Nicorette
Nicorette is a brand of nicotine replacement therapy products, primarily known for its chewing gum formulation containing nicotine polacrilex, designed to deliver controlled doses of nicotine to mitigate withdrawal symptoms during smoking cessation.[1] Developed in the 1970s by Swedish pharmacologist Ove Fernö at the pharmaceutical company Leo AB, the product originated from efforts to provide nicotine to submariners and aviators in smoke-restricted environments without the harmful effects of tobacco combustion.[2] First commercially launched in Switzerland in 1978, Nicorette received U.S. Food and Drug Administration approval as a prescription medication in 1984 for the 2 mg gum strength, followed by the 4 mg version in 1991, and later transitioned to over-the-counter availability.[3] The brand has expanded to include various delivery methods such as lozenges, patches, nasal sprays, and inhalers, all aimed at stepwise nicotine reduction to support abstinence from cigarettes.[4] High-quality meta-analyses of randomized trials demonstrate that nicotine replacement therapies like Nicorette increase the odds of successful smoking cessation by approximately 50% to 60% compared to placebo, though absolute quit rates remain modest, with many users requiring behavioral support for optimal outcomes.[5][6] While effective as an adjunct to quitting, Nicorette has faced criticism for potential side effects including oral irritation, gastrointestinal discomfort, and risks of prolonged nicotine dependence, which can perpetuate addiction rather than fully resolve it; empirical data nonetheless affirm its cardiovascular safety profile relative to continued smoking.[7] Early marketing efforts were complicated by opposition from tobacco interests, including pressure from Philip Morris to temper anti-smoking messaging, highlighting tensions between pharmaceutical cessation aids and the cigarette industry.[8] Currently marketed by Kenvue, a Johnson & Johnson spin-off, Nicorette remains a cornerstone of pharmacotherapeutic approaches to tobacco dependence, with products rigorously tested for efficacy in reducing cravings.[9]Overview
Composition and Mechanism of Action
Nicorette chewing gum, the original formulation of the brand, contains nicotine polacrilex as its active ingredient, a complex of nicotine bound to an ion-exchange resin (polacrilin) that facilitates controlled release and buccal absorption.[10] Available in 2 mg and 4 mg strengths (equivalent to nominal nicotine content), the gum also includes buffering agents such as sodium carbonate and sodium bicarbonate to elevate oral pH, enhancing the proportion of un-ionized nicotine for better mucosal uptake.[11] Inactive components typically comprise gum base, sweeteners like sorbitol or xylitol, flavors, acesulfame potassium, and coatings such as carnauba wax, with variations by flavor (e.g., mint, fruit).[10] Other Nicorette formats, such as lozenges, employ similar nicotine polacrilex, while patches use nicotine in a transdermal matrix and inhalers deliver vaporized nicotine solution.[12] The mechanism of action for Nicorette products centers on nicotine replacement therapy (NRT), where exogenously supplied nicotine binds to nicotinic acetylcholine receptors in the brain, particularly in the ventral tegmental area, mimicking the pharmacological effects of nicotine from tobacco while alleviating withdrawal symptoms such as cravings, irritability, and anxiety.[13] In gum form, chewing promotes release of nicotine from the polacrilex resin into saliva, with absorption primarily through the oral mucosa rather than swallowing, achieving peak plasma levels slower than smoking (typically 20-45 minutes post-dose) to provide sustained relief without rapid spikes that reinforce dependence.[14] This behavioral component—chewing as a substitute for smoking gestures—further aids in breaking hand-to-mouth habits, though the primary effect derives from receptor agonism reducing dopamine dysregulation from abrupt nicotine cessation.[13] Unlike tobacco, Nicorette avoids combustion byproducts like tar and carbon monoxide, focusing solely on nicotine delivery to support gradual weaning.[15]Intended Use and Regulatory Status
Nicorette products are formulated as nicotine replacement therapy to aid smoking cessation in adults by supplying exogenous nicotine, thereby reducing withdrawal symptoms including cravings, irritability, and anxiety that accompany abrupt tobacco cessation.[10][13] The therapy targets physiological dependence on nicotine while avoiding exposure to tobacco's combustion byproducts, such as tar and carbon monoxide, and is recommended for use in a structured quit attempt, typically involving gradual dose reduction over 8–12 weeks.[16][17] Users are instructed to abstain from smoking during treatment, as concurrent use increases nicotine overdose risk, and the products are contraindicated for non-smokers, adolescents under 18, or those with certain cardiovascular conditions without medical supervision.[10][18] In the United States, the Food and Drug Administration (FDA) approved the original Nicorette nicotine polacrilex gum (2 mg strength) on February 24, 1984, as a prescription drug for short-term management of nicotine dependence in motivated adults.