The Effects of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Smoking Behavior: An Ecological Momentary Assessment Study

Abstract

Background
In recent years, much research has examined the effects of various interventions and treatments for smoking cessation. The results suggest that interventions targeting changes of nicotine content can help smokers reduce tobacco use or quit smoking. A number of clinical studies show that smokers who received an immediate reduction in nicotine content to very low levels have significantly greater reductions in the number of cigarettes smoked and toxic substance exposure compared to those with gradual reductions. However, from the perspective of smoking craving, whether the immediate and gradual reduction in nicotine content reduce smoking by reducing cravings needs further investigation.

Methods
74 eligible Participants were randomly allocated to one of the two experimental conditions: (1) immediate reduction to 0.1 mg of nicotine per cigarette (n = 40); (2) gradual reduction from 1.0 (0.8 g ~ 1.2 mg) to 0.1 mg of nicotine per cigarette (n = 34). All participants completed 1-week baseline period during which they smoked their usual cigarette, followed by 16-week of interventions. The primary outcomes included cigarette cravings and number of cigarettes smoked per day (CPD); secondary outcomes included the number of cigarette-free day and emotional states.

Results
Among the 52 participants [51 (98.1%) men; mean (SD) age, 33.44 (6.71) years; mean (SD) CPD, 16.83 (9.94)] who completed the trial, significantly lower cravings for cigarettes were observed in the immediate (n = 25) vs. gradual nicotine reduction group (n = 27) in the morning (t = −2.072, p = 0.039) and after dinner (t = –2.056, p = 0.041). Compared with the baseline daily smoking, the number of cigarettes smoked per day was significantly reduced at the beginning of week 12 in the immediate nicotine reduction group (p = 0.001) and at week 16 in the gradual nicotine reduction group (p < 0.001). The number of participants with any cigarette-free day was not significantly different between the groups (p = 0.198). The number of cigarette-free days was significantly more in the immediate vs. gradual nicotine reduction group (p = 0.027).

Conclusions
The significantly lower cravings were observed in the immediate vs. gradual nicotine reduction group, and led to faster reduction in the number of CPD, and a significant increase in the number of cigarette-free days. These findings add to the evidence base for reduced nicotine content in cigarettes.

Clinical Trial Registration
ClinicalTrials.gov, identifier: ChiCTR2100048216.

Full text

CLINICAL TRIAL
published: 11 May 2022
doi: 10.3389/fpsyt.2022.884605
Frontiers in Psychiatry | www.frontiersin.org 1May 2022 | Volume 13 | Article 884605
Edited by:
Yanhui Liao,
Zhejiang University School of
Medicine, China
Reviewed by:
Yan-Xue Xue,
Peking University, China
Pinpin Zheng,
Fudan University, China
*Correspondence:
Yonghui Li
liyonghui@psych.ac.cn
Specialty section:
This article was submitted to
Addictive Disorders,
a section of the journal
Frontiers in Psychiatry
Received: 26 February 2022
Accepted: 20 April 2022
Published: 11 May 2022
Citation:
Li Q, Chen X, Li X, Gorowska M, Li Z
and Li Y (2022) The Effects of
Immediate vs Gradual Reduction in
Nicotine Content of Cigarettes on
Smoking Behavior: An Ecological
Momentary Assessment Study.
Front. Psychiatry 13:884605.
doi: 10.3389/fpsyt.2022.884605
The Effects of Immediate vs Gradual
Reduction in Nicotine Content of
Cigarettes on Smoking Behavior: An
Ecological Momentary Assessment
Study
Qianling Li 1,2 , Xijing Chen 1, Xiuli Li 3, Monika Gorowska 1,2 , Zimin Li 1,2 and Yonghui Li 1,2
*
1Chinese Academy of Sciences (CAS) Key Laboratory of Mental Health, Institute of Psychology, Beijing, China, 2Department
of Psychology, University of Chinese Academy of Sciences, Beijing, China, 3YiDu Central Hospital of Weifang, Weifang, China
Background: In recent years, much research has examined the effects of various
interventions and treatments for smoking cessation. The results suggest that
interventions targeting changes of nicotine content can help smokers reduce tobacco
use or quit smoking. A number of clinical studies show that smokers who received
an immediate reduction in nicotine content to very low levels have significantly greater
reductions in the number of cigarettes smoked and toxic substance exposure compared
to those with gradual reductions. However, from the perspective of smoking craving,
whether the immediate and gradual reduction in nicotine content reduce smoking by
reducing cravings needs further investigation.
