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Na fa-~ a/- N/C IJIL~I~~~ Qc•~ P't t)i eo Se ' . .. r,I. Cigarette Smoking: A Dependence on High-Nicotine Boli* M. A. H. RUSSELL Addiction Research Unit Institute of Psychiatry no Maudsiey Hospital London, S. E. 5, Engisnd and C. FEYERABE\D Poisons Unit New Cross Hospital London, S.E. 14, England 1. INTRODUCTION .. . .. . .. . . . . . . . . . . . . . . ... . ... .. .. . . 30 .:• U. CIGARETTE S:.IOKIKG AND NICOTINE DEPENDENCE ........... .......................... 3 M. DEFINiTIO:r' OF "DEPET:DE2:CE" AND "A DDICTIO\" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 IV. A'ICOTII:E AND ITS METABOLITES .................. 33 • V. : THE lA1PORTA:CCE OF pN .......................... 34 •Preseat.ed at S}•mpositm on Drug Disposition In.Man Deld In Sara- sota, Florida, November 6-11, 1977 under the auspices of the Ameri- can Society for Phsrmacology and E:cpcrtmental Therapeutics. 29 COpyfi{hl 0 1971 by Mair) 9t1\ct• Inc. All Ric1.11 Rrxr•rd \ttihU tLn -ort not any fart r.ay be upaolrccd or tnmmdasJ in sny form or by any mrinr, rt<cuon.c or mrchsnrcal..nc7uJirc phaotoFr,nt, mierofirmnj, and rreordinj, or by any ,ntormanon uo.+tr rnC ume.bl +)+rrm, ',,r14AYi p•itCWICt11A -.I1IR1 from IM p.b:uRrc.

VI. ABSORPTION OF NICOTIA'E . . . . . . . . . . . . . . . . . . . . . . . . 36 A. Buccaland Nasal ............................... 36 B. Ingestion of Nicotine ............................ 37 C. Absorption through -heLungs .................... 39 VII. PLASMA v1COTINE AFTER INHALATION AND 1\TR.aVE1Ol;S DOSAGE . ........... ......... 41 VIA. URI\ARY E?CCRETIONOF NICOTI\E ................ 43 1X. RECYCLING OF N1COT1NE ......................... 44 X. PROLONGED HEAVY S,'%1Oh7NG ..................... 44 \'I. PLAS%tA 1l?.LF-LIFE OF A'ICOTINE ................. 46 XII. DECAY CURVE REBOUNDS ......................... 49 XIII. DISTRIBUTION OF N1COTIrE TO THE BRAIN ........ 50 XIV. "PEAK-SEEKERS" AND "TROUGN-.NiAlINT.4IIERS" ... 51 XV. HISTORICALASPEI;TS ............................. 52 XVI. MCOTINE BOLL'S DEPENDENCE .................... 53 Acknoa•led.-mcnts .................................. 54 Refcrenccs ........................................ 54 1. INTRODUCTION Tobacco smoking is a form of drug dependence, and the modern cigarette is a highly efficient device for self-administering the drug nicotine. By inhaling, the smoker can get nicotine to his brain more rapidly than the beroin addict can get a"buzs" when he shoots heroin Into a vein. It takes only 7 sec for nicotine absorbed through the lungs to reach the bnin, compared with the 14 sec It takes for blood to flow from arm to brain. Furthermore, the smoker gets a "shot" of nicotine after each Inhaled puff. At 10 puffs per cigarette, the pack-a-day smoker gets more than 70,000 nicotine shots to his brain in a year. It is hardly surprising that cigarette smoking is so ad- dictive. In this paper we shall not go into the evidence showing that smokers. smoke for nicotL)e, nor shall we go into all the pharmacologic effects of nicotine which may be highly rewarding and a source of so much pleasure. This is a conference on drug disposition, not drug action. i

TV.~ ~;,y;. g p g g highly addictive. and noninhaled pi In tnbacoo chewin e and ci ar smokin ) is so ?=~ by it Is that cigarette smoking In particular (as opposed to snuff- 31 o:, A e shall, however, try to show that throughout history the way people ve used tobacco can be eNplained by the pharmacokinetlc chanc- ;.a"r%.•tertsttcs of nicotine within their bodies. We shall also try to show t -T`~L~~X . • L~.~i'•1iS` CIGARETTE SMOKl\G ~ • ^`~~w U. CIG?rRETTE S11OK1\G AND NICOTINE DEPENDENCE Three out of four smokers either wish to or have tried to stop smoking [1, 2), yet no more than one in four of them succeed in stopping permar,cntly befot•e the age of GO (3). Thus most people smoke not because they want to but because they cannot easily stop, andJor such cases smoking is obviously a compulsive activity rightly classed among the addictive behaviors. indeed, cigarette smoking is probably the most addictive and depinder.ce-producing form of object- specific self-administered gratification known to man (4, 5). This simply means that, throughout history, no other single biologically >'necessary object F3s meant so much to so ma.ny people who, after so few initiating experiences, have needed to have it so often and so regularly, for so many ycars. despite trying so lard to do without it; and for which there is no other adequate substitute. Stated plainly, tobacco smoking is a form of drug dependence different but no less difficult to overcome than dependence on other addictive drugs [G, 71. The majority of people who drink alcohol or use cannabis are able to limit themselves to occasional use and easily tolerate periods free of the pharmacological effects. No more than 5% or so of people who use these drugs become dependent. t1'ith cigarette smoking the situ- tion Is altogether different. No more than 5% of smokers limit them- selves to occasional smoking; once or twice a weck or less. The ma- jority are regular dependent smokers who seldom go more than an bour or two without smoking, and over 60% report that, when they have no cigarettes, they frequently feet a craving for one (1). Fur- thermore, dependence on alcohol or cannabis tends to arise In set- tings of social or psychological problems whereas with cigarette smoking the most stable, well-adjusted person will, it be smokes at all, sooner or later almost tnevitably become depcndent. The nsual smoking of more than 2 or 3 cigatettes during adolescence is almost invariably followed by eventual escalation to regular depen- dent smoking which then, in the majority, continues until middle-age or beyond [1).

32 RUSSELLAi.*D FEYERABEND For the past 20 years tbere have been all manner of antismoking eampaigns, in the press, on radio, on television, in schools, and at places of work. Health warnings have been put on cigarette packet.s. Restrictions have been imposed on smoking in certain public places. Advertising of cigarettes has been banned on television In some countrtes, and banned altogether In others. Cigarette withdrawal clinics have been opened (and closed). All this has-achieved very little. There has been a modest decline in smoking among men of middle-age and high socioeconomic status (6), but women and children smoke as much as ever (3). Some 20 million Britons and almost 60 million America:.s still smoke. Follow-up results after successful treatment at withdrawal clinics show the same high re- lapse rate for cigarette smoking as occurs in the case of treatment forheroin addiction and alcoholism (8). There is little doubt, therefore, that ciprette smoking Is a highly refractory dependence problem and there is much evidence that the main determinant is nicotine (5). Smoking doses of nicotine produce a g-reat variety of pharmacological effects, centrally and peripherally, by direct action and via the release of neuro-transmitters. Ilese ac- tions and the evidence for the centr.il role of nicotine in the generation of cigarette dependence have been recently reviewed elscwherc (5). III. DEFI\1TION OF "DEPEKDE\CE"AN*D "ADDIC7lO1" In essence, the terms "dependence" and "addiction" refer to a state In which the urge or need for something is so strong that the individual suffers or has great difficulty In going N•itbout it, and In extreme cases appears unable to stop using it voluntarily when it Is available. We do not propose to discuss here the nature of dependence or addiction, the interaction of conditioning and pharmacological factors, nor do we In- tend to go into a setnlntic and concepttal clarification of "physical" versus "psychological" dependence. We use the terms "dependence" and "addietton" Interchangeably to refer to the urge or need for an ob- ject or activity. How high a degree of dependence Is required before it Is labeled a"dcpendence disorder" or "oddtctlon" Is somewhat ar- bitrnry. Furthermore, pharmacologicai rewards, both primary (e.g.. stimulant, cuphoriar.t, anxiety-reducing actions) and acquired (relief or avoidance of physical withdrawal effects), are really no more than classes of reinforcer, just as psychological rewards or so- cial pressures are other classes. The degree of dependence on a par- ticular object or activity Is governed by its power as a reinforcer

