
==== Front
Pharmacol Res Perspect
Pharmacol Res Perspect
10.1002/(ISSN)2052-1707
PRP2
Pharmacology Research & Perspectives
2052-1707
John Wiley and Sons Inc. Hoboken

10.1002/prp2.70016
PRP270016
PRP2-2024-08-0277
Original Article
ORIGINAL ARTICLE
Pharmacology and Regulation of Appetite and Food Intake
Nicotine addiction and the influence of life adversity and acute stress on PYY: Prediction of early smoking relapse
Miller et al.
Miller Amanda A. https://orcid.org/0000-0003-1247-6463
1
Nakajima Motohiro https://orcid.org/0000-0002-3153-6372
1 2
DeAngelis Briana N. https://orcid.org/0000-0001-6001-8497
1
Hatsukami Dorothy K. https://orcid.org/0000-0002-1108-2609
3
al'Absi Mustafa https://orcid.org/0000-0003-4531-038X
1 malabsi@d.umn.edu

1 Department of Family Medicine and Biobehavioral Health University of Minnesota Medical School Duluth Minnesota USA
2 Eikei University of Hiroshima Hiroshima Japan
3 Department of Psychiatry & Behavioral Sciences University of Minnesota Twin Cities Minneapolis Minnesota USA
* Correspondence
Mustafa al'Absi, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA.
Email: malabsi@d.umn.edu

24 9 2024
10 2024
12 5 10.1002/prp2.v12.5 e7001611 8 2024
03 9 2024
© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Early life adversity (ELA) is associated with earlier initiation and maintenance of tobacco smoking and with a greater risk of subsequent relapse. There is growing evidence that appetite hormones, including peptide YY (PYY), which modulates craving and satiety responses, play a role in stress and addiction processes. This study employed a quasi‐experimental design to examine the association between ELA and circulating PYY stress responses in smokers and nonsmokers (N = 152, ages 19–73 years) to examine the effects of nicotine addiction. Smokers initiated a quit attempt as part of the study and were classified as either abstinent smokers or relapsed smokers based on their nicotine use during the follow‐up period. PYY levels were measured at five timepoints during three lab sessions and compared between nonsmokers and the two smoking groups (abstainers, relapsers): while smokers were using nicotine ad libitum, 24 h after smokers initiated a quit attempt, and 4 weeks after smokers initiated a quit attempt. Multivariate analyses showed the main effects of time on PYY, which decreased over time within each session. The main effects of ELA during the first (ad libitum smoking) and second (24‐h post‐cessation for smokers) sessions indicated that experiencing ELA was associated with lower PYY. No systematic effect of nicotine addiction or relapse was observed in this study. These findings suggest that adults with higher ELA may experience lower PYY. Additional research is needed to further explore the role of PYY in stress and addiction processes.

Peptide YY (PYY) decreased after acute stress exposure. Early life adversity was associated with lower overall PYY but not altered PYY responses to stress. No systematic effect of nicotine addiction or relapse was observed in this study.

acute stress
appetite hormones
early life adversity
peptide YY
relapse
smoking
tobacco
National Institute on Drug Abuse 10.13039/100000026 R01DA016351 R01DA027232 source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:24.09.2024
Miller AA , Nakajima M , DeAngelis BN , Hatsukami DK , al’Absi M . Nicotine addiction and the influence of life adversity and acute stress on PYY: Prediction of early smoking relapse. Pharmacol Res Perspect. 2024;12 :e70016. doi:10.1002/prp2.70016
==== Body
pmc1 INTRODUCTION

Experiences of early life adversity (ELA) are a major source of chronic psychological stress that have a long‐term impact on stress neurobiology 1 , 2 and they are an important predictor of urges to use nicotine during quit attempts 1 , 3 and of nicotine relapse and withdrawal in adulthood. 4 , 5 , 6 Many biological markers (e.g., glucocorticoids and inflammatory cytokines) have been examined as potential indicators of vulnerability to and/or resilience against stress‐induced relapse during cessation attempts. 4 , 5 , 7 , 8 Yet, less research has examined the role of appetite‐regulating hormones—especially, the gut hormone peptide YY (PYY)—in the relationships among stress, nicotine use, and nicotine relapse. 9 , 10 , 11 This study examines PYY response to acute stress in smokers and nonsmokers and within the context of smoking relapse and ELA.

Recently, researchers have begun examining the role of appetite‐regulating hormones in nicotine use and relapse in adults. 9 , 10 , 11 , 12 , 13 Here, we focus on PYY, which is an anorexigenic, short‐chain 36‐amino acid peptide synthesized and released from enteroendocrine cells in the ileum and colon as part of the feeding inhibition response. 14 Operating via the gut‐brain axis, secreted PYY acts on the hypothalamic presynaptic Y2 receptor to induce satiety and can suppress food intake. 15 Higher PYY may additionally modulate hedonic brain regions associated with motivation and reward circuit pathways to influence food intake and satiety, 16 operate on shared pathways that facilitate serotonergic neurotransmission, 17 and buffer against corticotrophin‐releasing factor release after stress to mitigate stress‐induced feeding responses. 18 Higher levels of circulating PYY are related to lower tobacco craving, less urge to smoke during withdrawal, and more positive effects. 9 , 10 Despite its implication in stress and craving processes, 9 , 19 much is still unknown about the role of PYY in stress responding and the consequent risk of maintenance of tobacco smoking and smoking relapse.

