii lilu *.II, u;*, n i l;.al ilr.a hi.TYlb 110· 1(: Llnilrd Xingdol. I It ydlt hlY. E~L. I.PIIIP fhdt dP O~ilithl ~i ~IYLm~lt :_ publicity and conpany promotion would have produced an even ore rcnrkable witch in brands to lower nicotine and tar yields in the following ten years, and the sales-weighted average nicotine per cigarette would have decreased at.'i~ast a further I.O mp to 0.3 q. In tact, cigarettes with a nicotine I~ content of 0,3 Ipg and correspondingly low levels of particular matter are not popular, and the sales·weighted average level of nicotine in UK cigarettes has been 1.3 · 1.4 mg per cigarette for the past B years, and in the United States it is only approaching i.l lag. In GenPany there is a siaildr pattern and the sdles·ueightrd average of nicotine did drop to 0,6 mg but is nov around 0,8 ng, The Germany figure may be lower because the Ph of alkaline so increasing Absorption (see Section lI a), NicPtine- free cigarettes have been a total disaster, even though nany people have tried them. Clearly, sox~kers not only prefer nicotine-containing cigarettes, but most sreckers select brands which give a Pschine sllpking delivery of f:: above 1.0 mo of nicotine, i*t~'. It could he argued that thess observations on cigarette preferences do not provide convincing evidence for the importace of nicotine because nicotine usually co·varies with particulate matter in cigarette brands as a conseql~ence of the Ipanufacturing techniques, However, one controlled s.: study has tested cigarettes vith independeUy varied nicotine and tar levels, IColdfbrb, Jarvik and Glick, 19701. Smokers were allowed to snake as D8Y as they wished of these cigarettes with va~fng amounts of nicotine and the n~PSer of cigarettes thatthey smoked correlated with nicotine content but not tar content. Ratings of satisfaction and the perceived strength of the cigarette were sinilarly correlated with nicotine content rather than tar content, leuertheless, it is interesting that non-nicotine cigarettes were smoked to some extent over the three weeks of the test when there were no other alternatives, Although low and zeID nicotine cigarettes allow the s~3ker to go through the rituals of lighting, raniplating, and puffing the cigarette as well as inhaling the srmke, the lack of nicotine results in lower consumption. however, it uould be fallacious to conclude that fLvour i. froro the pcticolar phase of tobacco smoke plays no part in the aeeepbbility of a cigarette. Nevertheless, the inference from these surveys and studies is that nicotine is an essential ingredient of the i. cigarette for the stoker and this eMlclusior! becomes even clearer when a rmre. complete assure of smoking behaviour, than nunber of cigarettes srroked, is used, I I jO Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill ~~·r · II--- - 8, rnhalation 1 as discussed In Section ii, smoke inhllation results in very efficient absorption of nicotinei the large percentage of so3kers vho inhale provides evidence that the aloof smoking is to ~~13 nicotine, LpideniolDgical studies of swke·related diseases have surveyed self reported inhalation hehavtour (Doll and Hill, 1961; Hamrnnd, 196~. Doll and Hill's study showed that BO - 90 per cent of cigarette I~klr~ reporting inhaling, and la~Pd found that 966 pr cent of lookers, aged betveen ilO id (9, laid that they inhaled to some extant and 85.6 pr cent thought that thy were moderate to deep inhalers, Todd 11968; 1970 reported similar data vith 9 per cent and B per cent of oookers believing that they did not inhale at ~· all and 77 par cent Paying that they inahlad"a lot" or *a air aoount", 1 L CLI rifh LI ·~I ·It~ L ~ Lt it vy L ~lli beeaPse lahre underestimate de extent to which thy inhale (e~dlcdcab and Gale, ~al, rhn8n the p,aabC of il~cn ia probably higher than these surveys suggest, strengthening the argument that smokers use cigdrottec to obtain nicotine. C. SD~lng pattern The hypothesis that smokers attempt to slotain minimum br above) 1 levels of nicotine is supported $ studies of plasma levels of nicotine throughout the day Ouracll, Wilson, Patel, Cole and Ic~rabsnd, 1973; r Russell, Wilson, Patel, Fcysmhnd and Cole, U751. lhe half-life ol nicotine in plasma bcs Blctla rI) is a~Pt 20 ~ 30 dpptll Id .ia·1 13s alll 6 ta 1 d.nl t my. i, dC.Dl.lq 30 to 50 minutes lexcluding meals and sleepl. Russell's studies demonstrated that the rid-arn~ng levels of plasma nicotine were rercarkably consistent vithin s~jeets across days (soall standard error), although the levels for individuals ranged from 5.6 to 83.3 ng/ml. R determination five hours later h in the aftcrnnon shoved that these levels vele either virtually the sap I:c, a higher vMcl again npanr the hypothesis that ro3kara vee cigarettes :]b d to obtain aicottn~, e O r0 O 'd ClibPDF - v~~fastio.soni ,t d~~e - - -- "' ' '` '-· . " ~ -·-· · · · ·· ··. . . "7 ..'TI ' ""` D, Nicotine Titration In this part ~ will consider the direct evidence for smokers 1 controlling their nicotine intake either by smoking less intensely with ii higher delivery cigarettes or smoking n~re intensely with lover delivery 4 brands. For convenience this section will be sub-divided into cigarette consumption, smoke generation and smoke manipulation, and within each sub-section, the cthods of study. I i. Cigarette Consumption The number smoked is the most obvious way for smokers to control their 1 ~1 nicotine intake and It is the easiest to study. However, as we shall see, 1 It is not without its problems, for instance, the number of cigarettes: ~: in a pack has a strong i~lflwnc~ on consumption. ~hr first studies examined the effects of changing the cigarette brand on consumption. 1:· a. Cigarette switching The findings of Russell et al (1973; 1915), which strongly hinted that smokers control their nicotine intake were explored further by switching the subjects from their usual brand (i,S mg average) to both high (3.2 mg) and low I0,3 mg) nicotine cigarettes on different days. The number smoked during the five hours in the middle of the day was recorded. When switched to the high nicotine cigarette, consumption of the group dropped by 37 pet cent, from 10,8 ~ 3.5 to 6.1+1.6, and increased, by 17 per cent, from 10,7 ~ 3.5 to 12.5 + 3.2, when they changed fromtheir usual brand to a low nicotine cigarette (average · mean ~ standard deviation). The decrease with the high nicotine delivery cigarette was significant but the increase with the low nicotine delivery cigarette was not. However, in terms of nicotine delivery of the latter product, subjects would have needed to smoke five times as many O compensate lan increase from 10,7 to 53.5) if they did not change other aspects of their sn,king behaviour in any way. 3 v Cliljp~i~~r~i~~rp~··~B~n~lt~ I··*·· ·I P~i~t~j~fY~ :,;,,,, ,~F ~a . I large scale interview study which looked It the number ssYJkad hi given similar findings lor switching to lower yield bonds, and horn (1968) interviewed a group of 1466 