~~•' j•::?..`x~~ ~ . ) i.~.n.-~:• '"'CIGARETTE SMOKING • 33 ~ r. '•~•.~•-•: + rp ..;. :t,'rather than the class of reinforcement It provides. Thus strong psy- ~ cbological or social rett•ards will make for a higher degree of depen- dence than weak pharmacological ones. If the term addiction Is used to denote strong depende:tce, it need not be restricted to refer only t;::• }.•: to strong pharmacological needs but could equally apply to strong non- ta;,._ t,•:• pharmacologic needs as in the case of addiction to gambling, television ,~ . ~IIj.'vieWing, or sweet tasting substances. SI:r.ilarly, dependence based '.+i.on powerful primary pharmacological effects, as in the case of cocaine '': : for example, can be as strong or even stronger than dependence which :'. lnvolves pharmacodynamic toler:.r,ce and physical withdrawal effects. With tobacco smoking there is no shorta;e of potential reinforcers. c•`:' Besides the variety of psychosocial, sensory, manipulatory, and oral rewards of smoking, nicotine produces a whole array of potentially rewarding pharmacological effects. Tolerance occurs :o some of its actior.s and there are ohe:t physical effects as well as psychological symptoms on withdrawal [5]. Thus whatever cri:er:a of dependence or addiction are applied, nicotine is an addictive drug and to5acco smoking a highly addictive bets~•iar. IV. NICOTINE AND ITS M F"fAIIO11TES \icotine Is one of the few natural liquid alkaloids. It is colorless, volatile, and strongly alkaline. It turns brown on exposure to air and gives off a characteristic tobacco smell. It is readily soluble in «•a- ter, alcohol, and etber, and forms water-soluble salts. Under at- mospheric pressure, it bolls at 346°C. It is volatilized in the cone of burning tobscco, 800°C, and the free base Is present In the smoke stspended on minute droplets of lar (0, 3 to 1.0 pm) which are small enough to reach the small airways and lung alveoli. Nicotine has the empirical formula CtoHt,Nz. Its molecular structure Is that of a pyrid(ae combined to a pyrrolidine ring (see Fig. 1). The metaboltsm of nicotine will not be discussed in detail here. Recent review•s are available [5, 9). The two main raetabolites of nlcottne excreted in the urine of smokers are cotinine and nicotine- 1'-N-oxide'(see Fig. 1). They are formed respectively by a-carbon oxidation and N-oxidation of the pyrrolidine ring. There are individ- ual and sex differences In the extent to which these two patbx•ays are used [10). Smokers metabolize a greater proportion than nonsmokers of as lajected doze of nicotine [11]. This may be due eitber to inher- ent differences or to taduction of enzymes in the smokers. ldeubo- Itaa of nicotine occurs mainly in the liver, also in several other

;\~ R S' ~~T~• ~i~ ~~~ '' L .o! ...~~.~vr/~w~.r~.~r~ ~rr•.~e ~ti5• ~.1~`}~~"'~S,-v_~i•t Nicotine-N-CaiOe FIG. 1. \icotine and its two main meLZbolites. The stx-atom ring is the pyridine ring; the five-atozl one Is the pyrrolidine ring. tissues, but not In the brain. Neither metabolite has any appmclable psychopharmacological activity, with the possible exception of co- tinine [12). Vfcotine-N-oNide Is reduced to nicotine by intestir.al bacteria. This recycling of nicotine Is discussed below. V. THE I>1PORTAICE OF pH The absorption of nicotine, its disposition, metabolism, and ex- cretion, have recently been reviewed elsewhere (5, 9, 13). In this paper we will not go over all this ground nor even attempt to sum- marize it. Instead, we will focus on those aspects which have par- ticular relevance to tobacco smoking and which may throw some light on the high dependence-producing potency of cigarettes. We will also present some prelitnfnary new data pertaining to these relevant areas. In contrast to the nlcotinium Ion, as the undissociated (free) base nicotine Is lipid-soluble and readily permeates cell membranes. As such, It Is rapidly absorbed. not only through the lungs but through the skin, the buccal snd nasal mucosae, and the gastrointestinal tract. As the free base, It 1s also rapidly reabsorbed through the bladder and renal tubules. The pKa of nlcotlne Is 7.9. Thus, under acfdlc conditions very little nicotine Is present as free base, whereas at pH 8 the proportion of free base Is 52%. The absorption and urinary excretion of nicotine are therefore pit dependent. Flirtbermore, pH partition considerations mean that where pH differences exist across cell membranes, the concentration of nicotine will be higher on the side where the pH is lower. Thus one would expect the concentration

ir:r r CIGARETTE SMOKING . rs, . .• ti220 200 1so 521iv7 20; 120 100 E9 60 40 1 y Plzsms U 0 10 20 30 U 50 bl ~ Time, min Nicotine injection FIG. 2. Plasma and salivary nicotine concentrations after rapid inlravenous injection of 1.711 mg nicotine base given over 1 min (see Fig. 6). 35 of nicotine in gastric juice to be many times bigher than in plasma; almilarly for parotid saliva which in man has a pH of about S. 5(14 ). The auloradiograms of mice following intravenous Injections of "C- nicotine by Schmiterlow and his colleagues (35) show clearly that nicotine is concentrated in the salivary glands and stomach. To our irnowledge, there are no published studies comparing plasma and salivary nicotine levels in man. Such study obviously requires that the nicotine be administered so as to avoid cootamirating the mouth. Figure 2 shows that following an Intravenous injection the concentra- tlon of nicotine is very much higher In saliva than in plasma. The average ratio of the saliva to plasma nicotine concentration In Fig. 2 is 12.7. The picture is much the same when nicotene is adrninistercd by ingestion In gelatinc-coated capsules (see Flg. 5 below). The high