The accumulation of burdens due to ELA may lead to excessive or prolonged activation of biological stress arousal systems (e.g., the hypothalamic–pituitary–adrenocortical axis), increasing allostatic load on these systems and altering psychobiological processes related to addiction and relapse. 1 , 3 , 20 Dysregulated stress response processes can contribute to either (1) sensitized or (2) blunted arousal systems, with negative neurobiological consequences for addiction and relapse risk. 1 , 21 Changes in stress responses may also contribute to more maladaptive cognitive‐behavioral responses that increase the risk of nicotine relapse. For example, adults with higher ELA tend to engage in maladaptive regulation strategies, including avoidant and substance‐related coping strategies, to alleviate psychosocial stress. 22 , 23 Since ELA is often linked with dysregulated stress response 1 , 24 , 25 and psychosocial stress increases cigarette craving, 26 adults with more ELA may experience nicotine cravings more intensely during nicotine withdrawal. 4 In sum, there is evidence to suggest that ELA may contribute to nicotine addiction and relapse risk through biopsychological mechanisms of stress.

Prior research has shown the long‐term influence of ELA on psychological and physiological stress processes in adult smokers. 1 , 4 , 9 Although some links have been drawn between lab‐induced acute stress and PYY responding, 18 , 19 less is known about the impact of adverse life events on this association. At this time, no studies have examined the potential relationship between ELA and PYY responses to acute stress. This study extends previous research 9 , 10 , 11 by using primary data to examine associations between ELA, smoking relapse, and serum PYY responses to stress. Since prior research shows limited findings for associations between relapse status and PYY 11 and less is known about the role of ELA on PYY responses to stress, we sought to investigate whether experiencing ELA was associated with a change in PYY (H1, hypothesis) and smoking relapse status (H2, hypothesis 2) during stress.

2 METHODS

2.1 Participants

Flyers posted in communities and social network advertisements were used to recruit potential participants. Interested responders were phone‐screened for preliminary eligibility, and then were invited to an on‐site medical screening for additional assessment of eligibility. Eligible participants (N = 152; ages 19–73; M (SD) = 37.97 (13.52)) were included if they consented to participation. Participants were categorized as smokers (i.e., tobacco users; n = 104) and nonsmokers (n = 48). Eligibility criteria for tobacco users included smoking ≥5 cigarettes per day over the past 2 years and strong motivation to quit (i.e., ≥4 on a 5‐point scale question asked during the phone and on‐site screenings). Criteria for nonsmokers included being free from cigarette use over the past 5 years and smoking <100 cigarettes over the lifetime. Participants who were pregnant or who received treatment for hypertension, renal or liver disease, cardiac disease, endocrine or metabolic disease, mental illness, or drug or alcohol addiction were also excluded. The Institutional Review Board of the University of Minnesota approved this study.

2.2 Procedures

Participants who met eligibility criteria completed self‐report questionnaires, and smokers were asked to set a quit date and complete three laboratory visits: an ad libitum smoking session (ad lib, Lab 1); a 24‐h post‐cessation session (quit day, Lab 2); and a 4‐week post‐cessation session (post‐cessation, Lab 3). Nonsmokers were asked to complete the same laboratory protocol (sans smoking). Prior to each lab visit, participants were instructed to avoid the following before testing: caffeine and strenuous exercise (4 h prior), alcohol (24 h prior), and pain medication (including over‐the‐counter drugs; 24 h prior). To control for the effects of diet on participant hormone levels, nutrition intake was documented over the preceding 3 days of each lab visit and participants were issued a pre‐prepared meal 2 h prior to the lab (data to be published elsewhere).

Self‐reported smoking and expired carbon monoxide (CO) were collected to monitor tobacco use. Following standardized threshold level conventions for expired CO, 27 research staff followed‐up with smokers who had CO ≥9 ppm and/or who reported smoking in the past 24 h during the quit day session. Participants who did not comply with the protocol were rescheduled. After the quit day lab, participants completed three weekly follow‐up visits (data not reported here) and then the third laboratory session at the fourth week (i.e., post‐cessation). Participants who were smokers were provided practical counseling sessions (approximately 30–45 min) on smoking cessation (including the dangers of smoking, benefits of quitting, and discussion of the physical and psychological effects of smoking) during each visit and offered physical hand‐outs with smoking cessation resources, including. Non‐smokers were offered optional counseling sessions, which focused on stress management and problem‐solving. Counseling sessions for all participants provided advice on coping strategies to deal with negative emotions and relaxed breathing techniques. Relapse status was assessed using self‐report and verified using expired CO during the weekly follow‐up visits and at the third laboratory session.

