Acute effects of nicotine on resting metabolic rate in ...

Acute effects of nicotine in cigarette smokers13 Kenneth

A Perkins,

Leonard

on resting

H Epstein,

Richard

L Stiller,

The acute effects ofnicotine

ABSTRACT to identify

a mechanism

that

may

help

metabolic

rate

Bonita

and RolfG

Jacob

rate (RMR)

were examined

L Marks,

on resting

explain

the

metabolic

inverse

association

between

smoking

and

body weight. Multiple administrations of two nicotine doses (moderate [15 zg/kg body wt] and low [7.5 ag/kg body wt]) and a placebo (0 g) were presented to 18 male smokers via nasalspray

solution

circuit

on

indirect

three

separate

calorimetry.

of 6% above

than the nonnicotine

3% increase cigarette

base

line

after the suggested

while

nicotine

after

RMR

levels

both

assessed

reliability

and

doses

were

low

examination effect was

Nicotine,

dose-response,

metabolic

Introduction Cigarette

smokers

and

(1-4)

to gain

tend

weight

to weigh

after

less than

stopping

nonsmokers

smoking

(5-8).

Weight gain after smoking cessation has been cited significant factor in precipitating relapse to smoking

The

mechanisms

accounting

for

the

relationship

as a (9).

be-

tween smoking and body weight are not known but the absence of differences between smokers and non- or cxsmokers in total caloric intake (1 , 2, 7, 10) and physical activity ( 1 , 7, 1 1) strongly suggests that smoking may cxert its effect on body weight by increasing resting metabolic rate (RMR). Even small alterations in RMR may

have profound effects on body weight over time because RMR can account for 70% oftotal daily energy expenditure (12). Research with animals (1 3-1 5) indicates that nicotine may be the primary component of tobacco smoke responsible for the effects of smoking on body weight. Chronically administered doses of nicotine have been

Abuse.

3 Address

reprint requests to KA Perkins, Western Psychiatric tute & Clinic, 381 1 O’Hara Street, Pittsburgh, PA 15213. ReceivedJuly 14, 1988. Accepted for publication October 20, 1988. AmJCIin

Nutr

l989;50:545-50.

Printed

in USA.

© 1989 American

Insti-

Society

RMR

significantly

greater

to elevate

isolated from tobacco also indicate that nonto acutely increasing

cigarette RMR

smokers

in animals

(16-1

8). However,

re-

search with humans has produced inconsistent results. Early studies found that tobacco smoking acutely increased RMR ( 19, 20) whereas more recent studies reported no effect (8), a very small increase (2 1), a small decrease (22), and an increase due to intermittent ing in total 24-h energy expenditure, integrated

periods

ofphysical

inconsistency

delivering ity

in

activity,

has

nicotine puffing

been

as well as in RMR

due

in part

by cigarette

topography

to the

smoking.

and

smokacross

(23). This

difficulties

Wide

inhalation

in

variabil-

patterns

of

smokers prevents the administration ofprecise measured doses of nicotine via cigarette smoking (24, 25), and the separation ofnicotine’s effects on RMR from the potential effects of the ‘-4000 other components of tobacco smoke is difficult (26). Alternative methods of delivering nicotine dosing

generally or involve

greatly different izability ofresults (27,

From the Department of Psychiatry, University of Pittsburgh School ofMedicine, Pittsburgh, PA. 2 Supported by grant DA/HL 04174 from the National Institute on I

Drug

rate, inhalation,

shown

open-

of dosing.

of the effects of smoking a due to acute metabolic conse-

quences of inhalation. These results confirm that intake of nicotine, smoke, significantly increases RMR in humans. However, the results pharmacological, behavioral aspects of smoking may also contribute RMR in smokers. Am J Clin Nutr 1989;50:545-50.