cigarette sm3kars in 1964 and again in 1966, They found no evidence that ePkers, who switched to loller delivery cigarettes, increased their conr~t~~. Hcvcver, it was again assumed that the lakers did Mt change their enoking behaviour to obtain ~rs nicotine, Iussell (1976) has also pointed oat that there ap have been self-selection in tbs sense that only Ilblrl with a low r~quirelcPt for nicotine switched blade and so could accept the reduced delivery without feeling deprived, In a shorter tent laboratory study, Prltk (1971) gave smokers ci~arct~ts with delivaIiw pt 1.OZ mg, 1.37 me and 2,11 eg ct nlcetiae i: to sloka on single days, The nlrmber of cigarettes tha~ w;r'a snoked I was recorded throughout Me day fret 9.00 ala to 5,00 pn, and the u, · J~keIJ alJD rated their ds~ire to swke bs~ra md a~tr ~ch one, ki·' In inverse relation was found between the nuaber of cigarettes ID~d and the nicotine level. Sub)ects ~so said thlclh,y tound the high -· · ~ delivery cigarette are satisfying then the low delivery, UnfDrtunatel:(, tile tar 1I~1 of Me lowest cigarette was half that of Ma highest (14,6 against 30,8) and so Me subjects could easily detect the differences between the products, In I better two hour experiment, Idcrl were given specially prepared cigarettes which were either of low nicotine delivery lO,Zmg) pr high nlcotinedelivery 12.0 n~ Narvik, PPpk, Schneider, Baer-Weiss and Gritr, 1978). The tar levels i~" oI the cigarctlae were idPntLal se that the taste diIierence was small. S~jact~ I~k~ DIO Of ~e 10vel d,lfvcry thin ths higher dllivary cigarette which gives persuasive support for nicotine ra~lat~n, ii · ~~r oon. td· hi* IrY it I.I~ ii I~ gl Lti. i ID the first, spokers were given a ledll delivery cigarette for ~e first week, a low to mdip cigarette in the second week, and a low cigarette in the third week (1Praer, Sillet and hall, 1971). 1 ~·~~ subjects compensated by loHlp siaifielltll are cigarettes when they switched hot the rdia to the Iw-rdia cigarettes, but there was little change after Me second switch fron low-oedium to Me low D delivery praLrt. 1 kmglr study OrecLlp and Fletcher, 1)70 'ic~f)~E~ ClibPDF - v~~fastio.soni : ~t "' "; !~a··~BP3;li~.~.~t!~~~: examined the changes in consu~aption over a 20 month period when f' smokers were switched from a conventional medium (1,39 mg) nicotine cigarette to a lover ~ediP (1.01 mg) cigarette containing 30 per cent tobacco substitute, The average number of cigarettes smoked remained constant for the first 15 months, but increased slightly in the last 5 m3nths, Although consistent with nicotine regulation, chis small but significant increase was surprising in view of the siml.larity of the nicotine yields of the two cigarettes, 'Ihe problems of cigarette consumption experiments were highlighted by long term studies by Adams (1976; 1978) of smokers from the Imperial Tobacco Company Research Division and Head Office which will also be referred to later. ~I\Jo sets of subjects smoked their own brand for a Week, then medium nicotine (1.4 mg) cigarettes for five! weeks and'~ then a low-medium nicotine (0,8 mg) cigarettes for four weeks. Two central groups smoked their own brand for a week and then either the low cigarette or low-medium cigarette for the remaining nine weeks. The Research Division subjects increased their weekly consumption Parkedly When switched to the low nicotine product while the Head Office subjects increased their number only slightly, Adams believes that members of the Head Office smoking panel were less familiar with the ::·::~ experimenters and were inhibited in their demands for pore free i.· cigarettes. An equivalent psychological barrier may operate in real life where sakers may choose a lower delivery brand but are reluctant to purchase are cigarettes than they usually do, A methodologically sophisticated long term study was performed by Finnegan, Lrson and Haag (1945) using tobacco leaf with naturally low nicotine content made into a low nicotine (0.34 mg) cigarette or the same leaves sprayed with nicotine and IMde up into a high nicotine (1.96 mgl cigarette, Thus the pressure drop of the cigarettes and the tar level would be the same and, although the nicotine would give a slightly different taste, it was possible to test the effects on i;., consumption Without the subjects being certain about the difference, Subjects were given 100 of the high nicotine product followed by a .mpnrh oh th~ L nimtln, haa and then ri~chcd bach to (W pt the i;l - Ilff o high nicotine cigarette. The authors claimed that there was no 1·~ Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill correlation between the number of cigarettes smoked and the nicotine level, a finding which argues against compensation, However, an interesting picture emerged when Russell (19761 examined the distribution of withdrawal symptoms in this studyi subjects who did not increase their ronsw~ptlon on the low nicotine cigarette experienced lack of atisfaction, irritability and poorer concentration. Instead of examining a mixed set of subjects, as In the last study, Schachter (1977) selected an "addicted" group and a "non-addicted" group. The addicted group m~m5ers had smoked at least 20 cigarettes a day for many years, they smoked regularly throughout the day from m3tning to night, they inhaled the smoke, they were not trying to stop or cut down at the tile of the study, and, if they had tried to abstain, then they had experienced abstinence symptoms, ·Aall the :: sdjccts were given low nicotine (0.3 mg) cigarettes for the first week and half were given medl~ nicotine (1.3 lgl cigarettes for the first week, then they were switched to the other cigarette for the second week. Although the experiment was carried out double blind the cigarettes differed to some extent in tar content, As a group, the addicted swkers smoked 24 per cent mote of the low nicotine cigarettes (42.931 than the high nicotine (34.571, while the light sPlokers used ]6 per cent more of the i, nicotine 110,191 compared with the high nicotine cigarette (8.811. Sehachter reorted that three addicted subjects, vha only increased consumption f~~·· E~::· by 14,3 per cent compared with 33.6 per cent for the rat, experienced 5; severe abstinence symptoms, Thus the last two studies show that sPokers who do not regulate their nicotine intake, suffer deprivation : ::. symptoms. b. Ventilated Holder !j ' Another method of Wrying smoke delivery to the smoker is to use a Mmal cigarette but smoked through a ventilated cigarette holder. i.: Tvo holders producing nicotine dilutions of 23 per cent and 58 per cent j .. were used to study titration ISutton, Russell, Feyerabend and Sallojee, 19181. Smokers used each holder for a week and kept a diary of their cigarette consumption, Consumption remained constant Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill '1- :: throughout the study and no titration was seen on this measure, Aouever, as we will see later, mnpenration