Each of the three laboratory stress sessions included six periods: (1) instructions and IV catheter preparation; (2) baseline rest (~20 min); (3) acute stress (~40 min); (4) post‐stress 1 task (~10 min); (5) post‐stress 2 task (~20 min); (6) recovery (~20 min). Blood samples were collected at the end of the baseline, acute stress, post‐stress, and recovery periods (a total of 5 times). Acute stress tasks included public speaking, mental arithmetic, anger recall, and cold pressor. The acute stress task order was fixed, with each task lasting approximately 10 min except for the 3‐min cold pressor task, which consisted of a 90‐s period where the participants submerged their hands in an ice water bath, promptly followed by a final 90‐s recovery period. Stress task protocols were part of an established laboratory procedure employed in previous research. 9 , 28

2.3 Measures

2.3.1 Participant characteristics

Demographic information collected in the medical screening included biological sex, age in years, years of education, marital status (single, married, divorced, separated/widowed), race, ethnicity (1 = Hispanic, 0 = Not Hispanic), alcohol use frequency (Never, Rarely, Sometimes, or Often), smoking history (cigarettes per day, years of smoking, age of onset of regular smoking), and the 6‐item Fagerström Test for Cigarette Dependence (FTCD). 29 The FTCD is scored by summing item responses; lower scores indicate lower dependence on nicotine and higher scores indicate higher dependence on nicotine. Participants' height and weight were measured during the initial medical screening and used to compute body mass index (BMI; kg/m2) used in the present analyses.

2.3.2 Early life adversity

A modified, 8‐item version of the 10‐item Adverse Childhood Experiences (ACEs) Questionnaire 30 , 31 was used to measure ELA. The items asked about the presence or absence of eight types of ELAs (verbal abuse, physical abuse, sexual abuse, battered mother, household substance abuse, household mental illness, household member incarceration, parental separation, divorce). Participants were given 1 point for each domain where ELA was reported. Total ELA scores were calculated by taking the sum of all domain scores and used to classify participants into two groups: No ELA (total score = 0; n = 60) and ELA (total score ≥1; n = 92).

2.3.3 Biological measures

PYY (pg/mL) was tested using enzyme‐linked immunosorbent assay (ELISA) kits (#EZHPYYT66K, EMD Millipore). The five blood samples collected after the initial resting period (end of periods 2–6) during the first (ad lib), second (quit day), and third (4 weeks post‐cessation) laboratory were assayed for PYY. Blood samples were collected in EDTA tubes and stabilized after treatment with 4‐(2‐aminoethyl) benzenesulfonyl fluoride hydrochloride. 32 Following ELISA kit protocols and instructions outlined by EMD Millipore, samples were then processed and tested for PYY.

2.3.4 Smoking groups

Participants were classified into one of three smoking groups: non‐smokers, relapsed smokers (i.e., relapsers), and abstinent smokers (i.e., abstainers). Smokers completed a daily diary in which they recorded the amount of nicotine consumed each day between the quit‐day stress session and the 4‐week post‐cessation stress session. In addition to expired CO (see Procedures section), diaries and interviews were used to determine relapse among smokers. Relapsers were defined as adults who relapsed (i.e., smoked ≥1 puff of nicotine per day for 7 consecutive days) prior to the 4‐week post‐cessation laboratory session. 33 Smokers who did not meet these criteria for relapse were considered to have successfully maintained abstinence from smoking during this period and were classified as abstainers.

2.4 Data analysis

SPSS was used for data analysis. A quasi‐experimental approach comparing smokers and non‐smokers by ELA status. Demographic variables were analyzed using smoking group (nonsmoker, abstainer, relapse) × ELA (none, present) MANOVAs (continuous variables) and chi‐square tests (categorical variables). Thresholds for statistical significance were set to <.05 (p‐value). Due to occasional missing data, minor variations in degrees of freedom were anticipated. Participants with full PYY data during the ad lib session, and/or the quit day session, and/or the post‐cessation session were included in the analysis.

PYY was log‐transformed to normalize the distribution. MANOVAs were conducted separately for each lab session (ad lib, quit day, post‐cessation). For each laboratory session, a 3 smoking condition (nonsmokers, abstainers, relapsers) × 2 ELA (none, present) × 5 time period (baseline rest, acute stress, post‐stress 1, post‐stress 2, recovery) MANOVA with Wilks' lambda test was conducted on PYY. If there was a statistically significant interaction, a follow‐up analysis was conducted in each group (smoking, ELA) separately with Bonferroni correction. Area under the curve with respect to ground (AUCg) 34 was also calculated for raw PYY across three periods (baseline rest, acute stress, and post‐stress 1), then the natural log‐transformed, and subjected to a 3 smoking group × 2 ELA ANOVA, to examine ELA and smoking group differences in PYY stress responses at each lab session. Bonferroni corrections were applied to multiple comparisons. The area under the curve with respect to baseline (AUCi) was also computed for raw PYY from periods 2–4 and was examined via the same ANOVA models that were used for AUCg. Consistent with previous research, 35 the preliminary correlational analysis found that PYY was related to BMI (p < .05). Thus, additional analyses were run for PYY stress response, with BMI as a covariate.

2.5 Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 36 and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. 37

3 RESULTS

Descriptive characteristics and classifications of the study sample are in Table 1. Bivariate correlations of study variables are in Table 2. A total of 60.5% (n = 92) of the participant sample had ELA (M = 1.43, SD = 1.64). Among smokers (n = 104), n = 58 returned to smoking within the first 4 weeks of cessation (a.k.a., relapsers), and n = 46 smokers remained abstinent during this period (a.k.a., abstainers). Compared to 41.7% of nonsmokers, 69.6% of abstainers and 69.0% of relapsers had ELA (χ 2  = 10.448, p = .005). Smoking and ELA groups were not associated with age, sex, education, marital status, race, nor ethnicity (ps > .05; see Table 1). When BMI was included in the model as a covariate, the time effect remained significant but the smoking by ELA interaction was not significant (p = .09).