KEY WORDS

computerized

by

the

moderate

placebo. Subsequent that the small placebo

was

confirmed

28).

suffer slower,

from a similar gradual uptake

lack of precise of nicotine via

routes, thereby diminishing to effects ofnicotine intake

Consequently,

there

has

been

no

the generalby smoking direct

exami-

nation of the effects of nicotine alone, isolated from smoking, on RMR in cigarette smokers and thus the role of nicotine in explaining smoking’s influence on RMR remains unknown. The purpose of this study was to examine the specific effects ofnicotine on RMR by presenting cigarette smokers with two measured doses of nicotine corrected for forClinical

Nutrition

545

Downloaded from ajcn.nutrition.org by guest on June 2, 2013

increases

occasions

Plasma

546

PERKINS

TABLE

ET

AL

armchair

1

jects

Subject characteristicsC

within

initially

a climate-controlled experimental room. Subfor 1 5 mm to become habituated to the apparatus and then for two additional 15-mm

rested

measurement 22.4 ±3.6 176.3 ± 9.6 72. 1 ± 7.8 0.7 ± 9.7 20.4 ± 5.2 4.6 ± 2.8

Age(y) Height (cm) Weight (kg) Ideal weight based on height (percent over ideal) Cigarettes smoked per day Years smoking FTC-determined nicotine yield of preferred cigarette(mg)

0.93

periods

nasal-spray (72 kg),

± 0.14

intake (31)

SD

C ±

body weight and a placebo via nasal-spray dosing procedure produces rapid boosts tine in much the same manner as the

after

cigarette

smoking

(29,

solution. This in plasma nicoboosts obtained

30). Advantages

of this

pro-

cigarettes

to even the modest nicotine intake such as those who smoke low-nicotine

of

Subjects for the study

were

male

smokers(l5-40

cig-

arettes/d for 1 y)aged 18-30 y, within 20% oftheir ideal body weight based on height [according to Metropolitan Life Insurance Company tables (32)], and with no past or present history ofsignificant health problems or drug abuse. Characteristics of the 1 8 subjects accepted for study are presented in Table 1. All subjects received a physical examination involving review of systems (including nasal and oral mucosa) and blood tests, including

thyroid

screening

tests

[triiodothyronine

(T3),

consumption,

respiratory

the average-weight dose approximated

smokers

from

the

dose

approximated

low

subject in this study the mean nicotine

a single

typical

cigarette

(1 .0 mg)

a halfcigarette.

Each

dose

consisted of 1. 14 mL 0.9% sodium chloride solution together with the designated amount of L-nicotine and 10 mg of a peppermint flavoring oil (Lorann Oils, Lansing, MI), which was used to mask the taste and smell of nicotine. The solution was sterile and nonpyrogenic and it was buffered to a pH of 6.1. Each dose was administered in three equal-sized bolus presentations 40 5 apart, with each presentation sprayed to both nostrils in quick were instructed

succession to inhale

administration, 1). This

mm

with

periods)

the last trial

counterbalanced

any

Order and doses

lengthened

from

of plasma

(trial 15 mm times

(two

on

nicotine

was

double-blind.

ofour three

15-

of nicotine

across the three sessions

were administered

were obtained

for assessment

to 30 mm effects

to verify the reliability

samples

period

followed by three additional

extended

ofdoses

2 mm). Subjects spray. After dose

for a 15-mm

administration was repeated

to examine

after intake.

over each

was measured

of dose

measurement

2-4),

RMR

(ie, six sprays deeply during

RMR

procedure

ofmetabolic

(trials

blood

Methods

for oxygen

of most

In addition,

(3 1).

eligible

pump. For moderate

the

and

jects

Subjects

values

expenditure, and heart rate were obtained. values were obtained subjects were adminis(15 g/kg body wt), low (7.5 pg/kg body wt), dose of nicotine solution via a measured-dose

dosing

randomly

procedure, chosen

concentrations.

subAn

in-

dwelling butterfly cannula perfused with heparin was inserted into the cubital vein of the forearm before the habituation period and a 5-mL blood sample was collected 5 mm after the onset ofeach 15-mm measurement period. Each blood sample was collected into a 7-mL evacuated (EDTA) tube, which was kept at 5 #{176}C. Samples were mixed and centrifuged at 300 X g for 10 mm at 5 #{176}C in a CRU-5000 centrifuge. The plasma was separated and placed into a polypropylene vial and stored at

-60#{176}C. This

Board

protocol

was

for Biomedical

approved

Research

by the

Institutional

at the University

Review

of Pittsburgh

of Medicine.

School

thyrox-

inc (T4), and thyroid-stimulating hormone (TSH)], to confirm the absence of medical disorders. Subjects were weighed on a balance scale without shoes and this weight was used to determine appropriate nicotine dosing amounts in subsequent cxperimental sessions. Subjects’ informed consent was obtained after the nature and consequences ofthc study were explained.