Methods: 74 eligible Participants were randomly allocated to one of the two
experimental conditions: (1) immediate reduction to 0.1 mg of nicotine per cigarette (n=
40); (2) gradual reduction from 1.0 (0.8 g ∼1.2 mg) to 0.1 mg of nicotine per cigarette (n=
34). All participants completed 1-week baseline period during which they smoked their
usual cigarette, followed by 16-week of interventions. The primary outcomes included
cigarette cravings and number of cigarettes smoked per day (CPD); secondary outcomes
included the number of cigarette-free day and emotional states.
Results: Among the 52 participants [51 (98.1%) men; mean (SD) age, 33.44 (6.71)
years; mean (SD) CPD, 16.83 (9.94)] who completed the trial, significantly lower cravings
for cigarettes were observed in the immediate (n=25) vs. gradual nicotine reduction
group (n=27) in the morning (t= −2.072, p=0.039) and after dinner (t=–2.056, p
=0.041). Compared with the baseline daily smoking, the number of cigarettes smoked
per day was significantly reduced at the beginning of week 12 in the immediate nicotine
reduction group (p=0.001) and at week 16 in the gradual nicotine reduction group (p
<0.001). The number of participants with any cigarette-free day was not significantly
different between the groups (p=0.198). The number of cigarette-free days was
significantly more in the immediate vs. gradual nicotine reduction group (p=0.027).

Li et al. Effects of Low Nicotine Cigarettes
Conclusions: The significantly lower cravings were observed in the immediate vs.
gradual nicotine reduction group, and led to faster reduction in the number of CPD,
and a significant increase in the number of cigarette-free days.These findings add to the
evidence base for reduced nicotine content in cigarettes.
Clinical Trial Registration: ClinicalTrials.gov, identifier: ChiCTR2100048216.
Keywords: immediate nicotine reduction, gradual nicotine reduction, craving, smoking behavior, ecological
momentary assessment
INTRODUCTION
Smoking remains one of the leading causes of morbidity and
premature death worldwide (1–5). Long-term smoking can
affect many systems of the body, resulting in serious and life-
threatening diseases, such as ischemic heart disease, chronic
obstructive pulmonary disease, tracheal cancer, bronchial cancer,
lung cancer, stroke, etc., (5–11). According to data from the
Global Burden of Disease (GBD), in 2019, the number of smokers
worldwide increased to 1.1 billion, and smoking caused 7.7
million deaths worldwide. In China, the number of smokers
reached 341 million (30%), and smoking causes around 2.4
million deaths a year (5). The harmful lifelong consequences of
smoking lead to huge public health costs. It is estimated that
smoking causes economic losses of over US $500 billion annually
worldwide (12).
Nicotine is the main addictive component of cigarettes (2,13–
15). The essence of smoking addiction is nicotine dependence
(16) characterized in DSM-IV, by impulsive use, discontinuation
difficulty, and withdrawal symptoms after chronic use, and
craving which is one of the core symptoms of nicotine addiction
(17–22). Craving is common among smokers (23). Long-term
use of nicotine can induce changes in the neuroplasticity of
the cortex and striatum, thus forming a strong and lasting
memory of nicotine addiction, resulting in a continuous craving
for cigarettes (24). The existence of craving directly leads to
a series of adverse consequences such as smokers’ failure to
quit smoking or susceptibility to relapse (25,26). Craving is
an important indicator for maintaining addictive behavior and
predicting relapse after withdrawal (17,27–35). Moreover, some
studies have found that craving can significantly predict the
withdrawal rate after treatment (36,37), and therefore nicotine
craving has become a criterion for estimating the effectiveness
of treatment (38). Although the mechanism of craving is not
completely clear, it has become an important target for the
treatment of smoking addicts (39). The pain point of smoking
addiction is mainly manifested in the high relapse rate, and
craving is the key factor in precipitating relapse (40,41).
Thus, reducing craving has become the main target in clinical
smoking cessation.
Since craving is the main precipitator of relapse, creating
new intervention content that targets cravings could greatly
enhance the effectiveness of the treatment. In recent years,
some researchers have proposed that reducing the content of
nicotine in cigarettes is an effective strategy that reduces smoking
and improves public health (2,42–48). A gradual reduction in
nicotine content is a potential way to reduce the addiction to
cigarettes and promote smokers to quit smoking (42,44,49–51).