TABLE 1 Descriptive characteristics of study sample.

	Nonsmoker (n = 48)	Abstinent smoker (n = 46)	Relapsed smoker (n = 58)	
No ELA (n = 28)	ELA (n = 20)	No ELA (n = 14)	ELA (n = 32)	No ELA (n = 18)	ELA (n = 40)	
Female, n (%)	16 (57.1)	14 (70.0)	7 (50.0)	17 (53.1)	9 (50.0)	18 (45.0)	
Age (years), M (SD)	33.82 (12.95))	36.65 (17.20)	43.64 (11.04)	38.50 (12.46)	42.94 (11.84)	38.60 (12.18)	
BMI, a M (SD)	25.64 (4.53)	26.71 (6.93)	26.41 (3.22)	29.05 (7.99)	29.76 (6.37)	26.84 (5.67)	
Education b (years), M (SD)	15.75 (3.56)	14.65 (3.44)	14.46 (3.10)	13.79 (3.65)	14.00 (2.35)	13.55 (2.21)	
Marital status, n (%)	
Single	20 (71.4)	10 (50.0)	9 (64.3)	11 (36.7)	8 (44.4)	26 (66.7)	
Married	5 (17.9)	3 (15.0)	2 (14.3)	10 (33.3)	4 (22.2)	7 (17.9)	
Divorced	3 (10.7)	4 (20.0)	2 (14.3)	8 (26.7)	6 (33.3)	4 (10.3)	
Widowed/separated	0 (0)	3 (15.0)	1 (7.1)	1 (3.3)	0 (0)	2 (5.1)	
Race, n (%)	
Caucasian	21 (75.0)	15 (75.0)	11 (78.6)	22 (68.8)	14 (77.8)	31 (77.5)	
African American	1 (3.6)	1 (5.0)	1 (7.1)	4 (12.5)	3 (16.7)	4 (10.0)	
Asian	2 (7.1)	1 (5.0)	1 (7.1)	2 (6.3)	0 (0)	0 (0)	
American Indian/Native Alaskan	0 (0)	1 (5.0)	1 (7.1)	3 (9.4)	1 (5.6)	2 (5.0)	
Multi‐racial	4 (14.3)	2 (10.0)	0 (0)	1 (3.1)	0 (0)	3 (7.5)	
Hispanic, n (%)	1 (3.6)	3 (15.0)	1 (7.1)	1 (3.1)	0 (0)	0 (0)	
Alcohol, b , c n (%)	
Never	3 (10.7)	2 (10.0)	0 (0)	5 (16.1)	4 (23.5)	8 (20.0)	
Rarely	8 (28.6)	5 (25.0)	4 (30.8)	15 (48.4)	7 (4102)	18 (45.0)	
Sometimes	7 (25.0)	7 (35.0)	6 (46.2)	8 (25.8)	3 (17.6)	9 (22.5)	
Often	10 (35.7)	6 (30.0)	3 (23.1)	3 (9.7)	3 (17.6)	5 (12.5)	
Cigarettes per day, M (SD)	n/a	n/a	12.43 (3.18)	13.13 (4.77)	13.97 (3.24)	14.13 (6.10)	
Smoking duration (years), M (SD)	n/a	n/a	16.33 (13.80)	11.16 (11.01)	14.55 (12.55)	13.90 (12.28)	
Age of onset of smoking d (years), M (SD)	n/a	n/a	18.71 (2.73)	17.47 (5.61)	19.44 (6.15)	15.25 (3.77)	
FTCD, M (SD)	n/a	n/a	4.79 (1.67)	4.72 (1.91)	5.33 (1.91)	5.29 (1.97)	
CO (parts per million), M (SD)	
Ad lib b	n/a	n/a	13.51 (7.11)	13.65 (8.20)	18.47 (7.95)	17.60 (9.30)	
Quit day	n/a	n/a	2.87 (1.40)	2.95 (2.54)	3.22 (2.03)	2.66 (1.84)	
Post‐quit b	n/a	n/a	1.96 (1.22)	3.32 (2.59)	15.49 (7.39)	14.49 (8.93)	
Note: Sample characteristics reported for participants with full peptide YY data recorded during the ad lib session, and/or the quit day session, and/or the post‐cessation session. Percentages were calculated as the percent of valid responses within the column subgroup. Values for BMI were reported at the medical screening.

Abbreviations: BMI, body mass index; CO, expired carbon monoxide; ELA, early life adversity; FTCD, Fagerström Test for Cigarette Dependence; M, mean; n/a, not applicable; SD, standard deviation.

a Smoking group by ELA interaction was significant; ELA relapsers had a higher BMI than no ELA relapsers.

b Main effect of smoking group was significant.

c Rarely = a few times per year, Sometimes = several times per month, Often = several times per week or more.

d Main effect of ELA was significant.

TABLE 2 Pearson correlations of continuous study variables.