Procedure Each subject participated in three experimental sessions on three different mornings. All subjects arrived at the laboratory at 0800 after abstaining for at least 12 h (ic, overnight) from smoking, caffeine, and food as well as from strenuous physical exertion. Overnight abstinence from smoking was confirmed by an expired air carbon monoxide (CO) reading of 13 ppm (25, 33). Mean obtained CO was 9.8 ppm (range 3-13 ppm). Single sessions for four subjects were rescheduled because of failure to meet CO requirements. Silver-silver chloride electrodes were first attached for mea-

surcment of heart rate, followed by a respiratory mask for collection ofexpired air gases. Subsequently, and throughout each experimental session, subjects reclined in a large, comfortable

Assessment

ofmetabolic

rate and heart

rate

Assessment of metabolic rate involved placement of a Speak-Easy Il#{174} respiratory mask (Respironics, Inc, Monroeville, PA) on the subject’s face for collection ofexpired 02 and

CO2 into a 5-L mixing

chamber.

Volume

of expired

air was

measured by a Rayfield RAM-9200 spirometer (Rayfield Industries, Waitsfield, VT) while concentrations of 02 and CO2 were sampled from the mixing chamber at the rate of 500 mL/ mm by Beckman OM 1 1 and LB2 analyzers. Volume and gas concentrations were fed continuously into an Apple lie computer from which metabolic values (02 consumption [VO2 ,

mm],

energy

quotient equations Rayfield

expenditure

[RQ]) by use Industries.

were

[RMR, calculated

of data-acquisition The mask was

kcal/minj, from

and respiratory

standard

metabolic

software developed removed briefly from

by the

subject’s face after each assessment period and then reattached for subsequent data collection, which began ‘-3 mm after the completion ofdose administration.

Heart tinuously polygraph

rate (HR) in beats per mm (BPM) and determined that displayed

was recorded

by counting R-waves the EKG trace.

from

cona Grass


cedure over smoking in studies of nicotine include the reliable, dose-dependent increases in plasma nicotine it provides and the isolation of nicotine from other cornpounds oftobacco smoke. Nicotine doses equal to or less than the typical nicotine intake of most smokers from a single average cigarette were selected to enable us to re-

late our findings many smokers,

as baseline

quotient, energy After baseline tered a moderate or placebo (0 Lg)

NICOTINE

AND

RESTING

METABOLIC

RATE

547

100 90 80 70#{149}

60

w z 50

0 0

z 40 C,)

30’

-J

20 L

10

TRIAL

I

TRIAL

2

TRIAL

3

TRIAL

4

TRIAL

4

(16-30)

FIG 1 . Plasma nicotine concentrations after administration of placebo (open circles), low nicotine dose circles), and moderate nicotine dose (closed triangles) (1 ± SEM). Trial 4 was 30 mm long and is presented two 15-mm periods(minutesO-l5 and 16-30).

Statisticalanalysis Significance

RMR,

reflected

of the

effects

and HR across

sures ates.

analysis Follow-up

Plasma

protected

nicotine

Analytical is based on

a column

(34),

with between

on

VO2 , RQ,

by repeated-mea-

baseline doses

values as covariwere performed

least-significant-difference

test (34).

analysis

determination the extraction

This method plasma, with

dose

trials was determined

ofcovariancc comparisons

with Fisher’s

of nicotine

of plasma nicotine concentration technique of Kyermaten et al (35).

first involved N-ethyl-nornicotine

extraction

separating the nicotine from as the internal standard, by

method

rate

to plasma

tion

was performed

with

the

plasma mass

(1: 1) and

of6.7

nmol/L.

Each

of three

extracted

on a minimum

of those

sample.

Nicotine

spectrometry

and high-resolution

that

1 tL was injected

in

gas chromatograph with a 20-M The assay was sensitive and accu-

concentrations

mean

gel and

assays

as the

determination

concentrations utilized

were

capillary

selected-ion

determina-

assays, for

also verified

that

by

gas chromatography

creased

Plasma

nicotine

and heart

rate

sentations

increases 4) were

ofthe

above placebo ‘-38.7 nmol/L

L for the moderate

dose.

nicotine

dosing

linearly in 1, confirm-

procedure.