36 RUSSELLAh'D FEYERABEI.'D salivary concentrations were not simply due to the fact that the sub- jects had been loaded with ammonium chloride to acidify the urine, for the ratio Is similar when urinary pli is not controlled in this way. VI. ABSORPTION OF NICOTIb°E A. Buccal and Nasal As mentioned above, The absorption of nicotine is pli dependent. The Influence of pH Is more strongly evident where the surface area is limited as to the case of the buccal and nasal :nucosae. Armitage and his colleagues have shown that the rate of nicotine absorption from solutions in the mouths of cats was very much higher at plt 3 than at pH 6(16). and the results are similar in man. [17]. It. is not only expcrimental solutions, however, that have pli ranges span- ning the rise of the nicotine dissociation curve. The pH of air-cured tobaccos used mainly in pipes and cignrs, but also in some brands of cigarette. Is apparently aUalir.e (about p1i 9.5), whereas smoke from flue-cured tobaccos present in most bi:inds of British cigarette pro- duces a relatively acidic smoke (about p14 5. 5). Buffering capacity of the smoke is another pertinent variable. Before it wos possible to reliably measure nicotine levels in blood, Armitage and his colleagues developed a bioassay technique (16, 1S- 20 j. In a series of Lmportar.t studies, they used The effect of nicotine on the femoral arterial blood pressure of anestbetized cats as an in- dex of nicotine dosage. They were thus able to show that 30 25-m1 puffs of cigar smoke (pH 8. 5) Introduced into the mouth at 30-sec in- tervals over 15 min produced an Increase in femoral blood pressure, whereas a similar amount of cigarette smoke (pH 5.4) bad no effect (16]. This difference occurred even though the cigarette smoke con- tained more nicotine than the cigar smoke. They were therefore able to clearly demonstrate the pH dependence of the buccal absorption of nicotine. However, the effect of buccal absorption of the 30 25-m1 puifs of cigar smoke was small and slow to develop; whereas, in sharp contrast, a single 25-m1 puff (whether of cigar or cigarette smoke) Introduced into the lungs produced a far larger and almost instanta- neous effect (20), showing that buccal absorption is very much slower and less efficient than absorption through the lungs and that rapid ab- sorption through the lungs occurs even when the smoY.e is acidic. While more recent plasma nicotine studies (Fig. 3) certainly oon- firm that nicotine is absorbed rapidly when cigarette smoke Is inhaled

CIGARETTE SMOKING 37 h t~ tto t~ FIG. 3. Plasma nicotine concentrations in an L^haling smo::cr and a noninhaler during and after smoking one cigarette which was dis- carded at D= 0 rain. Plasma nicotine was measured by gas chroma- tography (from Feyerabend, I.eti•itt, and Russell (21;). but negligibly when it Is not Inhaled, there are still no human studies sbow•ing that nicotine is absorbed from pipe and cigar smoking with- out inhalation. This would require the demonstration of an Increase in plasma nlcottne witbout a concurrent increase in carbox)-b2emo- globin (COHb). However, chewing-gvr.t containing 4 mg nicotine and a buffer w'blch Y.eeps the pH in the mouth at about 8.5 does produce plasma nicotine levels comparable to cigarette smoking, although the rate of absorption is slowcr (see Fig. 4). B. Ingestion of Nicottne When nicotine Is absorbed via the gut into the portal system, it is mostly metabolized In its first passage througb the liver. Animal stvdies have shoWV that fatal doses of nicotine have little effect when giYen Into the portal system [23] and that blood and brain nicotine

0= 09 10 ll 12 13 14 15 16 Time (hours) Cigarcttc smoked I t t t I t t Urine pi) 5.0 4.7 4.8 4.7 4.7 4.8 4.7 4.7 01 09 10 11 12 13 14 Time (hours) 15 16 ritltn chewed reo m ~ ® ~ ~ a Urine pH 4.8 4.9 4.8 4.9 4.8 4.d 4.0 3.9 FIG. 4. Plasma ntcotine Ievcls while subject smoked one cigarette per hour and while he took nicotine cbe•.vin-gt:m hourly. Urine con- trolled at acid p)t (from Russell et at. [22)). levels are very much lower after (ntr3peritoncal as opposed to sub- cutaneous or intravenous injections (24). This point Is not always appreciated. In one study, five capsules containing 10 mg "nicotine tartrate" were ingested c+aiiy by volunteer smokers. The form of

39 t9rtrate was not stipulated so the equivalent of nicotiye base cannot be calculated, but it could have been as little as 3.3 mg per capsule. The authors, who believed that this dosage would substantially in- crease blood nicotine levels, interpreted the fact that cigarette con- sumption was reduced by only 7.4% as tndicating that nicotine is not an lmportant determinant of smoking behavior (25). We are not aware of any published data on plasma nicotine levels following the Ingestion of nicotine. One of our laboratory colleagues, who usually smoked just over 20 cigarettes per day, ingested nicotine bydrogen(})-tartrate in gelatin capsules (12 mg per c2psule, equiva- lent to 4.0 mg nicotine base). Starting with a dose of S mg nicotine base taken in the morning following at least 12 hr of abstinence from smoking and with his urine controlled at an acid p13 by ammonium chloride, we found no detectable elevation of plss= nicotine. The dose was gradually increased, and it took ;a mg of nicotine bsse to produce plasma nicotine levels around •10 ng/ml (Fig. 5). In the sa^:e subject (Fig. 4), under identical conditions (12 hr abstinence front smoking; acidic control of urine pN; ad libitum f'.uids), a plasma nico- tine concentration of 40 ng/ml was reached after the second ci;aret:e (1.2 mg nicotine per cigaretie) and after the fourth piece of r.icotine ctrewing guni (4 mg nicotine base per gum). The long delay of 31 hr before the appearance of nicotine in the plasma Was probably due to the fact that much of the dose remained in the stomach. When the subject drank 270 ml water with the capsules and a further 270 ml alter 30 min, absorption was improved and smoking levels of plasma nicotine were achieved by ingestion of 28 mg nicotine base (Fig. 5). Figure 5 also shows the high nicotine concentrations In saliva com- pared to plasma, as has been mentioned already. The average saliva to plasma ratios were 7.8 (SD 4.6) after 44 mg and 7.3 (SD 1.9) after 28 mg nicotine. The ratio is clearly less just after lunch, 4.6 com- pared to 13.2 (mean of the three values preceding lunch) for the 44- mg nicotine experiment, and 3, 0 compared to 10. 2 for the 2S-mg nicotine experiment, C. Absorption through the Lungs The contrast, found by Armitage ct aI. using their animal model [203, between the rapid response to a single puff of smoke Introduced into the lungs compared to 30 such puffs when restricted to the mouth has been mentioned above. Indeed, they went further to show that smoke containing 170 Ng nicotine introduced into the lungs of a cat had a similar effect on the blood pressure as 120 pg nicotine base injected into the femoral vein [20). a