war; achieved by increasfmi the amount of smoke inhaled, e, Partial Ci~arettes A third type of study has examined the number smoked when subjects were only allowed to smoke part of a cigarette for a week. Cold[arb and Ja!vik (1972) gave so~kers packs of cigarettes which were either cut in half or had a line drawn around them halfway down, and the nun~ier oI smoked cigarettes was counted. In comparison with Mking their own brand in week 1 125.5), smoking increased with the lined cigarette (27.21 and the cut cigarette (28.6~, but during the fourth vee); on their own brand srmking was also higher [27.3]. These group ~· · data give limited support for titration by increasing the number 1 in~* an·auu a Najutr aidl...' g .,,, ~r tin i a~y. I the lined cigarettes and by an average of seven a day on the cut cigarettes, A more extensive study (Russeli, S;tton, Feyerabend and "... ::i Cole, 19781 included a full length tedium nicotine (1,08 q) cigarette, a ~hreco~uarter length, low·medium nicotine 10.83 mq) cigarette and a half Irilgth, low medium nicotine (0,67 mg) cigarette. These cigarettes were ~mked in the laboratory on three separate afternoons. The number smoked increased from ]3.5 with the full length cigarette, 14.8 with the threequarteI length and 17.6 with the half length. Thus there was a clear and significant increase in consumption, in contrast to the rather small changes bound by Goldfarb and Janrik, d, Nicotine Preload A [ourth appmach has hen to prPhad the Eaters vith nicotine, either by injection or oral doses. The pioneer study of this type, and indeed /I j I I·. the first study of titration, was done by Johnston 119421. Ae inlected 20 Ipq of nicotine intrlvenollsly and reprted that swte!r found the sensation pleasant and did not want to smoke for some time aftervards, No details were given of nunber consumed, In a follow-up study (lucchcsi, Schuster and Emley, 1967), aub)eas were given intravcnalls 3 Inlucioel; of nicotine and their cigarette consumption examined. low Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill *3 - '~+lb~ri Ti~~n;c~ y h$' : doses of nicotine had no effect, but I q pr hour very significantly reduced COIII~IOP Of I cigarette Of ·,ptcltid delivery by 27 pt cant (10 to 7,3), Ilthough significant, this decrease in nulbers is tall in coDparison with the alount of nicotine given, but it lust he renembered that nicotine is rapidly netabolised by the liver (sae Section rI) so that the levels reaching the brain would be ranch 111313 than those infused, mt same problen affl ies to studies using oral nicotine whether in tablet or chewing gp fon so that It is scarcely surprising that a daily dose of five tablets of 1,0 rag of nicotine tedeced the nurnber of cigarettes used by only eight pr cent although this vasl significant decrease (31n~, Click and Ialamura, 1970), Nicotine ~ei~g gun has been prescribed as I stopping-sl3king aid, and sone- success has teen clalrd. in an eXPriraental study (RPZSI11, wilson, F~erabend and Cole, 1976), subjects were given either alkllina gun it section II ~.1), or a placebo, bth highly spiced so that the subjects Bi~=t: showed Mit nicotine was absorbed iron the nicotine gun although bl*d :I ~~"·' levels were lower than with sloking. subjects reduced their s~klap // on both guns but significantly lore so while taking the nicotine gin ;I 07 per ecntl than a:ter the non-nicotine gun 01 pr ceatl, Clearly, iI in spite of a placebo effect, when the subjects thought that they were getting nicotine gum, there was sell reduction of cosoPqtlon. c. ~dlficd Ercr~tion ~ iirml type of study lanipulated ni.cotine body levels by changing I urine acidity. If the urine is alkallne then less than one pr cent of i I! j~ the nicotine is excreted unchanged in the urine, if it If neutral i Il~i~ then seven per cent is excreted and if the urine is acid then J pr cat is excreted lnchbnged Ibeht ad h4e, ~PI, Pres~bly In increase in urinary excretion should lev6r plaPu levels I'! of nicotine and sc Schachter predicted that increasing acidity shoulb j; I II .increase sloking, In a test of this prediction (Schachter, Kotlowski I .: and Sllverstein, 191~ asccrbic acid (Vitalin C) or glutanie acid /i C~ ClibPDF - v~~fastio.soni r·4r , n :ir B '9~ i' bydrocbloride was given to snokers to acidify their urine and increase excretion, mere were increases in consumption from 23,1 to 26,7 (15.6 per cent) and 28.1 (21,6 pr cent) respectively. once again there was some evidence for control of nicotine intake by changing consumption . f, Nicotine Antagonists 1 complementary study to those on nicotine loading is one using the secondary allne, necamylamine, which crosses the blood brain barrier and blocks nicotinic synapses in the central nervous system IStoleraa, Goldfarb, Fink and Iarrik, 1913), gP~lrS were given this drug Or pentolinium, a nicotinic blocker which does notentsr the brain, and asked to record tbs n~cl that they smoked of their DJ;a1 cigarettes Irange 1.0 - 1.5 nicotine), Mac~yl~ine, (7,5 mg, 12,5 q, 17.5 Iq and 22.5 mql increased cigarette cbnsqtion by II much as 30 per cent, presumably smokers smoked more to overcome the partial nicotine blockade in the brain and so obtain the desired effects of ~. nicotine, When the smokers had taken pntol~i· there was no change in the number of cigarettes smoked which ruled out any influence of Be peripheral effects of nicotine on consumption, lhis study shows clearly that smokers are using cigarettes to obtain plasma levels of nicotine sufficient to affect the brain, 9· Summary nl ~~~r lb ~~ re rl~al ~u*e dmd* by dl~q de nunber of cigarettes that they smoke, in studies where abatfPeact s~t~s have been examined, pas smokers, who do not compensate, ;I i 111 1~ suffer from the effects of nicotine depristion, Aovever, negative I~*i ~ br qLb~ in ..r o[ dl~r in dbr Pulflng pr jr^ inhalatjcn. Data, that show these factors play a part, come from an expe!i~mt by Grits, Baer-Veiss and Jarvik (1976) in which sublects were given an equal nunber of full length cigarettes and half length cigarettes to sale In a week. OrinaV nicotine measures showed that ~~jects were able tb mtlin conalder~ly nole nteotlne than crpctrd 3 3 j· ; I ClibPDF - v~~fastio.soni ~::1Z;6P~~ from the half length cigarettes, and indeed almost as much as from the full cigarette, ms authors concluded that "froblnfl of puff, sire of puff or depth of inhalation must have altered on the shorter cigarette to maximise nicotine intake and achieve optimal titration", (P.55~), 2. Smoke Generation In the last section, the conclusions on cigarette consumption Were d· related to the nicctinc content of the c~lretta~ maP, nicctiee ~v~s were ca]clllated on the basis of nicotine deliveries that were obtained 1 from standard smoking machines. ~e machine smoking determinations enable comparisons of cigarettes, hut the smoking machine only produces an approximation of buan smoking. The underlying principle of the Ilehin;, 1 determination of smoke deliveries is that standard analytical proeedrss g are such that the yield is representative bf the smoke 1 cigarette delivers 1 to the smoker ii the same smoking parameters an applied, In In ipno~tirt series of studies, creiqhton and Lewis (1978 a and hi recorded the pattsm· - . 