Variable	1	2	3	4	5	6	7	8	9	10	11	
1. Age	—											
2. BMI	.114	—										
3. Edu (years)	.157*	−.145	—									
4. Cigarettes (per day) a	.298**	.186*	.119	—								
5. Smoking (years) a	.559**	.045	.009	.213*	—							
6. Smoking onset age a	.223*	−.068	.448**	−.001	−.138	—						
7. FTCD a	.188*	.008	.014	.500**	.121	−.041	—					
8. CO (ad lib) a	.286**	−.039	.068	.400**	.092	.064	.410**	—				
9. CO (quit day) a	.180*	−.074	.172	.309**	.076	.226*	.254**	.307**	—			
10. CO (post‐quit) a	.097	.080	−.026	.159	.060	−.016	.377**	.527**	.148	—		
11. ELA b	−.023	.179*	−.210**	−.099	.055	−.238**	−.055	−.109	−.119	−.106	—	
Note: Sample characteristics reported for participants with full peptide YY data recorded during the ad lib session, and/or the quit day session, and/or the post‐cessation session. Results reported for correlations without controlling for covariates.

Abbreviations: BMI, body mass index; CO, expired carbon monoxide; Edu, education; ELA, early life adversity; FTCD, Fagerström Test for Cigarette Dependence.

a Variables measured among smokers only.

b Sum score of Adverse Childhood Experiences Questionnaire.

* p < .05;

** p < .01 (two‐tailed tests).

Prior to cessation, smokers smoked 13.56 (SD = 4.93) cigarettes on a typical day for 13.46 (SD = 12.08) years, with FTCD total scores of 5.05 (SD = 1.88), suggesting that smokers had a moderate dependence to nicotine. Relapse status and ELA were not associated with these smoking variables (ps > .10). Presence of ELA was associated with earlier onset of regular smoking (F(1, 100) = 7.119, p = .009, η 2 = .066). On average, smokers showed a 74.7% reduction in CO between the ad lib and quit day sessions (24 h), and showed a 42.7% reduction in CO between the ad lib and post‐cessation sessions. Relapsers and abstainers did not differ in CO in the quit session (p > .10). Overall, this indicated that participants complied with the study protocol. There were no other main effects or interactions.

3.1 PYY

Within all three stress sessions, PYY decreased over time (ps < .001; Figure 1). Experiencing ELA was associated with lower PYY within the ad lib (F(1, 137) = 8.407, p = .004, η 2 = .058) and quit day sessions (F(1, 140) = 5.072, p = .026, η 2 = .035), but not in the post‐cessation session (F(1, 118) = 1.449, p = .231, η 2 = .012). There were no other main effects or interactions. Inclusion of BMI weakened the time main effects for the ad lib (F(1, 135) = 7.409, p = .007, η 2 = .052) and quit day sessions (F(1, 137) = 5.040, p = .026, η 2 = .035), and the time effect for the post‐cessation session remained insignificant (F(1, 117) = 1.520, p = .220, η 2 = .013).

FIGURE 1 Peptide YY (PYY) levels before and after exposure to acute stress.

For AUCg analyses of PYY, there was a significant ELA effect at the ad lib session (F(1, 138) = 6.053, p = .015, η 2 = .041) and at the quit day session (F(1, 138) = 4.694, p = .032, η 2 = .032), with higher PYY levels in those without ELA relative to those with ELA at both sessions. However, at the quit day session, this main effect was qualified by an ELA by smoking group interaction, (F(2, 138) = 3.100, p = .048, η 2 = .042). Follow‐up tests showed that PYY was higher in those without ELA relative to those with ELA, but only for abstainers (F(1, 138) = 6.884, p = .010). There were no other main effects nor interactions at any of the sessions. When BMI was entered as a covariate, the effect of BMI was significant at the post‐cessation session (p = .028), but not at the other two sessions (ps > .060). The main effect of ELA remained significant at the ad lib and quit day sessions (F(1, 136) = 5.358, p = .022, η 2 = .036 and F(1, 135) = 4.385, p = .038, η 2 = .029, respectively), and the interaction between ELA and smoking group remained significant at the quit day session, (F(2, 135) = 3.834, p = .024, η 2 = .051). While the main effects of ELA still indicated that those without ELA had higher PYY than those with ELA at both sessions, the interaction effect at the quit day session indicated that this was true for abstainers and relapsers (F(1, 135) = 5.942, p = .016 and F(1, 135) = 4.750, p = .031, respectively). There were no other significant main effects nor interactions.

When AUCi was examined, there were no significant main effects nor interactions. When BMI was entered as a covariate, there were no statistically significant effects for BMI nor for any of the other predictors.

4 DISCUSSION

To date, no study has examined the roles of PYY stress responses and ELA in the context of tobacco relapse risk. This research examined associations between ELA, smoking and relapse status, and PYY responses to acute stress in a sample of smokers and nonsmokers. Informed by current literature, we anticipated that experiencing ELA would be associated with a change in PYY (H1) and relapse status (H2) in response to acute stress. Findings indicated that PYY declined over time within all stress sessions and that experiencing ELA was associated with lower PYY in the ad lib and quit day sessions, but not in the final post‐cessation session. This study found no evidence of a significant association between PYY and ELA (H1), and it did not find strong evidence of a relationship between smoking status and PYY (H2).

Previous research has shown links between lab‐induced stress and PYY. 18 , 19 In this study, reductions in PYY were observed over time within each of the stress lab sessions. However, this study did not include a no‐stress control group (i.e., no‐acute stress) for comparison and to control for the effect of time on PYY; therefore, it is unclear whether the observed reduction differs from that which would be expected in the absence of acute stress. Further investigation is needed to determine the effect of different stressors on PYY accounting for the diurnal effect and time since the last food intake.