Multiple studies have shown that gradual reduction in nicotine
content reduces nicotine intake, without increased exposure to
tobacco toxins, and without significant “compensatory” smoking
(43,52–55). The gradual reduction in nicotine content is
considered a possible smoking cessation approach (42,44,49–
51), but it may take a long time to realize the potential health
benefits (42,56). Recent studies have found that reducing
nicotine levels faster may be the same even more effective than
gradual reduction (45). There is growing evidence showed that
immediate reduction in nicotine content reduces the number of
cigarettes smoked per day (45,47,57,58), reduces exposure to
toxic substances (43,45,52,57–59), reduces nicotine dependence
(45,47,57,58), increases smoking cessation attempts (43,45,
52,57–59), and “compensatory” smoking is rare compared with
the use of traditional nicotine cigarettes (43,45,52,57,60,
61). A comparison of the two reduction methods showed that
the immediate reduction in nicotine content has a significant
advantage, as it results in less exposure to toxic substances (60–
64), less smoking per day (61), less nicotine dependence (56,61),
and more cigarette-free days (60,61,64) over time. The answer
to the question of whether the gradual and immediate reduction
in nicotine content reduces smoking by reducing craving is still
unknown and thus has to be answered. Especially the dynamic
changes in cravings shall be assessed, and therefore it is necessary
to examine the relationship between daily craving changes and
smoking behavior in real-time.
Ecological Momentary Assessment (EMA) is an innovative
approach developed for real-time data collection, which greatly
improves the field’s understanding of the cognition, emotion, and
behavior of smokers as they occur in the natural environment
(65). The advantages of the EMA approach over retrospective
self-reporting include more accurate tracking of smoking
frequency and patterns, more detailed capturing of smoking
cravings, and high ecological validity of the data (65–67). Since
both craving and substance use are situational phenomena
related to emotion and environment (68–70), measuring these
variables in daily life may lead to more reliable answers.
Therefore, in this study, EMA was used to assess daily craving
changes and smoking behavior in real-time.
The main goal of this study was to examine the effects of
the immediate and gradual reduction in nicotine content in
cigarettes on cigarette craving, as well as to observe changes in
smoking behavior. The main hypothesis of this research was that
significantly lower cravings and lowered number of cigarettes
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Li et al. Effects of Low Nicotine Cigarettes
smoked per day will be observed in the immediate vs. gradual
nicotine reduction group for craving.
METHODS AND MATERIALS
This study has been approved by the Medical Ethics
Committee of Shougang Hospital of Peking University and
has been registered in the Chinese Clinical Trial Registry. All
participants provided informed consent after they were qualified
to participate.
Study Cigarettes
To avoid the problem that offering free cigarettes increases
smoking or increases the use of cigarettes with regular nicotine
content, cigarettes consumed in the study were purchased by
participants at designated regular tobacco companies. Study
cigarettes, both menthol and non-menthol, are all of the
same brand. In a study, researchers examined commercial
low yield cigarettes and found that little change was seen in
plasma cotinine concentration from 0.9 to the 0.4 mg nicotine
yield cigarettes, suggesting compensation in smoking behavior.
However, significant decreases plasma cotinine concentration
and carcinogen exposure biomarker levels were observed when
smokers were switched to 0.1 mg nicotine cigarettes, most
likely due to the extensive filter ventilation of these “ultra-low
yield” cigarettes, too much to be overcome by compensation.
In addition, the 0.1 mg nicotine cigarette also produced non-
significantly greater withdrawal (54). Other related studies have
shown that 0.1 mg nicotine cigarettes can reduce the amount of
smoking and exposure to harmful substances (52,71,72). Thus,
the cigarette with a nicotine content of 0.1 mg was used in the
immediate reduction group. Cigarettes with nicotine content of
0.6 mg (43,53,73–77), 0.3 mg (53,57,73,75–77) and 0.1 mg
(52,71,72) were selected in the gradual reduction group.
Participants
Participants were recruited from Daxing District, Beijing, by
handing out flyers and advertising on WeChat moments.
Inclusion criteria included participants meeting the legal age
for buying cigarettes (18 years old); the average daily smoking
amount ≥5 cigarettes for at least 1 year; no intention to quit
smoking in the past 30 days; and stable mental and psychiatric
conditions. Exclusion criteria included participants who intend
to quit smoking within the next 30 years; regular use of
tobacco products other than cigarettes; current use of nicotine
replacement or other tobacco products for cessation; symptoms
of severe mental or medical illness during the past 3 months;
and being pregnant or breastfeeding. A total of 94 people applied
for participation, of which 74 eligible participants were included.
One blinded researcher (XJC) who had no direct contact with the
participants did a computer-generated randomization to assign
participants to one of the two groups.
Study Design
This study was a randomized parallel experiment (Figure 1).
Participants (N=74) were randomly assigned to 1 of 2
experimental conditions: (1) immediate reduction to 0.1 mg of
nicotine per gram of tobacco cigarettes (n=40); (2) gradual
reduction from 1.0 (0.8 ∼1.2 mg) to 0.1 mg of nicotine per gram
of tobacco cigarettes (n=34).