1 1~ puff shape. may found that there vere Parked interindividu41 differences in smoking pattern and clear, but smaller, intraindividual ~ari~tiona. Therefore it was inevitable that a individual's pattern of generation Z: I I rarely matched the smoking machine's standard parameters. The conseqlenees of variations in smoking pattern for nicotine deliveries were srllcr than those for total prticulate Patter and carbon ronoxidc. Nicotine [ 113 ~.~ Llb·3·.~h*·s~l~lln 1 changes for puff interval and puff oolmc, while puff shape bad no effect on nicotine dtl~vcry. ( ·I The prbcticai eonlequence oi theet ~rLtl~E in ~~lnq pattern, in II tent of nicotine deliveries, was examined in 1 complementary study ufth I b ~I ~llr ~~C· ~ ~i ·I I ill 63s~ q the standard smoking machine yields from the actual values delivered I can be seen by ccmparing the average amount of nicotine that was deposited on the cambridge filter pad after duplicating the smoking patterns for 1 I , leniP delivery cigarette having a yield of i,a mp of nicotine when I an~ly~cd on a machine smoking O standard parameters, l"nis usa 2,25 lg ·3 ClibPDF - v~~fastio.soni r of nicotine for males and 2,0 mg of nicotine for females. Ihe coefficient of variation for nicotine deliveries between different subjects who smoked the same brand ranged from 24 pr cent to 38 per cent with a mean of around 30 per cent, clearly the machine estimated delivery is a limited index of the nicotine dose entering a smokers mouth, and so other estimates of nicotine delivered to the mouth should be used. B Some of the previous studier of nicotine regulation recorded puff variables as well as numbers of cigarettes consumed, Ihe experiment of Ftith (1971) demonstrated that, as well as smoking more cigarettes, smokers took larger puff volumes for some cigarettes than others. Lucchesi et al 11967) found that intravenous nicotine reduced the nlrmber of puffs and the subjects discarded their cigarette earlier. A similar study by KUIMT (Eumar, Coo)te, Lader and Russell, 19771, however, fowd no.changes in puff number, Interpuff interval, puff duration or puff volume on a 1.3 mg cigarette after 10 rapid injections of nicotinei either 0.035 mglkg or 0.07 mglkg spaced at one minute intervals in order to simulate 10 cuffs on a 0.85 mg or a 1.7 q cigarette. A cofipanio? stt~dy, with controlled Bg sm?kinrl of either a herbal cigarette, a 1.3 mg nicotine cigarette or two 1.3 nrj nicotine cigarettes tie 2,6 mg) did reduce the nurSer of puffs taken from a cigarette in a dose dependent fashion, The major problem with comparing studies of intravenous and inhaled nicotine is that some of the inl,ravcnous nicotine is mctablised before reaching the brain and so the dose is lower than that going from lung to brain. This evidence sug5~sts that s~kers can control the nicctine intake to their mouth by ch~nqing their smoke generation, Oirect studies of this behaviour have employed cigarette switching and partial cigarettes. a. Cliearett_q Switching er:tjutcs o[ nicotine which is drawn into the smokers mouth have been rode from analyses of the nicotine deposited in the cigarette filter and the filtration efficiency of the filter tip, One of the first st.udies on butt nicotine allowed spokers to smoke either a 1.0 q or i B i 2.1 q nicotine ciglrrtte while in a driving sin~ulatot (ashton and "*' Uatson, 19701. Records were made of puff number and depth of B inhalation while the bltts were collected. Depth of inhalatfon was ~O ~Ba Clit; PUF -!::!!::!!::!.f3 StlC.i: Dill 1 ·,c1?5;· :·· · ···'·r··· i ·:· ~' . ~.·~': *'~:'r'f ·s ;l::i unchanged hut puff nlupher was Lrge on the adium delivery cigarette j i and butt nicotine data shoved that about the saw amomt of nicotine was delivered to the muth from both cigarettes (1.31 nrl from the i 1.0 lag nicotine cigarelt?, a ratio of 1.31, and I.iS f!om the ~.! mi nicotine cigarette, a ratio of 0.741, Ihls study gave clear evidence of titration, by smoki.ng the lover delivery cigarette sore intensely and puffing the higher delivery product less intensely, In our own g studies (Warblaton and Wcsnes, 1978) we found similar changes during a vigilance test. Sekcrs smoked both a low nicotine 10.3 lag) delivery cigarette and a lou·liun nicotine (0.7 mg) cigarette ~re j intensely and an estimated 0.68 mg and 1.3 q of nicotine entered the routh (ratios of 2.18 and 1,851. When they smoked a 1.64 q nicotine i rigarPtlP, slightly lass inttnsaly, r$y obtained an ~rtiltld I.II nq of nicotine in the mouth (a puffing intensity ratio of 0.941· . 1 In t~le longer ten study by Turner et al (19741 there were differences 1 in thL niY~(T of tiplr9ftll ieoXld ~e:.pn a oodiu.nisotin, and a low-medium nicotine product but not between the ~ow-wdium and a ~ low brand. There was little difference between the medium and lou-medi~na ~j nicotine cigare~let Iputting intensity ratios af 0.62 and 0.711 hut subjects puffed the low delivery ~igarette rnre Intensely (a puffing ,*~ q] intensity ratio of 1.23). Clearly, the same subjects titrated by changing either the nuamer sloked or the smoke genention in order to I obtain their desired nicotine level, In the even longer study by Freedman and Fletcher (1916), in which there were only wall changes in the nupbers SllOked when subjects switched from a 1.39 mg nicotine cigarette to a 1.01 mg product, butt nicotine levels also shoved wire intense snokinq of the lover brand in comparison with the higher delivery cigdrett~. Puffing intensity ratios of 1.06 and 0.81 were found according to a reanalysis of the data by Rawbone (1916). In another long cross-eve! study, Ilaakpn vere studied for follr weeks, one uaek ii on their usual brand, two weeks on a low delivery cigarette and the fiM1 veek bdci; 9n their ovn cigarette (Forbtr, Rohlnron, Banley and Colburn, 1976), From hutt analysts there was poor evidence of cDaptnaalion although the rubjeerr were allowed t~ select their ovn .Ibv delivery product vllich makes is dif ficult to draw fin conclusions. \S ,, d ---·--,-~ ) b parr ~ adr *ih~ urfn9 sc rb nmd· id pll dlllaf, Creighton and Lvi~ (1978 a1 studied cigarette switching. Smokers smoked I medium nicotine ~.