Previous research shows that experiencing ELA is associated with greater risk of nicotine use and relapse, 5 which may be due, in part, to stress‐induced physiological dysregulation. 1 , 3 , 20 Exposure to psychosocial stress increases smoking desire and nicotine craving 26 and PYY is inversely associated with smoking urges during periods of nicotine withdrawal. 9 , 10 ELA has been linked with dysregulated biological reactivity to acute psychosocial stress, 38 and investigations of mechanisms involved in the relationship between ELA and reactions to stress indicate that experiencing ELA is associated with apparent dysregulation of reward systems that could explain vulnerability to engage in maladaptive or disordered behaviors. 39 Although we found that ELA was associated with lower overall PYY in two out of the three sessions, we found no evidence that ELA was associated with altered PYY responses to acute stress. In addition, we did not find strong evidence that PYY was associated with smoking relapse in this study. While the underlying links between ELA, PYY, and tobacco relapse risk remain unclear, these findings complement prior research linking ELA with more subjective (e.g., self‐reported craving and/or urges to smoke) and objective (e.g., circulating ghrelin) indicators of appetite stimulation processes implicated in nicotine addiction, 9 , 40 as well as related blunted stress hormone responsivity. 5 Further, considering that PYY may be a latent marker of stress resilience, 11 , 18 , 19 it is possible that a reduction of this peptide in the high ELA group in this study marks an indication of increased chronic stress and reduced resilience in this group. Additional research is needed to test this hypothesis. It is unclear whether individual differences in resilience factors, including stress‐risk appraisal and coping, may account for some effects. 41 Regardless, these findings help address the paucity of research on ELA and PYY in the context of nicotine withdrawal and relapse, and this study provides a basis for continued investigation in this area.

The strengths of this study include a relatively large sample size and the use of a systematic, repeated measures approach to examine stress responses during ad lib smoking and after both mandatory, acute (quit day), and optional, prolonged (post‐cessation) withdrawal. These findings are also novel and mark the first examination of PYY in response to stress within the context of tobacco withdrawal and relapse, and they extend the current literature by examining associations between stress, PYY, ELA, and relapse. 9 These findings constitute emerging research in this area and a basis for continued exploration. This study also had some limitations. First, the use of retrospective self‐evaluation of ELA, which may be subjected to self‐presentational biases or lapses in memory. 42 Second, this sample consisted of adults with no active nor previous health history of psychiatric disorders, and excluded individuals who use multiple substances. Future research may benefit from examining clinical populations of interest and from additional investigations of polysubstance use as it relates to PYY and ELA during acute stress. A third limitation is that this study employs a generous CO cutoff of 9 ppm or lower to determine smoking abstinence, rather than employing a stricter cutoff of ≤5 recommended elsewhere, 43 which may not have been sensitive enough to detect proof of abstinence in abstaining smokers. Finally, although the sample size in this study was large enough to sufficiently power our analyses, the cell sizes were generally small, and may have been a potential source for null findings (i.e., increased risk of Type 2 error). It may also be that, since a quasi‐experimental design approach comparing smoking group status by ELA status was used, further investigation is needed to determine whether PYY differences could be attributed to the influence of ELA. Thus, these results should be considered preliminary, and replication is needed, preferably with a larger sample size.

This research has potential clinical implications. First, identifying factors associated with relapse versus successful abstinence during nicotine cessation could help inform cognitive behavioral strategies to promote adaptive coping strategies during stressful situations and reduce the risk of stress‐induced nicotine relapse. Further, exploring the role of PYY in acute stress responses provides new knowledge on the role of appetite‐related peptides in stress‐induced risk of relapse in smokers undergoing abstinence. Since appetite hormones are implicated in craving, relapse, and reward processes associated with addiction, 10 , 42 having a better understanding of the underlying biological processes of stress responding, craving, and nicotine relapse risk could facilitate more personalized, effective treatment approaches to help mitigate nicotine maintenance and relapse, which could be implemented during times of vulnerability.

In conclusion, this study provides novel information about PYY responses to acute stress and their relationship to ELA and smoking status. These findings extend the current literature and suggest that experiencing ELA is associated with lower PYY. Gaining a better understanding of stress‐ and reward‐signaling pathways involved in the relationships among ELA, circulating PYY, and nicotine relapse could inform the development of evidence‐based interventions aimed at improving stress management and smoking relapse prevention.

AUTHOR CONTRIBUTIONS

MA conceived the study, designed the protocol, and supervised all phases of the study. MN performed the analyses. AAM, BND, MN, and MA interpreted data. AAM completed the initial manuscript with contributions from BND and MN. BND, DKH, and MA provided critical revisions. All authors approved the final version.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

All subjects provided written informed consent prior to enrollment in this study, participated voluntarily, and received a small compensation for their participation. This research was conducted according to the guidelines proscribed in the Declaration of Helsinki, and all procedures involving human subjects were approved by the Institutional Review Boards of the University of Minnesota.

ACKNOWLEDGMENTS

This research was supported by the National Institute on Drug Abuse of the National Institutes of Health; R01DA016351 and R01DA027232 (MA). The content of this study is solely the responsibility of the authors and does not necessarily represent the views of the NIH.