Procedure
Cigarette smokers were contacted by the researcher and were
screened for eligibility over the telephone. Participants were told
that the goal of the study was to examine how changes in nicotine
content in cigarettes affect smoking behavior over time. They
were also told that if they participate in the research, they would
need to buy their own cigarettes during the course of the study.
Eligible participants completed a baseline period of 1 week and
then were randomly assigned to 1 of 2 experimental conditions
for 16 weeks. Participants smoked their usual brand of cigarettes
during the baseline period and used the cigarettes they were
assigned to purchase during the 16-week experimental phase. In
the immediate reduction group, the participants were required
to smoke 0.1 mg of nicotine per gram of tobacco cigarettes
for 16 weeks. In the gradual reduction group, the participants
were asked to reduce the nicotine intake once every 4 weeks
(0.6 mg of nicotine per gram of tobacco cigarettes were used
from week 1 to week 4; 0.3 mg of nicotine per gram of tobacco
cigarettes were used from week 4 to week 8; and 0.1 mg of
nicotine per gram of tobacco cigarettes were used from week
8 to week 16). During the experiment, participants were told
to use the designated brands of cigarettes (Study cigarettes)
and try not to use their usual brand of cigarettes (Non-study
cigarettes). If both types of cigarettes are used, record them
and inform the researchers. Participants were required to buy
the designated cigarettes during the experiment to avoid the
problem that providing free cigarettes would increase smoking
or use of more cigarettes with regular nicotine content. At the
end of the experiment, participants were paid according to their
compliance with participating in the experiment, everyone was
paid for U200—U400.
EMA Assessment
During the baseline and experimental periods, this study used a
score table to record the emotional state and craving degree of
the participants before and after smoking in the morning and
evening. The scoring method was 1–9 points to record emotional
state (78), when the degree of craving was assessed, 1 indicated
not wanting to smoke at all, and 9 indicated being very eager
to smoke (Table 1). At the same time, the number of cigarettes
smoked per day (study cigarettes and non-study cigarettes) was
recorded on the score table.
All participants were asked to put a score table in the cigarette
packs (Table 1). In the morning when they have their first
cigarette, they were asked to timely estimate their emotional state
and craving values before and after smoking; in the evening,
when smoking their last cigarette, participants were requested to
timely estimate their emotional state and craving values before
and after smoking and write down the number of cigarettes they
smoked that day. The following three ways were used to provide
feedback on the daily smoking to the research staff. The first one
was to directly send the information on the score table to the
staff through WeChat or SMS on the same day; the second one
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Li et al. Effects of Low Nicotine Cigarettes
FIGURE 1 | Flow chart.
required the information on the score table to be filled into the
questionnaire and submitted to the staff before going to bed every
night. The third one required filling in the information on their
own score table in an Excel file every day and sending it to the
staff regularly.
Questionnaire Assessment
The following measures were taken at the baseline and after
the intervention: Fagerström Test for Nicotine Dependence
(FTND) (57), WHO Quality of Life-BREF (WHOQOL-
BREF) (79); Self Rating Anxiety Scale (SAS) (80); Self-rating
Depression Scale (SDS) (81). Profile of Mood States (POMS)
(82). Demographic data and smoking history were collected
at baseline.
FTND: A total of 6 items, and the score of the scale
ranges from 0 to 10, with higher values indicating greater
dependence. The degree of nicotine dependence can be divided
into five levels: very low dependence (0–2), low dependence (3–
4), medium dependence (5), high dependence (6–7), and very
high dependence (8–10).
WHOQOL-BREF: An international scale developed by the
World Health Organization to measure an individual’s health-
related quality of life. 5-point scale was used to measure the
quality of life from four aspects: physical health, psychological,
social relationships and environment. The higher the score in
each area, the better the quality of life, and the most likely area
scores are 35 (physical health), 30 (psychological), 15 (social
relationships) and 40 (environment).
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Li et al. Effects of Low Nicotine Cigarettes
TABLE 1 | Daily smoking score table.
The
number of
non-study
cigarettes
The
number of
study
cigarettes
Time Emotion Craving degree
Before
smoking
After
smoking
Before
smoking
After
smoking
Morning
Evening
SAS: It is used to evaluate the anxiety symptoms of adults.
Compiled by W.K.Zung in 1971, there were 20 items and
four grades.