(except for 16-30 mins for the low dose and 76.7

This

dose-dependency

Mean of trial nmol/

was also

after

both

the

low

(C

the

placebo.

no significant

effects

of nicotine

=

was significantly p < 0.02). Compared

4.68, RMR was significantly

of the moderate (t 2.65, p < 0.02) nicotine

low

and

moderate

=

doses

after the placebo. after the first significantly

across

dose

(1 .20 ± 0.03 kcal/min), of counterbalancing dose

2, RMR

dose (F placebo, =

after

4.98, moderate

=

and the lack ofsession-order

in Figure

tion

BPM

on baseline RMR the effectiveness

change increased in Figure

adminis-

rate were

observed mediately

Plasma nicotine concentrations dose-dependent fashion, as shown

ing the reliability

1 .2 ± 0.5

session firming

the

Results

dose

p < 0.001) doses and the difference between and low doses was marginally significant (1 = 1.7 1, p < 0.10). Mean (±SEM) HR increases above baseline across the four trials were 2.8 ± 0.6 BPM after the low dose and 4.9 ± 0.9 BPM after the moderate dose whereas HR de-

2.63, doses

doses did not differ from each tude of RMR increase above

monitoring.

followed

(C

There

solution

silica

that

cebo, HR was significantly greater = 3.26, p < 0.01) and moderate

Metabolic

equipped column.

a 3-mL

changes

was highly significant with HR after the pla-

a

a nitrogen-selective carbowax ultrabond

uses

HR

tration because the effect of dose (F = 7 1 .46, p < 0.001). Compared

3-mL octyl (C8) column piggy-backed with a column adapter. The eluates were concentrated to dryness with a Savant concentrator under vacuum. Added to the nicotine residue was 50

tL of toluenc-ethanol

that

in the

(closed here as

effects.

As shown

affected by nicotine with RMR after the

greater after p < 0.02) but

the

administra-

and low (C two nicotine 1). The magni-

other (C < baseline averaged whereas

6% for

a 3% change

was

These increases occurred dose administration, did trials

or conpre-

(ie,

no significant

imnot effect

of trials or of dose x trials interaction on RMR), and were maintained during the second halfoftrial 4, 16-30 mm after Effects

RMR, nificant

the last dose of nicotine

administration. on VO2 and

RQ,

used

to

derive

were also analyzed separately. There was a sigeffect of dose on VO2 (F = 6. 1 5, p < 0.005) be-


(0-15)

PERKINS

548

ET

AL

.11

.10 09 C

.08

E .07 .06

z w U)

.05 .04

w ‘I

0

.03

z .02 .01

TRIAL TIME

1

TRIAL

15

(mm)

2

30

TRIAL

3

TRIAL

4

TRIAL

(0-15)

(16-30)

60

75

45

cause the increases above baseline in V02 after the low (0.239 to 0.256 L/min) and moderate (0.241 to 0.257 LI mm) doses were significantly greater (C of 2.86 and 2.73, respectively; both p < 0.01) than the change after the placebo (0.243 to 0.25 1 L/min). There was no significant effect oftrials (F = 1 .56, p > 0. 10). The effect of nicotine

dose change

on VO2

occurred

The

baseline

in the absence

3% increase found

in total

in RMR

volume

of any

significant

air (VE) after placebo, low, or moderate doses (all t < 1). In contrast with VO2 there was no significant effect of dose on RQ (F = 1 .67, p > 0. 10) because RQ decreased from baseline after administration of the placebo (0.868 to 0.841), low (0.873 to 0.828), and moderate (0.855 to 0.8 1 8) doses, similar to effects observed after tobacco smoking (8, 19). There was also a significant main effect of trials (F = 6.74, p < 0.001) because RQ remained lower across trials 1-3 and the first half of trial 4 (0-15 mm) before returning to baseline levels during the second halfoftrial 4 ( 1 6-30 mm). to that

from

after

ofexpired

the placebo

was similar

in previous studies that used the control procedures of sham-smoking (2 1) and smoking a nonnicotine cigarette (36). All three of these controls (placebo spray, sham-smoking, and a nonnicotine cigarette) involve inhalation, as does the typical intake of nicotine by smokers (ie, inhaling cigarette smoke). To help determine whether the unexpected increase after the placebo spray might be due to the effects ofinhalation, three subjects returned for two additional sessions in which they either inhaled on a nicotine-free cigarette (Free#{174}brand, International Brands, Los Gatos, CA) or rested continuously without presentation ofnasal-spray solution or cigarette (ic, no inhalation). In the session that involved smoking the nicotine-free cigarettes, the procedure was nearly identical to the previous sessions, with two 15-

mm

baseline

after administration triangles) (± SEM).