DATA AVAILABILITY STATEMENT

Data not publicly available. All measures and statistical scripts for the analyses are available by request to the corresponding author. This study was not preregistered.
==== Refs
REFERENCES

1 al'Absi M , Ginty AT , Lovallo WR . Neurobiological mechanisms of early life adversity, blunted stress reactivity and risk for addiction. Neuropharmacology. 2021;188 :108519. doi:10.1016/j.neuropharm.2021.108519 33711348
2 Kraynak TE , Marsland AL , Hanson JL , Gianaros PJ . Retrospectively reported childhood physical abuse, systemic inflammation, and resting corticolimbic connectivity in midlife adults. Brain Behav Immun. 2019;82 :203‐213. doi:10.1016/j.bbi.2019.08.186 31445966
3 al'Absi M , Hatsukami D , Davis GL . Attenuated adrenocorticotropic responses to psychological stress are associated with early smoking relapse. Psychopharmacology. 2005;181 :107‐117. doi:10.1007/s00213-005-2225-3 15834539
4 al' Aabsi M , Lemieux A , Westra R , Allen S . Early life adversity influences stress response association with smoking relapse. Psychopharmacology. 2017;234 :3375‐3384. doi:10.1007/s00213-017-4724-4 28875309
5 al'Absi M , Nakajima M , Lemieux A . Impact of early life adversity on the stress biobehavioral response during nicotine withdrawal. Psychoneuroendocrinology. 2018;98 :108‐118. doi:10.1016/j.psyneuen.2018.08.022 30130691
6 Lemieux A , Olson L , Nakajima M , Schulberg L , al'Absi M . Life adversity is associated with smoking relapse after a quit attempt. Addict Behav. 2016;60 :71‐77. doi:10.1016/j.addbeh.2016.03.017 27100471
7 Nusslock R , Miller GE . Early‐life adversity and physical and emotional health across the lifespan: a neuroimmune network hypothesis. Biol Psychiatry. 2016;80 (1 ):23‐32. doi:10.1016/j.biopsych.2015.05.017 26166230
8 Piazza PV , Le Moal M . Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu Rev Pharmacol Toxicol. 1996;36 (1 ):359‐378. doi:10.1146/annurev.pa.36.040196.002043 8725394
9 al'Absi M , De Angelis B , Nakajima M , Hatsukami D , Allen S . Early life adversity and appetite hormones: the effects of smoking status, nicotine withdrawal, and relapse on ghrelin and peptide YY during smoking cessation. Addict Behav. 2021;118 :106866. doi:10.1016/j.addbeh.2021.106866 33640833
10 al'Absi M , Lemieux A , Nakajima M . Peptide YY and ghrelin predict craving and risk for relapse in abstinent smokers. Psychoneuroendocrinology. 2014;49 :253‐259. doi:10.1016/j.psyneuen.2014.07.018 25127083
11 Lemieux AM , al'Absi M . Changes in circulating peptide YY and ghrelin are associated with early smoking relapse. Biol Psychol. 2018;131 :43‐48. doi:10.1016/j.biopsycho.2017.03.007 28300626
12 Potretzke S , Nakajima M , Cragin T , al'Absi M . Changes in circulating leptin levels during acute stress and associations with craving in abstinent smokers: a preliminary investigation. Psychoneuroendocrinology. 2014;47 :232‐240. doi:10.1016/j.psyneuen.2014.05.008 24954303
13 Potretzke S , Lemieux A , Nakajima M , al'Absi M . Circulating ghrelin changes as a biomarker of the stress response and craving in abstinent smokers. Pharmacol Biochem Behav. 2022;218 :173423. doi:10.1016/j.pbb.2022.173423 35750154
14 Troke R , Tan TM , Bloom SR . Chapter 157: PYY. In: Kastin AJ , ed. Handbook of biologically active peptides. 2nd ed. Academic Press; 2013:1160‐1165. doi:10.1016/B978-0-12-385095-9.00157-3
15 Hirsch D , Zukowska Z . NPY and stress 30 years later: the peripheral view. Cell Mol Neurobiol. 2012;32 :645‐659. doi:10.1007/s10571-011-9793-z 22271177
16 Woodward OR , Gribble FM , Reimann F , Lewis JE . Gut peptide regulation of food intake—evidence for the modulation of hedonic feeding. J Physiol. 2022;600 (5 ):1053‐1078. doi:10.1113/JP280581 34152020
17 Lin HC , Neevel C , Chen JH . Slowing intestinal transit by PYY depends on serotonergic and opioid pathways. Am J Physiol Gastrointest Liver Physiol. 2004;286 (4 ):G558‐G563. doi:10.1152/ajpgi.00278.2003 15010361
18 Forbes SC , Cox HM . Peptide YY, neuropeptide Y and corticotrophin‐releasing factor modulate gastrointestinal motility and food intake during acute stress. Neurogastroenterol Motil. 2014;26 (11 ):1605‐1614. doi:10.1111/nmo.12428 25238483
19 Kiessl GR , Laessle RG . Stress inhibits PYY secretion in obese and normal weight women. Eat Weight Disord. 2016;21 :245‐249. doi:10.1007/s40519-015-0231-y 26497508
20 al'Absi M . Hypothalamic‐pituitary‐adrenocortical responses to psychological stress and risk for smoking relapse. Int J Psychophysiol. 2006;59 (3 ):218‐227. doi:10.1016/j.ijpsycho.2005.10.010 16442170