SDS: It is used to evaluate the depressive symptoms of
adults. Compiled by WilliamW.K.Zung in 1965, with 20 items
and four grades. The severity of depression was measured
from 4 aspects: psycho-emotional symptoms (2 items), somatic
disorders (8 items), depressive psychological disorders (8 items)
and psychomotor disorders (2 items).
POMS: The Chinese Profile of Mood States (POMS) revised
by Zhu Beili (83) contains 40 items with a grade of 5. It contains
seven dimensions: tension, anger, fatigue, depression, energy,
panic and self-related emotions. The reliability is between 0.60
and 0.82.
Statistical Analysis
SPSS 21.0 data analysis software was used for statistical analysis.
The primary end points of this study need to be evaluated
continuously every day, and the intervention time is as long as
16 weeks. Most of the dropouts dropped out of the experiment
in the first few days of the intervention period, and the real-time
data of the primary end points were greatly missing, and there
was no late follow-up data. Thus, the analysis method used in
this study is per-protocol (PP) analysis, that is, participants with
good compliance and completion of the study were analyzed.
Chi-square test and independent-sample T-test were used to
analyze the differences demographic characteristics of the two
groups of participants. A Chi-square test was used to compare
the completion rates at week 16. Changes in cigarette craving
and emotion were analyzed using a generalized linear mixed
model, and the number of cigarettes was analyzed using repeated-
measures analysis of variance. A Chi-square test and negative
binomial regression analysis were used to analyze the number of
participants with any cigarette-free day, the number of cigarette-
free days among all participants. Subjective reports were analyzed
by an independent sample T-test.
RESULTS
Demographic Characteristics and Smoking
History
A total of 74 participants (40 in the immediate reduction group
and 34 in the gradual reduction group) were eligible, and 52
participants completed the experiment (25 in the immediate
reduction group and 27 in the gradual reduction group). The
completion rate of the immediate reduction group was 62.5%,
and the completion rate of the gradual reduction group was
79.4%. The dropout rate of the immediate group is 37.5% (n
=15), and that of the gradual group is 20.6% (n=7). In
the later stage of follow-up, the dropout of participants in the
immediate group was mainly due to the poor adaptability of
some participants to very low nicotine cigarettes, and adverse
events such as dizziness and nausea occurred in the first few
days of using very low nicotine cigarettes, resulting in negative
emotions of participants, which resulted in participants quit
the intervention. The gradual group being resistant to changing
cigarettes during the nicotine content change from 0.6 mg to
0.3 mg nicotine cigarettes, resulting in more dropout.
Table 2 shows the demographics and smoking history of the
two groups. There is no significant difference between the two
groups in demographics and smoking history, indicating that the
participants in the two groups were similar (Table 2).
Smoking Cravings and Emotional Change
in the Immediate Reduction vs. Gradual
Reduction Group
The changes of cigarette craving after getting up in the
morning and after dinner (before smoking-after smoking) were
analyzed by generalized linear mixed model. The results showed
that the smoking cravings after getting up in the morning
were significantly lower in the immediate vs. gradual nicotine
reduction group (12 week, t=–2.091, p=0.038; 16 week, t=–
2.072, p=0.039) after 12 weeks of intervention; and the smoking
cravings after dinner were significantly lower in the immediate
vs. gradual nicotine reduction group (16 week, t=–2.056, p=
0.041) after 16 weeks of intervention. Smoking cravings were
significantly lower in the immediate reduction group at 4 week
(t=5.789, p<0.001), 8 week (t=6.386, p<0.001), 12 week
(t=5.227, p<0.001), and 16 week (t=4.861, p<0.001) of
intervention vs. baseline smoking cravings after getting up in the
morning. Smoking cravings were not significantly different in
the gradual reduction group at 4 week (t=1.593, p=0.112) of
intervention vs. baseline smoking cravings after getting up in the
morning, but were significantly reduced at 8 week (t=3.440, p
=0.001), 12 week (t=2.442, p=0.015), and 16 week (t=2.464,
p=0.014) of intervention. Smoking cravings were significantly
lower in the immediate reduction group at 8 week (t=2.385, p=
0.018) of intervention vs. baseline smoking cravings after dinner,
but no significant difference were observed at other time periods
(4 week, t=1.837, p=0.068; 12 week, t=1.559, p=0.120; 16
week, t=1.865, p=0.063). Smoking cravings were significantly
lower in the gradual reduction group at 8 week (t=2.183, p=
0.030) of intervention vs. baseline smoking cravings after dinner,
but no significant difference were observed at other time periods
(4 week, t=1.545, p=0.124; 12 week, t=1.435, p=0.153; 16
week, t=1.358, p=0.0176) (Figures 2A,B).