~ q) cigarette for cne month, a high nicotine (1.8 lgl cigarette for the second month and the pediur cigarette again for the third month. mt estimated aunt of nicotine that was delivered to the mouth of the smoker was assessed frcln ten laboratory sessions within each month. It was found that the loll of nicotine delivered to the mouth stayed constant because subjects re~~od their puifing intensity uhen they ~i~bed flm ~di~ delba~ to high delivery cigarettes and increased their smoking intensity for the ~~te sw~ch Iron high cigarettes back 0 nedium delivery products, However, subjects did not achieve mouth deliveries of 2.0 mg; men obtained 1.7 mg but women only achieved 1.0 mq in spite j of their increased sloking intensity. Crci~~n and Levis (1978 1~, believe that this effect was due to cigarette construction fe, j ventilation an~ longer apparent tip which inhibited aPking to the usual butt length, me clear conclusion was that sm3kers Ehnged their sPkinF Intensity in the direction of equalislpg nicotine dclivcriaJ, mere var no evidence, in this study, that smokers modified the o~r smokca cafh by, " Imda uda ai nm~LC oi rrh Cm~oq ICII (1976; I nll lneasurcd puff I·*L pdi vDluK rd pvff duratlcn, 4 veil r f~; butt nicotine. lle also found that smokers behaved d~illrlnlly on a low-medium nicotine (O.B mg) cigarette in comparison with a msdi~ delivery (!.I ~1 c~~rs~~i they peIfed harder on the lower delivery pr~luct and leit a shorter butt. 8utt nicotine analysis confirmed that m3re i~enee snoking resulted in ProFartionelly more alrotins being .taken into de mouths 01 smokers from the low nicotine than from tile higll nicotine ejglrette~, ~ similar switching experiment (Rau~n~l lar~~, Tate and I1ne, ]glQ studied smokers before and after they switched from their own medium delivery band (averaqe 1.22 q of nicotine] to In undefined *1~" delivery product. mly found ~~t i I 1 lUbjeCll IPhd ~dl Dn bl E~[ 61l~9 dCn~e in ~Ppdgl with their medium cigarette and compensated quitewell (0.83 Ig fo~ I low-medium against 0,9( 1( mt the Idia delivery bands), II I alh d ~~eld pB ·II+ Np hceac in m~qU· pt X·· : ~ ClibPDF - v~~fastio.soni sl pr :II~ 3. ~It~ !~~~· . s · ·'i ·~· ~!4,~.a~" i : Yi :P*?~,: L I I bl partial d~arctta in a partial cigarette study, khton and her colleagues (Alhtan, Stepnsy and n~np~on, 197~ tested subjects with b versions of ~ail usual cigarettes thrauqhout the atudyi a full length and a $ ·r·h~ ~~·, whiCh ·I.~~L~ fDr ·b hld~d inthl follouing manner. Subjects brought in the butts of their cigarettes, I 'o' "~h~p~d,.d ~Mlm n~~~, m,,,, ~~, cigarette normally saDked was calculated and then 1 mark was made on I dt ppr it tvo dlml of BL ~qd O indleete de c··t of tobacco that they could sote, The subjects uc~ issued with the same :· hd Ilh!d IIiked dpna·u ~4 ~( labd rlcpa~· hi ·d h asked not to supplement then, Tn this way each smoker vl~ deprfvld I b ·L ·e d~al bvt nD:by ·~ ·e ~~t, ··~. ~n~~ studies in La 1~8~q daed that rub)ects, ~418( btYds i cigarettes, ine!Ldscd their puff duration and decreased their puff interval showing sore intensive smoking of the reduced cigarette. ~· lor~a, ch( b~t dm~n stbna 9·d that auhjcets id net ~_ ~ 8. compensate for the reduction sufficiently to obtain their usual amount or dm~a, I Iakarr bd b* h ulI *pg I;Edh It d nns ~ The reason for this difference lies in the part of the cigarette that :1 was smoked In the two studies. It is thought that about 6] pr cent I ~~md~~g, Idl .~91 m·~ h. ~I~U~~, cigarette nearer the filter, and only 39 par cent from the other hall lCIitz ct al, 1976] and so the subjects were not able to compensate sufficiently In the Ishton It al study. I e. Sula~ n~sl EIUdipl have exanined the Ipki~ iulensity of 1~ mC high dellvc~ brands by estimating the nicotine delivered to thc mouth of a II lobn frDn lither d( 1·: of nimtine It pr dCdbd in the cigarette butt or puff ~plicltlon, ma conservative conclusion ~· ·h boayoi ~· h IL bl, nl ·~ In.·t.~, ~,.u~ lnachlne deliveries being ncrdy yields obtained from sloking ~1 a standard set of parameters), and that subjects tend to smoke low de]ivr!ry cigarc~ca an intensively and snake high delivery brands 3 r- ·-I~m~· . \(3 ClibPDF - v~~fastio.soni U g 1., a,,,,,,. ,,,,,,,,,,,,,,!,~t lal tii~, tip analysis method (Crelghton and Levis, 1978 al, It should be noted that although the filter tip analysis and puff duplication give an estimate of the amount of nicotine that la delivered to the aauth of the saPker, the value does not represent the ei[cctive dose because nicotine is not readily absorbed by the mouth from acidic snDte (see Section II A.I), Cigarette smoke must be inhaled for maximum absorption of nicotine. Of course over 90 per cent of snnkers say that they usually inhale to some extent and 77 per cent say that they usually inhale ha lot" or "a fair alaunt" [Todd, $ 1112 TRCI io it it likely sat a high percentage of the niroli. actually retained in the mouth is lade available for absorption by the lungs, but accurate neasures of the nicotine titration can only.. corm! from first estimating the amount of unuanted nicotine rejected fron the mouth before inhalation Ithe "vaste slnoke') and then leasuring inhalation itself, ]· ml~n~lllatian jl:; Sie manipulation pal·ticularly inhalatipn vas apparently the msrt NIF~il I*cl * Ihl nol.( hlbir $I MI SpialB rh.6:lf au ~ ,.. ~,;.. m., ,i,~,,,,.,.~,,,,.,~ .ss i; nicotine absorption. One index of nMnipulntion is the amount of carbon nonoxide exhaled after a cigarette, Carbon m3noxide is absorbed into the bloodstream from the lungs and not in the mouth, so that increased car~xyhaernnqlobin occurs only after inhalation, When the Ieaid~~ll sw~e has bean ~xpellad ilom the iungi, alter 1 iigarpltp, carton IDMtid~ exchange irol the blood to the lungs will occur so that the level of LlhUIPd Cnd·tindj Lllbn IPMXidP PILIYidCI an ind. ai uptakeal the lungs and so enables comparisons of smoke enipulation. a. Cigarette Switching in a study referred to twice before, svitching from smoking medium ( iou nicotine (0.3 mgi cigarettes was compared over a five hour work \O period by measuring exhaled carbon anoxlde (aussell at P, ]973), C: I i bPD F - !::!!::!!::!.f3 st I c.;: n ill ''"" ini(·u~:: !:* I' The problem of Interpreting the results was the difference in carbon m~tloxiJe yields of the two cigarettes and the fact that the subjects slightly increased mnslllapticn of the low delivery and decreased thl: number of higher delivery cigarettes smoked, Exhaled carbon wjnoxide decreased for both switches and Russell has argued post hoc that the decrease with the high cigarettes represented less inhalatlon While the decrease with the low cigarette! was attributable to the lover carbon msnoxide yield of that product. Plasma nicotine i, ncasures shoved clear titration in half of the subjects when switched to the high nicotine cigarette while there vas sDlhe evidence of 8i ·: titration for the group as a whole when pitched to the low nicotine cigarette, When Ashton and Pelford (1911) used unspecified high nicotine cigarettes and low nicotine cigarettes but With the same carbon monoxide delivery, the levels of exhaled carbon ano~ide were inversely proportional. to the nicotine deliveries of the cigPI·ottes giving evidence of titration sMke manipulation, ~:.:: Strong suprart for this conclusion was obtained from subjects who svitc)led from a high nicotine (1,7 mg) cigarette with 17.2 mq of b: cdrbon a,noxide to a lov-mt!dium nicotine (0.7 mg) cigarette with only 11,4 mg of carbon monoxide for