21 Danese A , McEwen BS . Adverse childhood experiences, allostasis, allostatic load, and age‐related disease. Physiol Behav. 2012;106 (1 ):29‐39. doi:10.1016/j.physbeh.2011.08.019 21888923
22 Curran E , Perra O , Rosato M , Ferry F , Leavey G . Complex childhood trauma, gender and depression: patterns and correlates of help‐seeking and maladaptive coping. J Affect Disord. 2021;292 :603‐613. doi:10.1016/j.jad.2021.06.011 34153831
23 Shiffman S , Wills TA . Coping and Substance Use. Academic Press; 1985.
24 Bunea IM , Szentágotai‐Tătar A , Miu AC . Early‐life adversity and cortisol response to social stress: a meta‐analysis. Transl Psychiatry. 2017;7 (12 ):1‐8. doi:10.1038/s41398-017-0032-3
25 Carroll D , Ginty AT , Whittaker AC , Lovallo WR , de Rooij SR . The behavioural, cognitive, and neural corollaries of blunted cardiovascular and cortisol reactions to acute psychological stress. Neurosci Biobehav Rev. 2017;77 :74‐86. doi:10.1016/j.neubiorev.2017.02.025 28254428
26 Childs E , De Wit H . Effects of acute psychosocial stress on cigarette craving and smoking. Nicotine Tob Res. 2010;12 (4 ):449‐453. doi:10.1093/ntr/ntp214 20100807
27 Irving JM , Clark EC , Crombie IK , Smith WCS . Evaluation of a portable measure of expired‐air carbon monoxide. Prev Med. 1988;17 (1 ):109‐115. doi:10.1016/0091-7435(88)90076-x 3362796
28 Kirschbaum C , Pirke KM , Hellhammer DH . The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28 (1–2 ):76‐81. doi:10.1159/000119004 8255414
29 Heatherton TF , Kozlowski LT , Frecker RC , Fagerstrom KO . The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86 (9 ):1119‐1127. doi:10.1111/j.1360-0443.1991.tb01879.x 1932883
30 Anda RF , Croft JB , Felitti VJ , et al. Adverse childhood experiences and smoking during adolescence and adulthood. JAMA. 1999;282 (17 ):1652‐1658. doi:10.1001/jama.282.17.1652 10553792
31 Felitti VJ , Anda RF , Nordenberg D , et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: the Adverse Childhood Experiences (ACE) study. Am J Prev Med. 1998;14 (4 ):245‐258. doi:10.1016/S0749-3797(98)00017-8 9635069
32 Blatnik M , Soderstrom CI . A practical guide for the stabilization of acylghrelin in human blood collections. Clin Endocrinol. 2011;74 (3 ):325‐331. doi:10.1111/j.1365-2265.2010.03916.x
33 Hughes JR , Keely JP , Niaura RS , Ossip‐Klein DJ , Richmond RL , Swan GE . Measures of abstinence in clinical trials: issues and recommendations. Nicotine Tob Res. 2003;5 (1 ):13‐25. doi:10.1093/ntr/5.1.13 12745503
34 Pruessner JC , Kirschbaum C , Meinlschmid G , Hellhammer DH . Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time‐dependent change. Psychoneuroendocrinology. 2003;28 (7 ):916‐931. doi:10.1016/S0306-4530(02)00108-7 12892658
35 Cahill F , Ji Y , Wadden D , et al. The association of serum total peptide YY (PYY) with obesity and body fat measures in the CODING study. PLoS One. 2014;9 :e95235. doi:10.1371/journal.pone.0095235 24743402
36 Harding SD , Sharman JL , Faccenda E , et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2019: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 2018;46 :D1091‐D1106. doi:10.1093/nar/gkx1121 29149325
37 Alexander SP , Christopoulos A , Davenport AP , et al. The concise guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. Br J Pharmacol. 2023;2023 (80 ):S23‐S144. doi:10.1111/bph.16177
38 Brindle RC , Pearson A , Ginty AT . Adverse childhood experiences (ACEs) relate to blunted cardiovascular and cortisol reactivity to acute laboratory stress: a systematic review and meta‐analysis. Neurosci Biobehav Rev. 2022;134 :104530. doi:10.1016/j.neubiorev.2022.104530 35031343
39 Akkermann K , Kaasik K , Kiive E , Nordquist N , Oreland L , Harro J . The impact of adverse life events and the serotonin transporter gene promoter polymorphism on the development of eating disorder symptoms. J Psychiatr Res. 2012;46 (1 ):38‐43. doi:10.1016/j.jpsychires.2011.09.013 22018958
40 Wiss DA , Avena N , Gold M . Food addiction and psychosocial adversity: biological embedding, contextual factors, and public health implications. Nutrients. 2020;12 (11 ):3521. doi:10.3390/nu12113521 33207612
41 Shiffman S . Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol. 1982;50 (1 ):71‐86. doi:10.1037/0022-006X.50.1.71 7056922
42 Reuben A , Moffitt TE , Caspi A , et al. Lest we forget: comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health. J Child Psychol Psychiatry. 2016;57 (10 ):1103‐1112. doi:10.1111/jcpp.12621 27647050
43 Perkins KA , Karelitz JL , Jao NC . Optimal carbon monoxide criteria to confirm 24‐hr smoking abstinence. Nicotine Tob Res. 2013;15 (5 ):978‐982. doi:10.1093/ntr/nts205 22990219