The emotional changes of smoking after getting up in the
morning (before-after smoking) were analyzed. The results
showed that there was no significant difference between the
immediate reduction group and the gradual reduction group (t
=–1.285, p=0.200). The emotional changes of smoking after
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Li et al. Effects of Low Nicotine Cigarettes
FIGURE 2 | (A,B) Smoking cravings indicate changes in cravings before-after smoking after getting up in the morning and after dinner, respectively. (A,B) Significantly
lower cravings were observed in the immediate vs. gradual nicotine reduction group. (C,D) The emotional changes of smoking indicate changes in cravings
before-after smoking after getting up in the morning and after dinner, (C,D) there was no significant difference between the immediate reduction group and the gradual
reduction group. *p<0.05.
FIGURE 3 | (A) Total cigarettes per day includes study cigarettes and non-study cigarettes. (B) Study Cigarettes are low nicotine content cigarettes used in the
experiment. (A,B) There was no significant difference in the number of cigarettes per day between the immediate and gradual reduction group, but the number of
cigarettes per day fewer more quickly in the immediate reduction group compared to baseline.
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Li et al. Effects of Low Nicotine Cigarettes
TABLE 2 | Demographics and smoking history.
Immediate reduction group
n=25 (%)
Gradual reduction group
n=27 (%)
χ²p
Male 25 (100) 26 (96.3) 0.944 0.331
Married 21 (84) 21 (78) 0.324 0.569
Education
≤High school 7 (28) 10 (37) 0.482 0.488
>High school 18 (72) 17 (63)
M (SD) M (SD)F p
Age 34.48 (5.77) 32.48 (7.46) 0.560 0.288
Cigarettes per day 15.88 (10.89) 17.7 (9.09) 1.693 0.514
Years of regular smoking 14.72 (7.22) 13.74 (7.58) 0.000 0.634
FTNDa3 (2.68) 3.81 (2.68) 0.230 0.278
WHOQOL-BREFb
Physical health 56.71 (10.07) 53.17 (11.31) 1.833 0.240
Psychological 55.5 (11.52) 57.72 (12.27) 0.029 0.506
Social relationships 58.67 (14.92) 58.33 (14.80) 0.062 0.936
Environment 52.75 (9.65) 55.90 (13.04) 2.260 0.330
Brief POMSc111.36 (16.51) 107.37 (15.99) 0.326 0.380
SASd38.35 (7.68) 42.04 (8.23) 0.041 0.102
SDSe52 (9.56) 53.47 (8.10) 0.186 0.551
aThe FTND scale ranges from 0 to 10, with higher scores indicating greater nicotine dependence.
bThe WHOQOL-BREF produces scores for four domains related to quality of life: physical health, psychological, social relationships and environment, with higher scores indicating
better the quality of life.
cThe Brief POMS, with higher total of emotional disturb indicating a more negative emotional state, that is, a more disturb, upset or dysfunctional mood.
dThe SAS includes 20 items, with higher scores indicating greater anxiety level.
eThe SDS includes 20 items, with higher scores indicating greater depression level.
dinner (before-after smoking) were analyzed. The results showed
a similar effect pattern (t=0.121, p=0.904) (Figures 2C,D).
Total Number Cigarettes per Day (CPD)
Change in the Immediate Reduction vs.
Gradual Reduction Group
Two-factor repeated measurement ANOVA was used to compare
the reduction effect of different intervention groups after 16
weeks of intervention. Significantly fewer numbers of total
CPD were smoked in the immediate reduction group at weeks
12 (p=0.001) and 16 (p<0.001) vs. baseline smoking.
Significantly increased numbers of total CPD were smoked
in the gradual reduction group at weeks 4 (p=0.006)
and 8 (p=0.025) vs. baseline smoking, but significantly
fewer at weeks 16 (p<0.001). The same effect pattern
was observed in the study of cigarettes for several weeks.The
number of cigarettes significantly fewer in both the immediate
(p<0.001) and gradual reduction group (p<0.001) at the
weeks 16 (Figure 3).
The Number of Cigarette-Free Days in the
Immediate vs. Gradual Reduction Group
A Chi-square test was used to analyze the number of participants
with any cigarette-free day. The number of participants with
any cigarette-free day was not significantly different between the
immediate vs. gradual reduction group (p=0.198). Negative
binomial regression analysis was used to analyze the number
of cigarette-free days among all participants. The number of
cigarette-free days among all participants was significantly higher
in the immediate vs. gradual reduction group (p=0.027)
(Table 3).
Dependence, Quality of Life and Emotional
Symptoms in the Immediate vs. Gradual
Reduction Group
At week 16, significantly lower FTND scores were observed in
the immediate vs. gradual reduction group (4.629, p=0.000).