five weeks (Cuillerm and Rndziszeuski, ls101, Cons~~mption increased slightly by three a day but carbon Ip~naxide levels increased fro~ 5.78 pr cent to 1.43 per I cent even though the machine estimated delivery of carbon wnoxide from the lou-aedium nicotine cigarette was lower. D contrast, thj shorter study of Turner et al 119741 found only slight evidence for compensation by srmiie sanipul~tion On the lover delivery brands, F3re convincing evidence comes from an eleven week crossover study (hrhlon, Stepney and Tllompson, 19781 in which smokers svitched from thrjr usual medium (1.4 mg) nicotine brand to either high (1.84 mg) nicotine cigarettes ie an increase of 31 per cent in deliver~ or Iov-medium (0.6 mgl cigarettes ie a decrease of 57 per cent in delivery. Tile exhaled carbn oonoxide levels shoved an Increase of only ]O pei cent on the high nicotine cigarette, and were only IS P"' C':"t I""' an the lav·medium cigarette. The plasa nicotine r ]uvcls shovPd a similar pal:tern indicating that considerable pst 3 i i i /ii Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill "~ :·c~. ~· ijwd~ ~15e~~ pulling titration had occurred, Urinary nicotine excretion on the high dcoNns cigarette gave no support for titration when the Iachlne dclivcq of 31 per cent higher tban the usual brand was latched by urinary nicotine levels ~ per cent higher with the high nicotine cigarette than with the usual brand, Aowever with the low nicotine cigarette, at 43 per cent of the usual cigarette the 2( hour excretion was 94 pr cent. L-ltogether this study gives strong supp3rt for nicotine titration by ~~ks ~anipulation. ~· P~'t~!~e~4~. me txpeliment with half and Ihree·~arter length cigarettes of Russell et al (197p) also included determinations of exhaled carb3n Il~xida and plasma nicotine. lllthough I~kan used 1 greater ~~ir of the partial cigarettes, there was no evidence that they inhaled are carb3n moMlxide than would have bean expected from the sire of the ej9arettes and the pla6M nicotine was at the expected level as veil, suggesting no tftration, We Will return to.thi8 antndic$8 thSllti~P In the next sub-section, P~~· dr (~~5~~1 c, Vcntll4ted Holder L ~~ 81: ·' Tne results of the study on the ventilated holder (Sutton ct al, 191nl ~icb gnl m n~rt for titntlol i, tint oi the I~tr I·~pd i dd prcvidc pit evidence far titrlticn t ~h anipulation. 1 . I O~rLI oi thr b~n~ a II crnt nbaLI d ~r~,,,d' by II the nora ventilated hPlder at two days 1~ seven days with the expeted i ; reduction of 52 par cent showed partial but lignificant e~pnla~ion j I ~d u N~.hl d~~I ~ tlwi hn.-1W b · I compensation with the less ventilated holder which reduced c4r~n i ~ nonoxide by 15 percent, Tnl optep~ in ~1,,,1 pLII ILa~P4' ' r~ln~~el ot Ig a,,,,,,,,,,,,,,,, pr cat (R=/ I~·· which mnfins the effectiveness of Sake manipulation as a titr4tion nlehanism. This clear finding contrasted with the study of Russell et 41 ~918; Russell, 19801 inwhich partial cigarettes were J~kad, U~~ugh 8olerr ~nJPcd sore cigarettes in this study, their eqlrcd a Fllbl ~DIjdl and plasma nicotine levels were the sale as tbl~ i predicted if no titration had occurred, This study implies thlt I T~ s~ka concentration is the Ne for sake manipulation .because total ( O L r~ ClibPDF - vwwfastio.coni i. WIIYPti~ ·_· In~e inhaled increased for sP~e diluted by ventilation but not when I de ioh concentration *1 the pi · in the partial dCnan (Russell, 1980) , d. Nicotine Pteloadfn~ Rs pit ai a series of studier on titration we adninistsred an oral 1 1.0 Iq dole of nicotine to sokars prior to smoking a Iw·)ldi~ nicotine (0.6 ing) cigarette IWesnes, Pltkethley and Warburton, in propara~ionl~ The subjects were not told the true nature of the study and thought they were participating in a study of sinking and the eflect of absorption of pure nicotine on hand troer, puffing I ~*na4 *~ nicorinc and c(haled Ir~l pp~y( I· n·nb No di ffarences were seen In puff duration and puf f interval of the butt nicotine levels for the nicotine and placebo eonditioPI. BovcP,r, there was a significant reduction of exhaled carbon monoxide after the I subjects had received a nicotine tablet indicating reduced s~La intlalatlcn. eladrly the sm3kers vsrs titratfng bafr nicotine dose by ~ I ; j smoke manipulation according to some internal mechanism sensitive to plasma nicotine lovels. j 1 e. g~V~ I 1.' I Nicotine *Oh can be controlled bY the IIPr of I·hd inhaled as . well as by cigarette consumption and by sake generation. The aro~t j of sm3ke inhaled depends on 1 combination of the quantity of waste sole (the surplus expelled before inhalation) and the degree of 1 inhalatioa~ Raubane st at (1978) compared exhaled carbon monoxide levels with sate generation measures and found a correlation. Some g s~lerr puffed relatively little hut perhaps wasted little and inh~cd the rcuining sm3ke deeply, others puffed hard but perhaps wasted pre and inhaled little, Thus, mechanisms are not necessarily 1 intcrdrpendcnt, As far Is nicotine absorption is concerned, inhdlation is the final control on intake. I 1 P OU Clib~l- v~~fastio.soni a, Concl usions The experiments in this section were designed to investigate to what extent nicotine intake was controlled and the changes in smoking behaviour that enabled control, Taken together the studies show that nicotine intake 3 is tit.lld.ioin mn nimrba Imn la*r dliiarl Franrr,i mt less nicotine from higher delivery brands. The methods of titration are I IIIVbCI.L IYlitl I.Lld. thp LOlljLh PI Cipltt( ppled, Ihl ilnil$ of smoke gcnc·ration, and the amount of snwrke nwnipulation (waste smoke and inhalation), unfortunately, most studies have only studied one of these titration mechanisms and found that some subjects do titrate, some titrate I partially and some may not titrate at all using that particular method. Indeed it may be possible to titrate completely with some low delivery brands and the plasma nicotine levels in the studies of Russell stjppoit this j d(llltiOn. Evidence for control over the nicotine dose is important, It argues I:i.ii: not only for nicotine being a necessary condition for smoking but also -· · thit miierr Ire t:yiop. ~bllin~l dar~ uhiSh ulll pmduel dnind.r neekd pharmacological effects. Before considering the range of these pharmacological effects of nicotine it should be pointed out that the titration evidence suggests low delivery cigarettes will not necessarily be safer because they are oversr~3ked and tar exposure will Increase to medium delivery levels White the carbon nonoxide levels can exceed those of high delivety Eiqarettcs (hshton and Telford, 19731, Lovering ii :::·: 1~ deliveries can only be done effectively when we understand more fully the '' " C " cues and mechanisa that smokers use to adjust their nicotine intake. il·~·~. ii. :.··· i .. I ~·. · i:. 3 I ~seari: Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ~!