trials

followed

of placebo Trial 4 was

by three

15-mm

and

one 30-

mm measurement trials. At the beginning of each measurement trial, subjects were instructed to inhale from the cigarette six times, once every 20 s, to match the rate

and frequency ofinhalation During the continuous-rest

for the nasal-spray solution. session subjects participated

in the same number of baseline and measurement trials but were simply instructed to remain at rest and were not presented with any stimulus other than the removal and subsequent reattachment of the respiratory mask in be-

tween

trials.

modest

puffed

Similar

increase

to results in

RMR

on the nicotine-free

vs 3.0%

following

placebo)

RQ and no change RMR from baseline ous-rest

session

with

was

cigarette along

the placebo

observed

after

(4. 1% above with

a slight

in HR. As expected, was observed during

(+0.2%),

indicating

that

spray,

a

subjects

baseline decline

in

no change in the continupossible

disrup-

tion of the quiescent resting state achieved during baseline by the removal and reattachment of the respiratory mask was not responsible for the metabolic effect that followed

the placebo.

Discussion To our knowledge this is the first study to determine the acute effects of nicotine, separate from smoking, on RMR in cigarette smokers, as well as the first dose-response study of nicotine and RMR. Given that smokers typically self-administer nicotine ‘20 times per day (ie, 20 cigarettes), the increase in RMR observed here after administration ofnicotine doses equal to or less than that typically obtained from a single average cigarette mdi-

cates that nicotine intake via smoking lead to lower body weight in smokers

could, over compared

time, with


FIG 2. Mean (SEM) Increases above baseline in resting metabolic rate (RMR) (open circles), low nicotine dose (closed circles), and moderate nicotine dose (closed 30 mm long and is presented here as two 15-mm periods (minutes 0-15 and 16-30).

4

NICOTINE nonsmokers

even

the absence

in

AND

ofdifferences

RESTING

in caloric

intake and physical activity. This source of caloric cxpenditure would be removed after smoking cessation, thus leading to weight gain in ex-smokers.

Given

the acute

nature

of nicotine

administration

in

this study, it is not possible from our findings to clearly determine the magnitude ofweight gain that may result from removal of the excess caloric expenditure due to nicotine inhalation. A more extended dosing period, such as over the course of a full day, may lead to larger increases (ie, cumulative effects) or smaller increases (ie, acute tolerance) in expenditure after subsequent dose administrations. In this study there was no significant trend in either

direction

across

In addition

to the acute

ular

ofnicotine

intake

RMR

over

days

may

occur

to what

observed

in female

than males (9). Female than males

to weight

clear

of nicotine

which

chronic

only

effects

gradually

smokers,

who

gain

in ex-smokers.

degree

the

here

in male

may

acute

on pore-

Fi-

metabolic

smokers

be more

reg-

recede

cessation, thus providing another excess expenditure which, when

contributes it is not

more

also

concerned

with weight gain after cessation of smoking smokers metabolize nicotine more slowly and have higher plasma nicotine concentra-

tions after a given amount of nicotine intake (3 1), suggesting the possibility ofgreater metabolic effects per nicotine dose administration (ie, per cigarette) and thus a

greater

potential source ofweight gain after cessation. Although the results of this study clearly demonstrate an effect of nicotine on RMR over and above placebo, other findings indicate that nicotine’s influence in cxplaining the metabolic effects of smoking may not be complete or straightforward. First, increased RMR was maintained after the sharp decline in plasma nicotine concentration during the second half of trial 4, suggesting that changes in RMR may not directly parallel the

rise and fall ofplasma nicotine during smoking and may remain elevated for some time after a smoker finishes smoking. Second, despite the administration of clearly distinct

nicotine

dent plasma the moderate

doses

similar effect

of

RMR

increase

by the

dose-depen-

and HR increases, study resulted in very

6% increases in RMR, suggesting a nonlinear nicotine on RMR. Third, although this 6%

falls at the midpoint

ported range of increases 23), the RMR increase is half

as evidenced

nicotine concentrations and low doses ofthis

that

of the

two

of the generally

after smoking, after the placebo nicotine

doses,

re-

3-10% (19-21, was 3%, which indicating

that

the

metabolic effect of nicotine alone may be only 3%. The increase after the placebo was comparable to RMR increases in the subsample ofsubjects from this study who

smoked nonnicotine cigarettes that employed nonnicotine

and in previous studies cigarettes (36) or sham-

smoking control subjects (2 1), all involving inhalation similar to nicotine intake via smoking. The general increase observed in RMR due to inhalation or other nonnicotine influences suggest that meta-