' tuncl ^n4 r.icotine Use lire Ihl =^4 nicctir.e lire 11'.1 b11e FIG. 5. Plasma and salivary nicotir.e concentrations after inges- tion of nicotine in gebtin capsules. The doses a re expressed as nico- tine base. The subject took fluids ad llbitum after the 44-mg dose, but additional fluids were forced after the 29-:r:g dose when 270 ml Water was uken with the capsules at 10 A. M. and a further 270 ml at 10.30 A.M. and 3.30 P.M. Urine controlled at acid pli. no increase in plssma nicotine after smoking and tnhaling a cig- arette Is shown in Figs. 3 and 4. 7bese profiles are similar to those of otber stt:dles (26, 27]. It is clear from these plasma nicotine peaks that pulmonary absorption Is extremely rapid and of a similar order to intravcnous dosage. However, smokers vary greatly In the degree to which they inhale. Peak plasma nicotine levels of regular cigarctte smokers vary more than 10-fold and, In our expericnce, range from about 5 to 70 ng/ml. The level dcpends very much on the individual inhalation pattern of the smoker and correlates only about 0.6 with daily cigarette consumption and even less (0.4). with the nicotine yield of the cigarette smoked. In a technically sopbisticaied study, Armitage and Dollery (27), using ctgarettes spiked with "C-nicotine, showed that smokers who Inhale absorb up to 90% of the nicotine In the smoke which they draw N av N ~

i ~~ ' • z - CIGARETTE SDIOKI\G ,.~c~• 41 into their mouths; presumably the proportion is even higher for smoke taken Into the lungs. Although the pli of the smoke of many cig- arettes is acidic (see above), absorption of nicotine via the lungs is nevertheless extremely rapid. This Is probably partly due to "'. the vast surface area for absorption and partly that the pit of the alveolar surface fluids is around 7.4 as opposed to 5.5 in the case of cigarette smoke. Vll. PLaSNt.a NICOTINE AFTER INH.aL4TIOV AND 1\TRaVE\OUS DOV.GE Although Armitage's bioassay technique with cats showed that 170 pg nicotine Introduced into the lungs was equivaler.t to 120 Vg via the femoral- vein (20), human studies suggest that intalation is no !ess efficient than intrat•enous dosage, at least so fa r as the ger.era:'e:t of high plasma levels is concerned. With inlLiled ci;are:te smoking, nicotine dosage Is intermittent, takir.g the form of a series of high- nicotine boll associated with each Inhaled pulf. Though plasma nicotine levels produced by cigarette smol:ir.g can be studied; the amount of nicotine ukken in from a ci„aret:e is diffi- cult to determine. The nicotine yield of the cib.irece Is no guide as it depends on the n•ay the ciganntte is puffed, and the nicotine ir.tal:e then depends on the extent to which the puffs are inha!ed. The plasma levels are further influenced by the rate of puffing. Nicotine yields of cigarettes are arbitr-arily determined by standardized puffing on a smoking machine-one 35 ml puff of 2 sec duration taken at a rate of one per minute to a butt leagth of 20 mm or the tip ovcrWrap plus 3 mm, whichever is the greater, is the usual sund.•trd used. But some smokers take 70 ml puffs every 20 sec and smoke to a shorter butt lengtb, so that it Is possible for a smoker to gct more than double the standard yield of nicotine from a cip rette. On the other hand, some smokers puff and Inhale very little. The problems can be further illustrated by t3kir.g an example of two cigarettes with identical nicotine yields as measured by standard meth- ods. One Is a king-size cip rettr with a sttndard yield of 1.7 mg nico- tine from 30 puffs taken over 10 min. The other Is a small-size cig- arette (still very popular In England) which yields 1.3 mg nicotine from five standard puffs taken over 5 rnin. Not only will the concen- tration of nicotine per puff be twice as high with the small cig3rette (with implicattons for brain nicotine levels, see below), but the same dose will be taken in half the time.

25 , 201 101 SJ 0 10 20 :0 40 50 Go 0 to 9o loo an Time (mins) Bolus injettiur.s 4„er 4 minuies FIG. 6. Plasma nicotine levels after intr.tvenous nicotine (1 mg nicotine base given as five rapid bolus lnjcctioes at a rate of one per atinute), Subjects P.R. (W-t 157 ]b) and H.H. (wt 174 lb) were regular smokers of 20 or more cigarettes per day who claimed and appeared to Inhale deeply. M.R. (wt 182 lb) was an occasion.kl cigar smoker who had given up cigarettes 10 years ago. Urine eontrollcd at acid pH. To gain some idea of the relation of nicotine dosage to plasma levels, we measured plasma nicotine in three subjects following an Intravenous dose of 1 mg nicotine base given as live rapid bolus injections of 200 yg nicotine at a rate of one per minute. The subjects had not smoked for at least 12 hr and the urine was acidified by prior administration of ammonium cbloride. The results are shown In Fig. 6. The tacreases In plasma nicotine produced by the Injections were as follows: subject H. H. 6.2 ng/mt, subject P. R. 7. 5 ng/ml, subject At. R. 21. 0 ag/ml. The plasma nicotine increases after the first cigarette of the day was 7.2 ng/ml for subject H. H. and l l.1 r.g/ml for subject P. R. (see Fig. 7 below). Howevcr, as mentioned above, we do not :mow the true dose

;~.. . vii;• CIGARETTE SMOKING •i•s l 43 4 «, .r of nicotine they were inhalfng from tbetr 1.3 and 1.4 mg nicotine cig- 4t., A. -.arettes. It could have been as low as 0. 5 mg or over 2.0 mg. In another experiment (see Fig. 8 below), rapid injection of 1.78 mg Aa; nicwtlne base intraveneously produced plasma nicotine peaks equiva- lent to those obtained from smoking a cigarette with a nicotine yield •`~of1.2mg. .~y ,. ~ j~.• The plasma nicotine levels In Fig. 6 are lower than those shown In ~ Figs. 3 and 4. They are also lower than the cigarette smoking levels ;~ of the Isaac and Rand study [26], mean 25 ng/ml (range 12 to 44 ng/ ~:`ntl), and the Armitage and Dollery study [27], range 31 to 41 ng/ml, t•Thts might be partly due to the fact that most of the cigarettes used in these studies had nicotino yields which were slightly over 1 mg. However, as explained above, we cannot tell how much nicotine was taken In from these cigarettes to generate the plasma levels observed. The slightly higher levels of the Armitage and Dollery study are prob- ably due to the fact that they --•er•e from arterial as opposed to venous blood samples. Armttage and Doliery [27] attempted to make a direct comparison of nicotine intake by inhalation and intravenous injection and concluded that the plasma nicotine levels produced by the two troutes boresa similar relation to the dose administered. In general, it seems that plasma nicotine concentrations can be in- creased no less rapidly and efficiently by cigarette smoking than by in- trarenous In ection. The dilution and dispersal j greater of nicotine boll ; given Intraveneously see:n to roughly counterbala:,ce the time t4ken for absorption through the lungs so that the two routes of administration appear to genctate similar venous plasma levels. But it does not fol- low that In the case of brain levels (sce below) the relation of nicotine dosago to level produced would be so sirclla r for the two routes of ad- ministration. More systematic studies arc clcarly :,ccessary to es- tablisb the nicotine dosag¢ of habitual smokers. VllI. URI\ARY EICRETIO\ OF \7COTl;,%"E As Is the case with its absorption, the urinary excretion of nicotine to pH dependent. At a pli of 5.5 or )ess, the nicotine is almost 7.ctally lonized and cannot be reabsorbed through The rcnal tubules. Under these conditions, 30 to 40% of an intravenous dose is escre..ed in the urine as unchanged nicotine E103. On the other hand, at pH 8 most of the nicotine Is reabsorbed through the tubules and even the bladder. Excretion of the metabolites Is largely indcpender.t of pH. Beckett [10) concluded That urinary excretion of nicotine was unaftecsed by ot