~;JY~Y:X·""- ~PL~~· j~ i: . - r~4 : Xre ~~'u .H' It, NICOTINE ~I~MWMICS In this section we will discuss the actions of nicotine on the ncrwos j. : system and on behaviour which may be used to account for the smoking habit. The literature is vast and so only illustrative experiments will be cited, In the first section the emFhasis will he on the neurochemical changes that are produced by smoking doles of nicotine, In the second section the neurophysiological effects of nicotine will be outlined, In rhe third section these changes will be related to nicotine's effect on Psychophysio]ogical measures that have been associated with behaviour, The tinal, fourth section will discuss nicotine's action on human behaviour - the psyehopanbcology of nicotine, i : 1. Weurocheaical hction of #icotins Nicotine muld lnJdify neural tIanslpissiDn by inrcrfsring vith one or I nl o! lhl I~a~ Bn ul ~~~~I hr thl a~~~l Df I: transmitters ic (1) hlter transmitter synthesis byeither changing the -- 1· availability of transmitter precursors or changing the activity of the a~*~u* a~sL ~ hbdcr dL Le ~rp*Uc rtarlg, ~11 i! transmi tter, (3) Modify transmitter release into the synapse, (4) hirer I the rate of traasllrtcI inactivation by modifying the inactivating anrye or the presynaptie reuptake (Watburton, 1975), There is evidence in the literature f~l in vivo animalstudies tbat nicotine prodIlcel ehangca In the bnh lev~s pf catecholanines, indoleamines dnd acetyleholinp. Tne crucial questions are hou can thpse j · changes in levels be related to the dynamics of transmitter systems and whether these changes can be Ixtr~~latpd meaningfully to humans to explain tile snoking habit, 1 major problem, with the majority of these animal studies, is the unrealistically high dose levels of nicotine that have been tested, 1 j 75 kg person, wllo takes between 0,75 and 3.0 q of nicotine from a cigarette into his mouth, will receive a dose of between 10 and 40 ~q per r C \Cj \Cj O ~1 ClibPDF - v~~fastio.soni i $~i ~4/~L*·~ :":'~·: i '.iE*:: Irg, mis figure 15 close to that derived by Armitage (19741 who calculated that the dose inhaled from each puff by a snaker Is equivalent to an intravenous Injection of 1 to 2 pg per kg. Assuming about ID to 20 puffs per cigarette, this will give a dose of between 10·40 W per kg per cigarette. Ihele will Obviously be differences because of the route of adnlinistration (inhjlation and intravenous injection versus subcutaneous and intrapetitoneal injection) and the different metabolic rates of different species, but it is probably safe to conclude that in mice, rats at eats, any dose which is over 10 times this dose 10,1 mg/kg) is well outside the "snl~king" dose range. I. CJt~cllol amines r:. ~~ ·· Studies on the catecholamines, dopamine and noradrenalin have been j carried out by tiehtensteiqer and his co-worters (Lichtensteiiler, Felix, lienhait and Hefti, 1976; Lichtensteiger, Richards and Wppe, 19781 Lichtrnsteiger, 1979) by Fuxe and his colleagues (Fuxe, Rgnati, Eneroth, Cuslafson, Hsiifelt, tofstrom, Skett and Skett, ]977;.Eneroth, Fuxe, bs~tdfsdn, Hckfelt, Lofstrolo, Skett and Agnati, 1977 a and b) and Westfall's laboratory (Westfall, Flerninq, ~dger and clark, 1967i Westfall, 1974). These studies have given the same general picture in spite of wide / ;::: differences in nicotine dose levels, which ranged from 0,33 mg/kg in one of ~lchtenstejper's studies to four doses of 3 sglkg at 30 min intervals in one of the experilnents of Fuxe's group. tlchtensteiger reported that the fluorescence intensity of both dopamine and noradrenalin neurones was i (~·~:· with doses of 0.33 mglkg and 1.00 aglkg of nicotine, suggesting increased I~ increased in the substantia nigra nuclei, zone colnpacta and zone incerta activity in t~hese neurones. Tills conclusion uas supported by nicroelectrode I recording of the nlumnes and hiochemical analysis which shoved sons iI I' I:·i·· depletion of both uanlmitten, wesrfa)l has also found that dopnina was reduced in the striatu~n of the mouse after 1 aglkg of nicotine injected intnpritoneally, I ~·'I · i : Ilu 16 lichtenstciger also reported increased fluorescence of dopamine · i neurones in the rat median eminence of the diencephalon after 1 ng/kg I j:jG i~ 5~;6x ·· .t 1 1 of nicotine and weltfall had previously found that this dose produced about 20 per cent depletion of noradrcnalin in the sane region in the mouse, I loth of these findings would be consistent with increased neuronal activity In these catecholaline neurones and Lictensteiper demonstrated, with Ijcroelcetrodes, that there was increased neural activity in this region as 3 well as decreased growth hormone and prolaetin secretion In the blood stream ( dopallaels thought to be involved in the secretion of these hormones), I There was also ale evidence which us compatible with nicotine activating dopamine neurones controlling lutcinilinq hormone release, Fuxe and his group investigated the specific relation between nicotine, r catecholamines and gonadotrophin secretion. Unfortunately, they used large doser of i mg/kg, 2 mq/kg and 3 mgltg injected four tiles in 90 mins before ,· 1 sacrifice and assay. Nicotine produced a depletion of 25 par ~ant in · catecholamine levels ill the mediln palisade zone of the Iediln sninance of male rats (Fuxe ct al, 1977) but hcxamethonium prevented dapletion, I Ro changes were found in dopamine or noradrenalin receptor activity in i, vitro studies so the changes are secondary to effects on cholincrgie - · ~ · I neurones, They also observed a reduction of 1Ptcidrlng hormone and I::··, i ~· ·- prolactin secretion in flail rats, The implication of these findings for I human sraking is dubious due to the very high doses that were used and It would be quite wrong to conclude from this data alone that nicotine I could produce hormonal problems In pregnant and lactating women who smoked, 2. Indolcalines It ehlpges in the concentration and turnover of serotonin have been found after doses of nicotine. 1 dose of 1 mgltg of nicotine, intraperitoneally injected into lice, markedly increased the levels of serotonin in the L Rsencephalon and diencephalon within IS lies hut pot in the cortex (esslan, 1971). ra the same study SerotOnlP'I major metabolite, S.hydroXyindo] Plcetic L acid, was also increased but there us a decreased serotonln turnover rate of 20 pr cent and increased serotonin turnover tile (~300 per cent). These data are not simple to interpret but clearly with this Pdet~tcly i ~. . large dose there are increased serotonin levels in some brain regions i'J; r CllbPDi: v~~fastio.soni j~p~~r~i ,,,,, ,,, I~~::al ~b3*g: ~I L'*' ·~: prcbahly due to increased synthesis and decreased release At, In spite of the decreased release, the large intraneuroPa1 IccuPlltioa results in ~~ leakage which elevates the level of 5-hydmqlndolalcprle acid, it is not clear whether the changes In serotonln after a lnoderetely large dose of nicotine are important for hrn sIsokIng, Acetylcholine Nleotine Jcpletcs whole brain acetylchcline in the rat (PePeu, 19691 