Nicotine pouches are noncombustible products that contain nicotine but no tobacco plant material. With rising popularity and increased media attention surrounding ZYN and other nicotine pouch brands, questions remain about whether empirical evidence exists on the public health effects of these products. This review highlights how nicotine pouches, including ZYN, are rising in appeal and prevalence of use, particularly among adolescents and young adults. The use of nicotine pouches is also more prevalent among people who use other tobacco products (vs those who do not), including electronic cigarettes (e-cigarettes), and some people report using nicotine pouches to help reduce or quit the use of e-cigarettes or combustible tobacco products. Nicotine pouches deliver amounts of nicotine similar to other tobacco products and do so at a rate similar to other oral nicotine products, including some US Food and Drug Administration (FDA)–approved nicotine replacement therapies. In addition, nicotine pouches have the potential to be tobacco harm-reduction products if unintended harms can be minimized, although more research is needed to determine the health effect profile of nicotine pouches under naturalistic use conditions. Overall, additional research is needed to verify the results from industry-funded studies, further understand product characteristics that influence nicotine delivery and health effects, and translate findings to real-world use behaviors. This additional research could help determine whether nicotine pouches have a robust evidence base to meet the public health standard by which FDA evaluates new tobacco products. Felicione, PhD, University at Buffalo, Department of Community Health and Health Behavior, 320 Kimball Tower, Buffalo, NY 14214, USA. Email: njfelici@buffalo.edu Collection date 2026 Jan-Feb. © 2025, Association of Schools and Programs of Public Health PMC Copyright notice PMCID: PMC12037535  PMID: 40293136 Abstract Nicotine pouches are noncombustible products that contain nicotine but no tobacco plant material. With rising popularity and increased media attention surrounding ZYN and other nicotine pouch brands, questions remain about whether empirical evidence exists on the public health effects of these products. This review highlights how nicotine pouches, including ZYN, are rising in appeal and prevalence of use, particularly among adolescents and young adults. The use of nicotine pouches is also more prevalent among people who use other tobacco products (vs those who do not), including electronic cigarettes (e-cigarettes), and some people report using nicotine pouches to help reduce or quit the use of e-cigarettes or combustible tobacco products. Nicotine pouches deliver amounts of nicotine similar to other tobacco products and do so at a rate similar to other oral nicotine products, including some US Food and Drug Administration (FDA)–approved nicotine replacement therapies. Keywords: nicotine pouches, oral nicotine, public health, tobacco, nicotine Recent attention on nicotine pouches (NPs), such as ZYN, has raised questions about existing evidence regarding their public health impact. On April 4, 2024, the US Food and Drug Administration (FDA) issued 119 warning letters and 41 civil money penalty complaints against brick-and-mortar retailers engaging in the underage sale of ZYN NPs and selling unauthorized, flavored ZYN NPs. 1 NPs are noncombustible (ie, smokeless) products that contain nicotine but no tobacco plant material. NPs are intended for oral consumption and do not require spitting. 22 Similarly, <5% of adults who never or formerly used tobacco reported that they would buy ZYN, whereas 27%, 44%, and 64% of adults who currently smoked, used SLT, or concurrently used cigarettes and SLT, respectively, were likely to buy ZYN. 22 In a cross-sectional analysis of US adults surveyed in early 2021, 29% were aware of NPs, 6% had ever tried them, and 17% reported interest in using NPs in the next 6 months. 23 Consistent with previous findings, the prevalence of awareness and use has been higher among those who use other nicotine products (vs those who do not) across surveys occurring since 2017. Individual authors were supported, in part, as follows: National Cancer Institute grant U54CA229973 (Hrywna), National Heart, Lung, and Blood Institute grant U54HL120163 (Hart), and National Cancer Institute grants R21CA268198 and P01CA200512 (Felicione). ORCID iDs: Nicholas J. Felicione, PhD https://orcid.org/0000-0001-9034-3477 Jenny E. Ozga, PhD https://orcid.org/0000-0003-2543-561X References 1. US Food and Drug Administration. FDA issues warning letters to and files civil money penalty complaints against retailers for underage sales of ZYN nicotine pouches. April 4, 2024. Accessed April 8, 2024. Am J Health Behav. 2023;47(3):428-449. doi: 10.5993/ajhb.47.3.1 [ DOI ] [ PubMed ] [ Google Scholar ] 28. Rensch J, Liu J, Wang J, Vansickel A, Edmiston J, Sarkar M. Nicotine pharmacokinetics and subjective response among adult smokers using different flavors of on! ® nicotine pouches compared to combustible cigarettes. Psychopharmacology (Berl). 