RATE

bolic effects of tobacco solely to nicotine may cal (ie, nicotine) and

549 smoking previously attributed actually comprise pharmacologinonpharmacological, behavioral

(puffing, inhalation, etc) components, perhaps equal in their contribution to increased RMR. Consequently, the actual amount ofa smoker’s nicotine intake (ie, dose per cigarette) may be less relevant than the frequency of smoking (ie, number ofcigarettes per day) in determining excess

energy

expenditure

via RMR,

relative

to non-

smokers. One potential implication ofthis finding is that weight gains after smoking cessation may be comparable between individuals who smoke increasingly popular low-nicotine cigarettes and those who smoke higher-nicotine cigarettes. Epidemiologic evidence showing that weight gain after smoking cessation is associated with daily

smoking

frequency

(5)

is consistent

tion. Further

research

by which (23) found

nicotine acutely raises RMR. a substantial rise in urinary

should

focus

with

on possible

this

no-

mechanisms

Hofstetter excretion

et al of nor-

epinephrine but no change in epinephrine across a 24h period of regular smoking compared with a period of smoking abstinence. Cryer et al (37) determined that this increase

in

catecholamines

after

smoking

was

quite

rapid, perhaps explaining the sharp elevation in RMR observed in the present study after the first presentation of nicotine. These catecholamine changes do not return to baseline between cigarettes (27), which may account for the lack ofa decline in RMR at the trial ofthis study (16-30 mm after dose spite a sharp decline in plasma nicotine.

end ofthe presentation)

fourth de-

Finally, mechanisms that may explain the contribution ofbehavioral aspects ofsmoking, such as inhalation, to increasing RMR of smokers deserve closer examination. In this study increase in VO2 from baseline was related to nicotine dose whereas RQ decreased from baseline regardless of dose. Thus, changes in VO2 may be more closely related to amount of nicotine intake whereas changes in RQ may be influenced more by inhalation or other behavioral factors. (3 We thank lyn Fernstrom

John Foglia for helpful

for preparation of nicotine doses comments on the manuscript.

and Made-

References I. Albanes D, Jones Y, Micozzi MS. Mattson ME. Associations between smoking and body weight in the US population. Am J Public Health 1987;77:439-44. 2. Fehily AM, Phillips KM. Yarnell JWG. Diet, smoking, social class, and body mass index in Caerphilly Heart Disease Study. Am J Clin Nutr l984;40:827-33. 3. Jacobs DR. Gottenborg S. Smoking and weight: the Minnesota Lipid Research Clinic. Am J Public Health 198 1;7 1:391-6. 4. Kromhout D, Saris WHM, Horst CH. Energy intake, energy expenditure, and smoking in relation to body fatness: the Zutphen Study. Am J Clin Nutr l988;47:668-74. 5. Comstock GW, Stone RW. Changes in body weight and subcutaneous fatness related to smoking habits. Arch Environ Health l972;24:27 1-6.


nally,

effects

have

or weeks,

following smoking tential source of

moved,

the four dose administrations. metabolic effects ofnicotine,

METABOLIC

550

PERKINS

ET

KA, Denier CA, Mayer JA, et al. Weight gain associated in smoking rate and nicotine intake. Int J Addict l987;22:575-8 1. 7. Rodin J. Weight change following smoking cessation: the role of food intake and exercise. Addict Behav 1987; 12:303-17. 8. Stamford BA, Matter 5, Fell RD, Papanek P. Effects of smoking cessation on weight gain, metabolic rate, caloric consumption, and blood lipids. Am J Clin Nutr l986;43:486-94. 9. Wack JT, Rodin J. Smoking and its effects on body weight and the

23.

6. Perkins with

decreases

systems

ofcaloric

regulation.

Am J Gin Nutr

Hofstetter A, Schwa Y, Jequier E, Wahren J. Increased 24-hour energy expenditure in cigarette smokers. N Engl J Med 1986;3l4: 79-82. 24. Herning RI, Jones RT, Bachman J, Mines AH. How a cigarette is smoked determines blood nicotine levels. Clin Pharmacol Ther 1983;33:84-90. 25. Zacny JP, Stitzer ML, Brown FJ, Yingling JE, Griffiths RR. Human cigarette smoking: effects of puff and inhalation parameters on smoke exposure. J Pharmacol Exp Ther 1987;240:

554-64.