and ausl ~E51b~ ~~) In b~J of I lgl~, nenlotion of tran~l~sr could ~ a eonsquence 6f deeroa~d ~ynthesi~ incteassd nllase f,ol ~1 stonqa, increased release into the synaptic cleft or oora effective 5! ;x~~· ,elk autivation. There is p lvidencc th(t dedac lpdlfies P acetylcholine synthesis (llrdina, 1910 and the pnrylbtic inactivation of ~cctylchol!ne without any drug is extrclcly effective, which argues for a change in either s~raga of release, More ilprtantly, there is strong evidence for increased free acetylcholine at the cortex after a Is~kL~n dose ~O ~qlkg intravenourly) In the cat (~l~tagc, Hall, sellers, 19691 - - which is consistent with these two hypotheses, I ~· ~e question of nicotine-induced changes In bcetylcholine storage ~Dls was tackled by EJs~n (19i~, He found evidence of a decrease of ~~lpl~ ,~,~, brC* II·~*·~I~LLI·b namrtcx which suggests that aeetylcholine vas being released ira storage by nicotine, However there was no increase in the free acetylchoilne Pool i .R~'· concantntion which argues for increased release of the u~und trsn~aittsr .j . and subsepuent inactivation by IcctylF~linaes~rras. The phenoneron oi 'i· increased release at the cortex would be explained if nicotine enhanced prosynsptie release rchanisnJ in cor:ical tissue hut there is no In 11~4~. t~· ojhsr of el~rcr~ ade4 ~H1· ~al, I are LR db the Ct~se that it II increased activity in the cholinergie neurones to the cortex which produces the in Viro depletion. Conclusion ihcre is evidence that Iderate to a,mr doses of nicotine cause changes in catecholamines and indDlealine~ although the eatsebl~lne j chsngcr were being 8cdiated by chollnlrgic Pathways, However, 19 O ·ti rv ClibPDF - v~~fastio.soni ·rc:~·~ :.I"` ·· :·~ 31. : · ;···. ·· Donino (1973) pointed out in a review of the behavioural studies, we must be cautious:- "The relevance of such large doses of nicotine given subcutaneously to the much smaller doses inhaled by man is certainly to be questioned* (PfO). The major effect with "smoking" doses has been to increase cortieal release of acetylchoiine but there is no evidence that release is due to a direct effect on the presynaptic release mechanisms of cortical neurones, one solution to the paradox lies In indirect activation of acetylcholine neurones which form part of the ascending cholinergic pathways to the cotter; this is discussed In the next section, B. Neurophysiolgical Action of Nicotine The action of many drugs has been explored by using the more.teadily accessible neurones in the peripheral nervous system which are Pare ,i····.,- accessible than those in the central nervous system. Although caution must be Exercised when using this data to explain central nervous system phenomena, in general, the principles that have been derived from such j studies have proved useful in understanding the action of drugs on the brain. Thus the first studies will describe nicotine's action on these neural junctions. 1. Peripheral Nervous System The action of nicotine on the nervous system has been known sines the pioneering work of Dale who published a classic paper on acetylcholine "The action of certain esters and ethers of choline and their relation of muscarine" (Djle, 1914), This work established that nicotine mimicked the action of acetylcholine at autonomic ganglia and nwrornuscular junctions and later it was established that acetylcholine was a transmitter at these synapses. Dale's work also revealed that some acetyleholine s)napses, the p3st-ganglionic parasympathetic neurones, were better stimulated by muscarine than nicotine,and so it has become conventional to sub-divide perjrlleral nervous system neurones into "nicotinic" and "muscarinic" on O th! l;ilsis of their differential sensitivity to these twc, agcnists - the two sorts of ngonists that have been discovered. These neurones m C .:··· Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill : :. ~ : ;. · I~~tf:· I,_~r.~f; :.. .. · ···;· · 1:I I,i·5! I differ in the pst-synaptic reeeptors as defined by krehcott (1964):- "The specific molecular sites in (or on) the effecter cell with which the molecules of a specific agonfst must reset in older to elicit the I characteristic response of the fell to the aqonistn. In the case of nicotine the characteristic response is Fostsynaptic deplarltation. The effects of different doses of nicotine on cell me~rane i ~la~lrua~ia~ Ira rual.u~t Inipa atotilll n..rl~ bl Pit.n md ~etry, (1953) using the cervical ganglion preparation of the cat, The g drug was injected into the external carotid artery and all branches of the con~vnn carotid were blocked except the arterial branches supplying the ganglion itself, and the occipital artery to allow free blood flow past the cjangljon. Then 0.2 mi of the solution containing 50 eg of nicotine tartrate was injected into the external carotid artery, This concentration d is much larger than the 20-30 nglml found in the forearm vein after smoking (see Section II) but say he closer to the concentration ascending in the cdrot.id artery after inhalation because none of this nicotine will have been mttabolised, The effect of this dose was depslarizatian of the .J~: * ~;' . ·· I nabrin.d Knl eduotian of BI rubrqueat laj.l p~mtiali, a pBngl which was similar to, but more transient than,the effects of a small dbse of acety]choline. ~j·.·. O Aouever 0,3 ng of nicotine, six times the shove dose, produced prolonged :i: · ~···: ·': *·. ?r·:· depolarization and the action potentials uere a~lished ie ganglioniE blocking, a challenge vith a second dose of nicotine after the oricllanl I depolarization, but before recovery of the action potentials, produced less depolarization than previously which demonstrated that nicotine was D p'0dcing a co~:itivt blorli of eholiwgir.raptu. II vlrl hish doJa. Exactly the same phenomenon has been observed with high doses of fl acetylcholine at the motor end-plate so that once again nicotine is mimicking acetylcholine, It has been suggested that the desensitization 1 arises fret the transfor~tion of the aeetylcholine receptor complex into an inactive forte (Kat: and Thesleff, 1957) and that the same effect occurs I with nicotine, Whatever the reason, it seea unlikely that blood concentrations some 100,000 times that found in the human forearm vein ever occor in the saker's brain and hence unlikely that a depolarization block O occ~~rs In brain neurones after nicotine, In sunrmary, "snoking" doses of \O rrn CS C·l C ~~~c: :'~CyS~ Clit; PDF -!::!!::!!::!.f3 StlC.i: Dill ~#yy: 1 36, nicotine precisely mimic acetylcho!ine and produce the same neural changes I thlt ~uid.r.r Iml .fu* nPPuan.f thr rya,pll. The reason for the exact mimicking of aeetylcline by nicotine at some cholinergic synapses is the remarkable similarity between the 1 structures of the two molecules. Analysis by X-ray diffraction crystallcgr~phy has shown that in order to interact with nicotine receptors, s 1 nl~Ni, n~rr nnain pf,lla~a, aot~.(rPop r..I~Lllling