2021;238(11):3325-3334. doi: 10.1007/s00213-021-05948-y [ DOI ] [ PubMed ] [ Google Scholar ] 29. Liu J, Rensch J, Wang J, Vansickel A, Edmiston J, Sarkar M. Oral nicotine product marketing expenditures in the USA from 2016 to 2023: trends over time by brand and targeted media outlets. 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In this study, we used the large number of cases in the FDA adverse-event reporting system (FAERS) database to investigate risk factors for drug-induced hiccups and to explore the relationship between hiccups and gender. From 11,810,863 adverse drug reactions reported between the first quarter of 2004 and the first quarter of 2020, we extracted only those in which side effects occurred between the beginning and end of drug administration. Our sample included 1454 adverse reactions for hiccups, with 1159 involving males and 257 involving females (the gender in 38 reports was unknown). We performed univariate analyses of the presence or absence of hiccups for each drug and performed multivariate analysis by adding patient information. The multivariate analysis showed nicotine products to be key suspect drugs for both men and women. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon. It has been reported in animal experiments that the glossopharyngeal nerve (the 9th cranial nerve), the vagus nerve (the 10th cranial nerve), the nuclei of the solitary tract, the nucleus ambiguus, and the phrenic nerve are all involved in the afferent and efferent pathways of the hiccup reflex arc [ 3 ]. Although the exact mechanisms of the central link of the hiccup reflex arc are not clear, in their review, Nausheen et al. reported that the hiccup reflex arc is potentially mediated by central neurotransmitters (γ-aminobutyric acid (GABA), dopamine, and serotonin) and peripheral neurotransmitters (epinephrine, norepinephrine, acetylcholine, and histamine) [ 4 , 5 ]. We extracted drugs with an ROR greater than unity and a Fisher’s exact test p -value of <0.001, with more than 5000 reported adverse effects. We performed multivariate analyses on those drugs using gender and weight from the female data table. The results are shown in Table 4 . From the patient information, only age was extracted as a risk factor for hiccups. Four drugs—nicotine, dasabuvir, exenatide, and sodium oxybate—were extracted as independent risk factors for females. 3. Discussion FAERS is a global database of adverse-event reports from the U.S., Japan, EU countries, etc. This database is much larger than other adverse drug reaction databases. This is because nicotine is sold as a stop-smoking medication as an over-the-counter drug and is not included in the Japanese database. It is empirically known that smoking can cause hiccups, but the mechanism responsible for this is not clear. The inhalation of substances from smoking may irritate the lungs and induce hiccups as a vagal reflex. However, the sources of nicotine in FAERS are pharmaceutical gums or patches. Thus, the present study shows that the intake of nicotine other than by smoking can induce hiccups. This suggests that nicotine itself or its metabolites may be causing hiccups in the body. Although there have been no reports on the mechanism by which nicotine induces hiccups, it is possible to consider some hypotheses. Nicotine facilitates autonomic ganglion and neuromuscular-junction transmission by nicotinic acetylcholine (ACh) receptors (nAChRs). In addition, it causes membrane depolarization of many neurons in the central nervous system (CNS) and acts on presynaptic terminals to promote the release of transmitters [ 20 ]. Furthermore, nicotine is known to act on nicotinic receptors on dopamine nerve endings to stimulate dopamine release [ 21 ]. The hiccup is known as a reflex arc, and its pathways have been identified. The afferent pathway is the pharyngeal branch of the glossopharyngeal nerve, and hiccups are centered in the reticular formation near the nucleus ambiguous. In contrast, the efferent pathway is represented by the diaphragmatic nerve and the vagus nerve [ 3 ]. Baclofen, a GABA B agonist, has been shown to suppress hiccups, suggesting that the hiccup center is inhibited by GABA [ 4 ]. These findings suggest that nicotine induces hiccups by releasing dopamine, which is involved in GABAergic inhibition. In addition, hiccups are suppressed by chlorpromazine and metoclopramide, which are dopamine D 2 blockers, suggesting that a central dopamine receptor There have been limited numbers of reports on hiccups and these drugs, and no reports support a causal relationship. These are drugs that cause nausea, vomiting, and diarrhea as adverse events. These symptoms may stimulate the afferent tracts of the vagus nerve and induce hiccups. In addition, fluorouracil, capecitabine, and gemcitabine are highly emetogenic drugs, and they are often used in combination with steroids, such as dexamethasone, for CINV prevention; thus, the association with dexamethasone-induced hiccups should also be considered. There are no published reports on the relationship between sunitinib and hiccups, and the risk factors and mechanisms are unknown.