44 RUSSELL AND FEYERABEND urine flow, but we have found It to be proportional to the rate of urine flow under acidic conditions (26]. We have also found that plasma nicotine levels are affected slightly by manipulating the urinary pH with ammonium chloride and sodium bicarbonate (28]. L\. RECl'CLI1G OF XICOTL\'E There are at least three recycling processes which could affect plasma nicotine levcls. These will be mentioned only briefly as they have been discussed more fully elsewhere (5). 1. Sailvogaslric cycle: We probably to pH pariition mentioned above, nicotine Is excreted Into the saliva and stomach. This nico- tine would be reabsorbed in the intcstine, but since it w•ould then be largely metabolized in the liver, this cycle would have little effect on maintaining plasma nicotine levels, apart from small amounts of salivary nicotine ubich might be reabsorbed through the buccal mu- cosa. 2. Nicotine-N-o.%Ide reduction: There is an \-oxide reductase system in the colon (either in the intestinai wall or boH•el flora) which reduces nicotine-l-o.dde to nicotine. Any of the N-oxide excreted in the bile would therefore be reabsorbed as nicotine. Though this would mostly be returned to the liver and remctabolizcd, some must cscape into the general circulation as nicotine-1'-:i-oxfde ad:ninistered orally or rectally results in the appearance of nicotir.e In the urine (29). 3. Reabsorption from urinary bladder: Travell [30) has dcmon- stratcd rapid absorption of nicotine from the bladdcr under alkaline conditions. Under r,orr.ul conditions of fluctuating urinary pH, a sit- uation could occur where the bladder is half-filled with acid urine con- L-ktning a high concentration of nicotine. Subscqucnt addition of alka- line urine could raise The pli of the urine in the bladder sufficiently for the nicotine to be reabsorbed before the urine is voidcd. Such a cycle would be an in:ermittent rather than continuous evcnt. X. PROL401GED HEAVY S11OKIrG The data in Fig. 4 and the study of Isaac and Rand [26J suggest that some accumulation of nicotine occurs with repeated dosage. Fig- ure 7 shows the plasnta nicotine levels of two subjects over a 7-br period In which they smoked at a rate of three cigarettes per hour. C

45 • • • • L . . 1 . ^ k i. • i • . ~`. • : . , 7 G tiQM lur.ch !.7i1tJ ~ ^ • i • ^ i • • 10 cKUette fnctea tiqhl iuncn ~:•• ••: 1 rmc FIG. 7. Plasaa nicotine levels during forced prolonged heavy smoking at a rate of three cigarettes per hour for 7 br. Each cig- arette was smoked over precisely 5 rain, and blood samples were taken just before and 2 mLn after each cigarette. Both subtects were regular smokers whose usual smoking frequency was just over 20/ day. Nicotine yields of the cigarettes were 1.3 for P. R. and 1.4 mg for H.H. Urinary pH was uncontrolled. 6:

46 RUSSELLANM FEYER4BEND The blood samples were taken just before and 2 min after each ciga- rette which was smoked for precisely 5 min. The frequency of smoking was much higher than was usta3l for these subjects, but inhalatton was not forced. Apart from the peaks and troughs related to each ciga- rette, there Is a clear tendency for the plasma nicotine to increase over the first 3 hr after which It appears that a "steady state" is reached. This "steady state" is unlikely to be due to a high rate of urinary nicotine excretion as this was negligible (<1.0 mg in 7 hr) In the one subject ()ill) In whom it was measured. Apart from the increase In nicotine metabolism due to higher nico- tine concentrations, the maintenance of the "steady state" could de- pend in part on self-regulation by the smoker taking the form of a re- duction in inhalation. There is some suggestion that the two subjects inha)ed less nicotine once a"steady state" was reached but this was not statistically significant. The mean plasma nicotine 9ncrcase per cigarette was 9.4 ng/ml (SA 5.9) before lunch and 7.8 ng/ml (ED 6. 5) afterwards It = 0.0, df 19, SS) for subject P. R. ; 10.0 ng/rnil (SD 2.:) before and 6.7 ng/ml (SD a.;) after lunch it = 2.0, df 19, NS) for sub- ject H.H. The after-lunch means are similar to the increases shown by the same subjects after 1.0 mg nicotine IV (Fig. 6) w•hich were 7.5 and 6.2 ng/ml, respectively, for P.R. and 11. H. This suggests that after lunch they were both taking in about 1.0 mg nicotine from each cigarette, but that before lunch they were inha)ir.g a little more. \I. PLASNLk li4LF-LIFE OF h7COT1 NE There are no adequate p):armacokinetic studies of the elimination rate of nicotine from plasma. Isaac and Rand [26) simply stnted that "the plasma baif-life was less than 30 minutes In all four subjects." 71ey then went on to mention on initial rapid phase due probably to distribution and a slower phase possibly due to metabolism and ex- cretion. Armitage and Dollery (27) "assumed a one-compartmcnt model" but clearly meant a two-compartment model since they used points between 10 and 50 min after the completion of the cigsrcitc for their calculation. On this basis they found half-lh•es ranging from 24 to 84 min with a mean of 40 mLn. Both these studies based their cal- cul3tions an data from nicotine-dcplcted smokers who had smoked a sing)e cigarette and who had no control of urinary pH. In a recent study comparing plasma nicotine levels produced by cigarette smoking and nicotine chew•ing-g:.m i311, we had plasma nicotine data for 21 subjects who had been smol:Lng normally for

CIGARETTE SMOKING • {;~+~' - j; '• 10 / 60 i • g ~ ~ ,~ / / / ~ `d I •.~ 30 I 47 ,- 10X! S00 600 :03 FIG. 8. Plasma concentrations and urinary excretion of n?cotir.e following Intravenous nicotine injectior.s and cigarette smokino. The dose of nicotinv for all three injections was 1. 79 mg of the basc (0. 025 mg/kg) Injected rapidly over 1 min. The six cigarettrs were smoked at a rate of 2/br and blood samples were taren just before and 2 min after each cigarette (1.2 mg nicotine). Lrine controlled at acid pFi. several hours. The avcragc peak'.evel of 31.5 ng/ml at 2 min de- clined to only 25.2 ng/mI at 25 min after the last cip rette. Although only two points were avaiisble, this did suggest to us that after sev- eral hours of smoking the hatl-lifc of nicotir.e In plasma might prove to be more than 1 hr or at least somewhat longer than stated in the two studies cited above. In collaboration with G. Volans, we have just started a study to investigate The plasma half-life of nicotine with and without tissue saturation and under conditions of high and low con- centrations of nicotine. This study Is still In proyress but the data from the first subject are shown In Figs. 8, 9, and 10. After 12 br abstinence from smoking, the subject was given 1.78 mg (0.025 mg/kg) nicotine base by rapid I.v. injection over I min. Blood samples were taken over the next 60 minutes after which the subject smoked two cigarettes an hour for 3 bours, blood being sam- pled 2 minutes and 25 minutes after each cigarette was completed. The i.v.•nicotlnc tnjectton was then repea:.cd and followod by blood i. v. nicotine over Imin • ri4trftlt t^Cfe9 over S mi1 ~ 2 reus etttn in 10 min ,_ . Dltsma ourine \ / \ \` ~, \\ \ \ t;rine