1982; 35:366-80.

10. Robinson S, York DA. The effect of cigarette smoking on the thermic response to feeding. Int J Obes 1986; 10:407-17. 1 1. Blair S. Jacobs D, Powell KE. Relationships between exercise or physical activity and other health behaviors. Public Health Rep 1985; 100:172-80. 12. Garrow JS. Energy balance and obesity in man. 2nd ed. Oxford: Elsevier-North Holland Press, 1978. 13. Grunberg NE, Bowen Di, Morse DE. Effectsofnicotine on body weight and food consumption in rats. ‘ Psychopharmacology

26.

Dube

M, Green

CR. Methods ofcollection ofsmoke for analytical Adv Tobacco Sci 1982;8:42-102. Russell MAH, Feyerabend C. Cigarette smoking: a dependence on high nicotine boli. Drug Metab Rev l978;8:29-57. Svensson CK. Clinical pharmacokinetics of nicotine. Clin Pharmacokinet 1987; 12:30-40. Perkins KA, Epstein LH, Stiller RL, Jennings JR. Christiansen C, McCarthy T. An aerosol spray alternative to cigarette smoking in the study of the behavioral and physiological effects of nicotine. Behav Res Methods Instr Comput 1986; 18:420-6. Perkins KA, Epstein LH, Jennings JR. Stiller RL. Cardiovascular effects of nicotine during stress. Psychopharmacology 1986;90: 373-8. Benowitz NL, Jacob P. Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther l985;35:499-504. Metropolitan Life Insurance Company. Stat Bull Metrop Life

purposes. Recent

27. 28. 29.

l984;83:93-8. 30.

31. 32.

Found 1983;64:2-9. 33.

NL. The use of biologic fluid samples in assessing smoke consumption. In: Grabowski, J, Bell, CS, eds. Measurement in the analysis and treatment ofsmoking behavior. Washington, DC: US Government Printing Office, 1983:6-26. (NIDA research monograph 48.) Huitema B. The analysis of covariance and alternatives. New York: Wiley Interscience, 1980. Kyermaten GA, Damiano MD, Dvorchik BH, Vesell ES. Smoking-induced changes in nicotine disposition: application of a new HPLC assay for nicotine and its metabolites. Din Pharmacol Ther l982;32:769-80. Evans WF, Stewart Hi. The effect of smoking cigarettes on the peripheral blood flow. Am Heart J 1943;26:78-9 1. Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smokingassociated hemodynamic and metabolic events. N Engl J Med 1976;295:573-7. Benowitz tobacco

34. 35.

36. 37.


14. Morgan MM, Ellison G. Different effects of chronic nicotine treatment regimens on body weight and tolerance in the rat. Psychopharmacology 1987;9 1:236-8. 15. Wellman PJ, Marmon MM, Reich S, Ruddle J. Effects of nicotine on body weight, food intake, and brown adipose tissue thermogenesis. Pharmacol Biochem Behav l986;24:1605-9. 16. llebekk A, Miller NE, Mjos OD. Effects ofnicotine and inhalation of cigarette smoke on total body oxygen consumption in dogs. Scand J Clin Lab Invest l975;35:67-72. 17. Lupien JR. Bray G. Nicotine increases thermogenesis in brown adipose tissue in rats. Pharmacol Biochem Behav l988;29:33-7. 18. Schector MD, Cook P. Nicotine-induced weight loss in rats without an effect on appetite. Eur J Pharmacol l976;38:63-9. 19. Dill DB, Edwards HT, Forbes WH. Tobacco smoking in relation to blood sugar, blood lactic acid and metabolism. Am J Physiol 1934; 109:118-22. 20. Hiestand WA, Ramsey Hi, Hale DM. The effects of cigarene smoking on metabolic rate, heart rate, oxygen pulse, and breathing rate. J LabClin Med l940;25:10l3-7. 21. Dallosso HM, James WPT. The role ofsmoking in the regulation ofenergy balance. mt J Obes 1984; 8:365-75. 22. Warwick PM, Chapple RS, Thomson ES. The effect of smoking two cigarettes on resting metabolic rate with and without food. Int i Obes 1987; 1 1:229-37.

AL