There were no significant differences between the immediate vs.
the gradual nicotine reduction group in four areas of WHOQOL-
BREF scores: physical health (t=1.324, p=0.191), psychological
(t=–0.723, p=0.473), social relationships (t=0.093, p=
0.926), and environment (t=–0.966, p=0.339) at week 16. Total
scores of emotional disturbances as assessed by the POMS were
not significantly different for the immediate vs. gradual reduction
group at week 16 (t=0.817, p=0.418). Anxiety symptoms scores
as assessed by the SAS (t=–1.622, p=0.111) and depression
symptoms scores as assessed by the SDS (t=–0.687, p=0.495)
were not significantly different for the immediate vs. gradual
reduction group at week 16 (Table 4).
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Li et al. Effects of Low Nicotine Cigarettes
TABLE 3 | Cigarette-free days at week 16.
Measures Immediate Gradual Immediate vs. Gradual
No. (%) or Mean (SD) No. (%) or Mean (SD) Estimated OR/IRR (95% CI) p
Any cigarette free day during weeks 0-16, No. (%)b17 (68%) 18 (66.7%) 1.06 (0.33, 3.39) 0.918
Count of cigarette free days during weeks 0-16, mean (SD)c24.40 (30.22) 13.00 (20.18) 0.533 (0.30, 0.93) 0.027a
ap<0.05 for the significant difference.
bOdds ratio (OR) was estimated based on unadjusted analysis; no abstinence being assumed for days with missing Interactive Voice Response (IVR) data.
cIncidence rate ratio (IRR) was estimated based on unadjusted negative binomial regression; no abstinence being assumed for days with missing IVR data.
TABLE 4 | The questionnaire measures at week 16.
Measure Immediate vs. gradual reduction group
Mean difference
(95%CI)
p
FTND
WHOQOL-BREF
Physical health
Psychological
Social relationships
Environment
Brief POMS
SAS
SDS
0.166 (0.44, 1.10)
3.95 (−2.04, 9.93)
−2.37 (−8.96, 4.22)
0.38 (−7.89, 8.65)
−3.13 (−9.65, 3.38)
3.65 (−5.32, 12.61)
−3.44 (−7.71, 0.82)
−1.66 (−6.53, 3.20)
0.000
0.191
0.473
0.926
0.339
0.418
0.111
0.495
DISCUSSION
The present study aimed to examine (1) smoking behavior,
cravings and emotional change among smokers in their daily
life using Ecological Momentary Assessment (EMA) (84–86); (2)
compare the effectiveness of immediate vs. gradual reduction
intervention; and (3) explore whether two different nicotine
reduction methods affect smoking behavior by reducing craving
from a mechanism point of view.
In this study, the immediate nicotine reduction compared
with gradual nicotine reduction was associated with a faster
decrease in cigarette cravings, lowered cigarette cravings, faster
reduction in the CPD, and more cigarette-free days over time.
However, the immediate nicotine reduction caused a higher
dropout rate. The use of low nicotine cigarettes had no effect on
the quality of life and emotional state of the participants.
When these 2 methods were compared in this study, the
results demonstrated that with immediate nicotine reduction,
the smoking craving reduction could be realized sooner than
gradual nicotine reduction. Therefore, the immediate reduction
method is possible to facilitate cessation of cigarettes as quickly
as possible. Immediate reduction method is more effective
than gradual reduction method, because nicotine immediate
reduction method is more conducive to promote smokers to
quit smoking, faster to achieve potential public health effects.
In a large clinical trial involving 1,250 smokers from 10
academic institutions, immediate reduction in nicotine may
achieve positive public health effects more quickly (61).
The results of the comparison of both approaches have shown
that cigarette cravings were reduced faster and significantly
in the immediate reduction group. This is consistent with
other research (61,87). However, previous studies used the
smoking craving scale to assess cravings periodically during the
intervention, rather than continuously assessing the dynamic
changes of cravings during the intervention (61). Some studies
suggested that craving is an instantaneous state that changes
constantly, so it may be inaccurate to assess craving over a long
period of time (88). In addition, some researchers suggest that
craving is a measurable continuous state (89). Therefore, in this
research, we utilized EMA, to continuously assess the dynamic
changes of participants’ cravings over the course of intervention.
The results demonstrated that cravings were significantly lower
and decreased faster in the immediate nicotine reduction group.