48 100.1 50 RUSSELLAI.'D F£YERAI3END Ist injection I 2nd injKtion %J C C C C 3rd injeclion 0 1 t 1 luncn A S 6 T d Timt, hourS FIG. 9. Pa1se rate changes af:cr nicotine tnjections and after smoking cigarettcs (C) duri:g the cxperimcnt sLown in Fig. S. I sampling for a further 3 hr when a 3rd i.v. nicotine injection was given followed by blood sampling over the final 2 hr. Urine samples were collected hourly and the urine controlled at an acid pli by taking am- monlum chloride. The plasma levels and ur3nary excretion of nico- tine are shown in Fig. S. the pulse rate in Fig. 9, and the plasma nicotine profiles of the three I.v. Injections In Fig. 10. The Increase in pulse rate with each injection obviously requires a saline control. Howerer, it Is clear that despite the plasma nicotine peaks produced by each cigaretie, they soon lose their capacity to quicken the pulse. The preliminary analysis of the data shows biexponenttal decay which fits a two-compartment open model. The alpha half-life for the lsl to 3rd Injections Is 3.3, 2.1, and 3.4 rain, respectively, and the bMa half-li.fe 66, 81, and 93 min, respectively. The correlation between the actual data and the predictions from the model Is 0. 99 in all three instances. The results show that there Is no saturation of the overall biotransforai,tion processes at these concentrsttons, but the time-related increase in plasma half-life suggests the influence of a third slow perfusion compartment (e.g., fat). The fact that this is not picked up as a triexponential decay after each dose is probably due partly to the very low concentrations and partly to the relatively short time period studied (mar.imu.-n of 3 hr after the second tnjection).

:.,c, ~• ~: ''~ CIGARETTE S'\SOKING •• r 60 :r,d injNi•wn , ,to i njK!ien !Sl injtiliQn !ll ?J 30 40 5.3 0 rne, r,.in Injeclicn over I r..in FIG. 10,' Comparison of plasma nicotine conct•ntrations before and after three intravenous nicotine ln;ections (1,73 mg nicotine base given over 1 min) shown in Fig. 8. \D. DECAY CURVE REIIOU\DS We were surprised by the minor stir which was produced in this conference by John Wood's remarks on "bumps," "humps," "irregu- larities," and "rebounds" in the decay side of the blood level profiles after drug administration. Indeed, 2 years ago when discussing the ptssma nicotine profile shown in Fig. 3, we stated "the rebounds on the decay side of the curve are not errors and represent significant cbanges. These were also typical In lsaac and Rand's study, and are probably due to redistributions and metabolic recycling.... There are often 'bumps' In the ascent side of the curve, owing to the puff- by-pulf Intermittent bolus form of administration that characterizes inhaled cigarette smoking" [5]. Our data support John Wood's suggestion that these rebounds lend to occur when intravenous administration Is given relatively slowly and that with rapid administration they should disappear. In F!g. 6, there are numerous rebounds following I.v• nicotine given over 4 min.

50 AIiSSELLAND FEYEf{ABE?,'D In contrast, the curves a re extremely smooth in Fig. 10 where the I. v. nicotine was given over 1 min. XIII. DISTli1Bt;T1O4 OF i`'ICOT11.'E TO THE BRAIN The alpha-phase hslf-life of 2 to 3 min computed from the data in Fig. 10 Indicates how rapidly nicotine is distributed. The autoradio- gtaphic studies of Schmiterlow et a1. [15} show very high concen- tratlons of nicotine In the brhins of mfce 5 min after lntnvenous In- jection and that most of -he nicotine has been cleared from the brain after 30 mtn. Stalbandske ['341 using "C-nicotine showed that Intravenously In- jected nicotine Is immediately taken up in the brain of mice, reaching a maxi:num concentration within 1 min af'..er injcction. (The circula- tion rate In the mouse is obviously a lot quicker than in humans.) The brain level then !alls rapidly with a half-lifc of about 5 min, and by GO rnin it has fallen to 1`0 of the maximum levcl. The blood nicotine levels were also highest at 1 min after injection and fell steadily with 3 half- life as short as that of nicotine in the brain. One minute af:cr Injec- tion the ratto bet.vccn nicotine levels in brain and blood was 5.6, and this remained relatively constant until 1 hr after injection, by which time It was reduced (see Table 1). TABLE 1 Ratio of Brain to Blood Sicotine Levels after Intravenous and tntrapcritoncal Injection in Mices Minutes after Injection I. v. 1 5.6 1.6 2.5 5.2 1.9 5 5.1 3.0 10 - 2.9 20 5.8 2.2 60 4.0 2.7 °Aftcr Stalhandske (24).

i ~ry t<,~..,~'~•~.. ,p• vr~Y i .' ~ i!~ ~.: . .!s_L CIGARETTE SIMOKI3G .~. •f. ~~ 51 After iatraperltoneal injections the brain nicotine level was not -Q only very much lower than after an intravenous injection, but the con- trast between the brain and blood levels was very much less. This suggests that the brain to blood ratio is not entirely explicablc in ;.;t• ierms of lipid solubility, for it sbould not then differ after i.v. vs I.p. Injection. reitber is it due to differences in the blood levels of nicotine, for the plasma nicotine at 2.5 min after i.p. injection was ':;•: bigher than at 20 min after the I.Y. injection. Stalhands4:e himself offered no explanation. We suggest a combination of two possibilities: t;. a"bolus-upt3lce phenomenon" and a"differentis) retention." The large dUferences between brain and blood levels may have arisen because the brain level was derived from equilibration with an equally high bolus .,; • nicotine le el. The intravenous nicotine bol::s hat•inq passed a•ithin 1 min, the blood level would be very much lower, while the brain would be retaining nicotine taken up during the passa;e of the nicotine-fillcJ bolus. As no high-concentration bolus wculd have passed through -he brain after the intrapcritoneal injection, the brain level would not be as bigh and the braln-blood ratio not as great. The mainsenance of the higher braLn-blood ratio for at least 20 ntin after the i.v. botus has passed suggests that the braL) cells bind or reu:n nicotine against a g1-adient over and above «•hat is determined by lipid solubility. Apart from lipid solubility, another process has been described which con- founds the Issue, namely the possibili.y of active ,:pt:+l:e by the 5r3 in against a concentration gradient. The superior cen•icai ;-angiion has been shown to take up nicotine aa inst a concer.trtion gradient and to equilibrate at an ir.tra/extraceliular ratio of 6: 1 ("resting uptat:e"). An additional uptake of 25r,c ("activ:,tion upta::e") occurs on nicotine- induced depolarization of the cells [32, 33). These findings are in accord with Stalbandske's br3ia:blood ntios. Stalhandske's findings have been considered at length because they provide some evidence for a bolus-uptake pbenon;cr.on which seems so crucial it difference between inhaled cigarette smoking as opposed to ~ other forms of t.obacco use such as snuffing, chewing, or noninhaled cigar and pipe s=oking. XIV. "PE.+tK-SEEI{E?tS".1KD "TROL'CH-.Ni.xl\TAI\ERS" We are nowhere near the stage of knowing to..•}•.at extent smokers emoke for some positive effects of the plasma nicotine peaYs or to avoid K•hateti•er the pharmacological effects may be of failing below a certain plasma nicotine trough. It would net•ertheless seem from the