There was no significant difference in the number of CPD
between the immediate and the gradual reduction group in the
study. The results of this study are not consistent with those
of previous studies (61,64). Previous studies have shown that
significantly fewer numbers of CPD in the immediate than the
gradual reduction group (61,64). One possible explanation is
that the duration of this study was only 16 weeks, so there were
no significant differences in smoking reduction between both
interventions. Another possible explanation is that the sample
size of this study was too small. Compared with the baseline,
both the immediate and the gradual reduction groups were able
to significantly reduce the number of CPD after 16 weeks of
intervention, with a faster reduction in the number of CPD in
the immediate reduction group. The results have shown that
the number of CPD in the immediate reduction group was
reduced during the intervention and significantly reduced at
week 12, while the number of CPD in the gradual reduction
group increased at weeks 4 and 8 and significantly reduced at
week 16. There was a temporary increase in smoking in the
gradual reduction group, possibly due to compensatory smoking
in moderate nicotine cigarettes (45,52,53,61).
In the comparison between the immediate vs. gradual
reduction group, the results demonstrated significantly more
cigarette-free days among all participants in the immediate
reduction group. The results are consistent with those of
Hatsukami et al. (61). Both intervention methods had no
effect on the quality of life and emotional state of the
participants, indicating that switching to low nicotine cigarettes
may be more acceptable by participants who participated in the
entire intervention.
Frontiers in Psychiatry | www.frontiersin.org 8May 2022 | Volume 13 | Article 884605

Li et al. Effects of Low Nicotine Cigarettes
There was a higher drop-out in the immediate group.
However, the withdrawal rate was no different between the
immediate vs. the gradual reduction group. Other studies have
shown that immediate nicotine reduction is less satisfying (61,
87), leading to more severe withdrawal symptoms (56,61) and
a higher subjects’ attrition rate (61,87) than gradual nicotine
reduction. The reason why there was no difference in compliance
between the immediate and the gradual reduction group may
be due to the gradual nicotine reduction group being resistant
to changing cigarettes during the nicotine content change from
0.6 mg to 0.3 mg nicotine cigarettes, resulting in more subjects
dropout. In this study, participants were free to choose blended
/ flue-cured 0.6 mg nicotine cigarettes. However, when switched
to 0.3 mg nicotine cigarettes, only the blend cigarettes were
available. 75.0% of the participants in this study were flue-
cured cigarette users, and discomfort caused by different types
of cigarettes made it easier for participants to drop out during
this process.
Limitations
This study has several limitations. Firstly, the duration of this
study was only 16 weeks, and the long-term effects of the
two nicotine reduction methods were uncertain (61). Secondly,
there was no follow-up at the end of the study. Third,
the relatively small number of participants could limit the
universality of the findings (43,52). Furthermore, the average
level of education of the participants was higher, and the
universality of the findings is limited. Likewise, the selectivity of
cigarette types was limited, which may affect the measurement of
various outcomes. Moreover, the monitoring of adverse events
(any negative changes in physical or mental health) and the
measurement of withdrawal reaction were not carried out during
the study.Seventh, in this study, most of the participants were
male and there was only one female who completed the study,
the study didn’t compare the effectiveness of the two methods
in male and in female, future studies could further compare
the effectiveness of the two methods in male and in female. In
addition, in this study, there is a lack of objective indicators
to measure the intervention effect, and it may not be very
comprehensive and objective to evaluate the intervention effect
only from the self-report. in the future study, the intervention
effect can be measured from multiple perspectives, and the
mode of combining physiology with self-report can be adopted.
Biomarkers such as cotinine can be used for physiological
indicators. As well, in terms of efficacy analysis, per-protocol (PP)
analysis may overestimate the efficacy. The interpretation of the
results of this study is more applicable to participants who are
more compliant with low nicotine cigarettes.
CONCLUSIONS
Among smokers, the immediate nicotine reduction group led to
a faster and significant decrease in cigarette cravings, a faster
reduction in the number of CPD, and a significant increase in
the number of cigarette-free days among all participants in the
gradual reduction group.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding author.
ETHICS STATEMENT
The studies involving human participants were reviewed
and approved by Medical Ethics Committee of Shougang
Hospital of Peking University. The patients/participants
provided their written informed consent to participate in
this study.
AUTHOR CONTRIBUTIONS
QL and YL contributed in conceptualization and methodology.
YL supervised the study design and implementation. QL
designed the experiment, analyzed data, wrote the paper, and
revised the article. ZL designed experiment and collected
data. XC provided methodological and substantive support
throughout the manuscript process. MG, XC, and XL revised the
article. All authors contributed to the article and approved the
submitted version.
FUNDING
Funding for this study was provided by Scientific
and Technological Innovation 2030-Brain Science and
Brain-Inspired Technology Project (2021ZD0202100).
ACKNOWLEDGMENTS
We thank all the participants and researchers.
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