preliminary pharmacokinetic findings we have discussed that for those smokers who smoke at a frequency below one cigarette per hour, the predominant plasma profile would be one of repeated high nicotlne peaks, tiebereas the accumu!ation of nicotine in the body would suggest that those who smoke a cigarette every 30 minutes or less (provided they are inhalers) would tend to show peaks which are smaller rela- tive to the absolute level. They might therefore be more likely to be motivated by the need for "trough maintenance." - There is now a growing body of data (admittedly somewhat conflict- ing) which suggest that about 50% of smokers seem to modify their smoking patterns to regulate their nicotine intake. This so-called nicotine self-titration behavior has been reviewed elsewhere (51. However, there is no Indication so farwhetF.er';.eak-seckers" are more likely than "trough-:na intair.ers" to be the more avid "self- titraiors. " Throughout its history, tobacco use his flcctuted between chewing, snuffing, and smoking, but no population has dispersed with one form of tobacco use without replacing it with another. The only time the British gave up smoking was in the eighteenth century w•t:en they switched to snuffing for almost a hundred years. Rather than any other constituent of tobacco smoke (e.g., carbon monoxide which is absorbed almost ex- clusively through the lungs), the common factor is nicotine, which is absorbed through the lungs in the case of cigarette smoking, the buccal mucosa in the case of chewing tobacco and the nasal mucosa in the case of snuffing. Unlike most other addictive drugs, tobacco has cever been used as a substance for ingestion. It has oever been eaten like opium or can- nabis, nor used as a beverage like alcohol and caffeine. This Is doubt- less because with absorption via the gut Into the portal system most of the nicotine, in Its first passage through the liver, would be converted to metabolites which are psycbopharmacologically almost inert. With absorption through the lungs or the nasal and buccal mucosae, however, the liver Is bypassed, allowing the nicotine to get to the brain and other parts of the body in the active form. Thus historical evidence shows that tobacco has been used only in ways which enable nicotine to exert a pharmacologic effect. Finally, few would suggest tl~.at cannabis and epte_t are smoked pri- marily for the f:avor, the tar, or the ps)cbological image they migf:t

:ffr ~-,; CIGARETTE SMOKING 53 •~y.•a ±= provide. Smoking as a habit has never been practiced In the absence of a pharmacologically active alkaloid. It Is, therefore, most unlikely that tobacco would be smoked u ere it not for the nicotine. \'VI. NICOTINE BOLL'S DEPE• INDE\CE Historlcal evidence has shown that considerable satisfaction may be obtained from tobacco whether it is chewed, snuffed, or smoked in pipes or cigars, and that, over time, societies and Individuals have been able to switch from one to another of these forms of tobacco use. These were the ways tobacco was ussed until the twentieth cer.tury. The tobacco was air-cured and produced an alkaline smoke from which some nicotine may be absorbed through the buccal and nasal mucosae without any need for inhalation into the lungs. The absorption of nicotine from all these'routes (snuffing, chcwi.^.g, ncninhated smoking) is very simi- lar. There is a slow increase to relatively low blood nicotine lrcets and, in particular, no puff-by-puff r.icotir.e peaks in the case of r.cn- in>`31c-d smoking. The smoking of a whole pipe or cigar in this way provides but a single relatively r.onir.te.^.se pharmacologic re-ward or reinforcement. With modern cigarettes made from flue-cured tobaccos the situation Is altogether different. The aciuity of the smoke makes buccal adsorp- tion negligible, so that to obtain a pharmacological effect it is necessary to [nhale. The smoke is, at the same time, less irritating and there- fore easier to inhale than the smoke from pipes or cigars or, InCeed, cigarettes containing air-cured tobaccos. It has been discussed how i' rapid absorption through the lungs produccs, with each inhaled puff, a bolus of blood contnining s high conccntr..tion of nicotine, many times higher than the levels shown after rni~dng or those obtained by slower absorption of far larger quantit'.es of nicotine. Equally rapid uptake by ;.. the btain ensures that It equilibrntes with these bolus peal:s so that the brain cells have higher nicotine levels than occur in the blood following dispersion of the boll. Furthermore, the high nicotine levels in these bolt are in no way affected by acquired metabolic toleronce, wbich would tend to reduce the mixed blood levels, and hence the maximu.m levels obtained by slower buccal or nasal absorption. For some years, Armitage. (19, 20) has emphasized the puff-by-puff fingertip control a•hich the inhaling cigarette smoker has over his nicotine intake. By altering the force and size of the puff, the proportion tnA.aled, the dcpth of inhalation, and the time that smoke is held in the lungs, bot9 the size of the bolus and the concentration of nicotine in it can be indcpcndently controlled.

I 54 RUSSELLAAD FEYERABE'D The puff-by-putf bolus nicotine peaks provided by Inhaled cigarette smoking not only produce higher brain nicotine levels and a more in- tense effect, but also substantially increase the number of reinforce- ments. Twenty cigarettes a day is 7300 a year, each puffed 7 to 10 times. Nfagnitude and number of reinforcements are Important vari- ables in the strengthening of operant behavior. The time interval be- tween the response and the reinforcement is another Important varl- able, and delay Is minimal with Inhaled cigarette smoking. Mcotine absorbed through the lungs reaches the braia more rapidly than after an intravenous Injection. The arm-to-brain circulation time is around 13.5 sec while the lung-to-brain time is only 7.5 sec. It is suggested that it is the intermittent pulf-by-puff high-nicotine bolus that reaches the br-ain within seconds of inhaling which n:a'.•.es cigarette smoking so hibhly addictive. Once this has been es;.erienced, other forms of nicotine Intake no lon;er suffice. Nicotine chewin; gp::t produces equivalent plas:na levels but the ra:e of absorption is slower and, u•ithout the Lw1i, brain levels are u:like:}' to be appreciably higher than In the plasma, so Lhat it Is consequently less satisfyine. Simil:trll•, addicted cig:trette smokers who switch to cigars or a pipe almost in- evitably continue to inhale (34-36), It Is not just nicotine which is so dependence-producing, but the inhsl:ition-bo1::s form of intake which addicts the cigarette smoker and makes cigarette smoking one of the most addictive of the addictive behaviors. Acknowledgments We thank Jean Crutch for secreu riat nssistance, and the Medical Researcb Council and Department of Health and Social Security for financial support. REFERENCES [1] A. C. 11cKennell and It. K. Thomas. Adults' and Adolescents' Smoking Habits and Attitudes, Covernment Social Survey, Her Majesty's Stationery Officer, London, 1967. (2) M. A. H. Russell. C. Wilson, C. Taylor, and C. D. Baker, "General Practitioners Advice Against Srr.oking," In Prepara- tion. [3) P. V. Lee (ed.), Statistics of Smoking in the United Kingdom, Tobacco Research Council, Loodon, 7975.

i.~i. CIGARETTE SMOKING 55 ~rf (4) M. A. If. Russell, "The Smoking Habit and Its Classification," Practitioner, 212, 791-500 (1974). [5) J+1. A. H. Russell, "Tobacco Smoking a.^.d'~Scotfne Dependence," in Researcb Advances in Alcohol and Druq Problems, Vol. 3. (R. J. Gibbins et al., eds. ), Wiley, New York, 1976, pp. 1-47. [6] Royal College of Physicians, Third Report: Smoking or Health, Pitmans, London, 1977. (7) M. A. H. Russell, "Cigarette Smoking: Natural History of a Dependence Disorder," Br. J. Med. Psychol., 94, 1-16 (1971). (S) A. W. Hunt and D. A. Bespalec, "An Eval=tio:t of Currer.t Methods of',lodifying Smoking Behaviour," J. Clin. Psychol., 30, 431 (1974). (9) J. R. Gormd and P. Jcnner, "The Metabolism of Tobacco Alkaloids," in Essays in Toxicology, Vol. G. Academic, New York, 1975, pp. 35-7S. [10] A. H. Bt•ckett, J. W. Gorrod, and P. Jen-ner, "T!:e Analysis of Nicotinc-1'-\-oside in Urine in the Presence of Nicotine and Cotirine and Its Applic3tion to the Swd, of in vivo \icoti.)c 1letabolis^t in Man," J. Pharri. Pharn:acol., 23, 55S-G1S (19-,1). [11] A. H. Bcckett and E. J. Triggs, "Enzl•:nc Ind_ction to Man Caused by Smol;in;," Nature, 216, 587 (1967). [12) W. B. Essman, "\icotinc-Rclated Neurocl:er:icai Changes: So:r,e Implications for :+totivational Mechanis.^.is and Differ- ences," in Smoking Behaviour: Motives and Incentives (11', L. D.ir.n, (:. ), Winston, \ti'ashinb'ton, D. C. , 1973, pp. 51-65. [13] P. S. Larson and lt. Silvcttc, Tobacco: £xperlmental and Clinical Studies, Supplement 3, Williams and 1>,'ilkins. Baltimore, 1975. [14] S. H. Curry, Drug Disposition and Pharmacol:lnetics, Black- well, Oxford, 1974. [15] C. G. Scbmlterldw•, E. Hansson, G. Andcrsson, L. E. Applegren, and P. C. Hoffman, "Distribution of Sicotinc In Central Nervous System," Ana. N. Y. Acad. Scl., 142, 2-14 (1967). [16) A. K. Armitage and D. M. Turner, "Absorption of Nicotine in Cigaret'..e and Cigar Smoke tbrougb the Oral >]ucosa," Nature, 226, 1231-1232 (1970). [17) A. H. Beckett and E. J. Triggs, "Buccal Absorption of Basic Drugs and Its Application as an in vivo Model of Passive Drug Tintnsfer through Lipid )]embrnnes," J. Pharat. P`sar:nacol., 19, Suppl. 31 S•••41 S(196 7).

56 RUSSELLAND FEYEftABE\D [18) A. K. Armitage, "Effects of Nicotine and Tobacco Smoke on Blood Pressure and Release of Catecbolamines from the Adrenal Glands," Br. J. Pharmzcol. Cbemother., 25, 515-526 (1965). [19] A. K. Armitage, In Smoking Behaviour: Motives and lrcen- tives (1V. L. Dunn, ed.), Winston, 11'ashington, D, C. , 1973, pp. 83-91. [20] A. K. Armitage, G. H. Hall, and C. F. Morrison, "Pbar::ta- cological Basis for the Tobacco Smoking Habit," Nature, 217, 331-334 (1965). [21] C. Feyembend, T. Levitt, and M. A. H. Russell, "A Rapid Gas-Liquid C3romatograpbic Estimation of Nicotine In Bio- logical Fluids,"J. Pharm. Pharmacol,, 27, 434-436 (1975). [22] M. A. H. Russell, C. Feyerabend, and P. V. Cole_ "Plas:r.a Nicotine Levels after Cigarette Smoking and Chewing \3cotir.e Gur.t," Br. Med. J., I, 1043-10-116 (1976). 123) B. F. Lautenbach, "On aNc%v Function of the Liver," Phi13d, 31ed. Times, 7, 357-394 (1576-1577). [24) T. Sialhandske, "Ef'ects of Increased Liver Metabolism of Nicotine on Its Uptake, Elimination and Toxicity In Mice, Acts Physiol. Scand., 50, 222-234 (1970). (25) M. E. Jarvik, S. D. Gltck, and R. K. Kalar.tura, "Inhibition of Cigamtte Smoking by Orally Administered Nicotine," Clin. Pharmacol, 7hcr., 31, 574-576 (1970). (26) P. F. Isaac and M. J. Rand, "Cigarette Smot;ing and Plasma Levels of Nicotine," Nature, 23G, 308-310 (1972). [27] A. K. Armitaee, C. T. Dollery, C. F. George, T. H. Houseman, P. J. Lewis. and D. M. Turner, "Absorption and Metabolism of Nicotine from Cignrettes," Br. Med. J., 4, 313-316 (1975). [28) C. Feyerabend and M. A. H. Russell, "Effect of Urinary pl( and Ticotine Excretlon Rste on Plasma titcottne during Cig- arette Smoking and Cheuing Nicotine Gum," Br. J. Clin. Pliarmacol., S. 293-297 (1975), [29] P. Jenner, J. W. Gorrod, and A. H. Beckett, "Tbe Absorp- tlon of Atcotine-1'-\-oaide and Its Reduction in the Gastro- Intestinal Tract In %laa," Xenobiottca, 3. 341-349 (1973). [30] J. Tnvell, "Absorption of Ticotine from Various Sites," Ann. N. Y. Acad. Sct., 90, 13-30 (1960). [31] M. A. H. Russell, S. R. Autton, C. Feyerabend, P. V. Cole, and Y. Saloojee, "Nicotine Chewing Gam as a Substitute for Srnoking," Br. ,tcd. J., 1, 1060-100 (1977).

1 ! In Cat Superior Cervical and Nodese-Ganglia after Close-Ar- +' 57 1'•`~sf`[32~' D. A. Brown, P. C. Hoffmar.n, and L. J. Toth, "3H-Nicotine ,~... :P . P .:X CiG_kItETTE SM0hING • •, i .?:s~•: p ers by so ated Rat Ganglia In Relation to Receptor Activation," Ibid,, 42, 100- , • y'LS'..'Y~'• ~~ ~- 113 (1971). ~.~ [34] C. M. Castleden-and P: V. Cole, "Inhalation of Tobacco . .;r.s: . • r•;jrr Smoke by Pipe and Cigar Smokers," L3ncet, 2, 21-22 (1973). [35] J. R. Cowie, R. W. Sillett, and K. P. Ball, "Carbon-Mon- '~ oaide Absorption by Cigarette Smokers 11<'bo Change to Smoking ': ~ Ctgars, " Ibid., 1. 1033-1035 (1973). .: [36);':: J: A. M. TLt•ner, R. W. Sillett, and M. W. AicNicol, "Effect ';'•' •oC Cigar Smoking on Carboaybaemoglobin and Plasma \1icotinc J Concentrations In Primary Pipe and Cigar Smokers and Ex- cigarette Smokcrs," Br. Alcd• J., 2, 1357-1399 (1977). 3 D, A: Broe•n, J. V. Halliwell, and C. N. Scbolfield, "Uptake of Nicotine and Extrace11u1ar S ace Tfa k b I I ;+j}~. '::., •. terial Injection in vivo " Br J Pharmacol 35 40 (1969). - ~. ~. . ~:. r• j + ,:.•.. .. _.., ~i~i'~'~ . '~'R:i.t:~' ,°, ...ahY. .. .' •,!;1.~..:.a'lYi:~,• ~Y~^':t,:1•.~1_:. , . . ..'`. a-.• .~5:11: .., , . . - .~ ~M.i..