[19][20] The 4 mg strength followed in 1994, with all gum formulations switching to over-the-counter (OTC) status effective April 1996 following demonstrations of safe self-use without healthcare oversight.[21][20] Later variants, including lozenges (approved December 30, 2009) and mini-lozenges, also hold FDA OTC monograph status under 21 CFR 356 for smoking cessation, classifying Nicorette as a non-prescription drug rather than a tobacco product.[22][23] In Europe, Nicorette holds marketing authorizations as a medicinal product from national competent authorities rather than centralized European Medicines Agency (EMA) approval, with formulations like gum, sprays, and patches licensed for nicotine withdrawal relief in smoking cessation programs.[24] For instance, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted authorizations for products such as Nicorette QuickMist (e.g., 1 mg/spray, approved via national procedure) and various gums, enforcing similar indications and warnings as FDA guidelines, including restrictions on use during pregnancy or with ongoing smoking.[24][25] These approvals emphasize evidence-based efficacy for complete abstinence, not smoking reduction, aligning with pharmacovigilance requirements under EU Directive 2001/83/EC.[26]Efficacy and Clinical Evidence
Randomized Controlled Trials and Meta-Analyses
A meta-analysis of 56 randomized controlled trials involving 22,581 participants demonstrated that nicotine chewing gum significantly increases the likelihood of long-term smoking abstinence (at least six months) compared to placebo, with a risk ratio (RR) of 1.49 (95% confidence interval [CI] 1.40 to 1.60).[27] This effect corresponds to an approximate 50% relative increase in quitting success, though absolute abstinence rates remain modest, typically elevating from around 10% in placebo groups to 15-17% with gum.[28] Subgroup analyses within the review showed consistent benefits across settings, including primary care (RR 1.58, 95% CI 1.35 to 1.85; 16 trials, 7,277 participants), though efficacy appeared lower in hospital settings (RR 1.11, 95% CI 0.86 to 1.43; 3 trials, 2,194 participants).[27] Earlier meta-analyses corroborate these findings for nicotine polacrilex gum, the active ingredient in Nicorette. A 1987 review of trials in specialized cessation clinics reported six-month abstinence rates of 27% with gum versus 18% with placebo (n=734).[29] A 1993 meta-analysis of 33 studies further confirmed gum's efficacy in controlled settings, with pooled odds ratios indicating a significant advantage over placebo, particularly when combined with behavioral support.[30] Dose comparisons in individual RCTs, such as those evaluating 2 mg versus 4 mg gum, suggest higher doses may benefit heavier smokers, though meta-analytic evidence does not show a statistically significant dose-response effect overall.[27] The broader Cochrane review encompassing all nicotine replacement therapies (NRT), including gum, across 133 trials and 64,640 participants yielded an overall RR of 1.55 (95% CI 1.49 to 1.61) for abstinence, underscoring gum's role within NRT's established efficacy profile.[27] However, real-world effectiveness may be tempered by adherence issues, as many trials report lower long-term success when support is minimal, and gum's benefits are largely independent of intensive counseling.[31] No significant increase in serious adverse events, such as cardiovascular incidents, was associated with gum use in these analyses.[27]Long-Term Success Rates and Factors Influencing Outcomes
Nicotine replacement therapy (NRT), including Nicorette gum, modestly improves long-term smoking abstinence rates compared to placebo or no aid. A Cochrane meta-analysis of 117 trials involving over 50,000 participants found that NRT increased the odds of sustained abstinence (typically assessed at 6-12 months or longer) by 55%, with an odds ratio of 1.55 (95% CI 1.49-1.66), translating to absolute abstinence rates of approximately 15-17% versus 10% in control groups.[32] For nicotine gum specifically, across 56 trials, the odds ratio was 1.43 (95% CI 1.33-1.53), yielding similar absolute improvements of 2-4 percentage points over controls.[32] However, beyond 12 months, relapse rates averaged 30% (95% CI 23.5-37.5%) in both NRT and control arms, indicating limited additional benefit from NRT in preventing late relapse.[32] Extended or maintenance use of NRT beyond standard 8-12 weeks has been tested in randomized trials, showing short-term gains but diminishing long-term efficacy. In a trial of smokers with COPD, long-term NRT (up to 12 months) achieved 12-month abstinence rates comparable to standard 8-week therapy (around 10-15%), with no sustained advantage at 24 weeks due to high relapse.[33] Another study reported 27.2% abstinence at 24 weeks with extended gum therapy versus 21.7% with standard treatment, but rates declined thereafter without preventing eventual relapse in most participants.[34] Overall, long-term success remains low, with fewer than 20% of users achieving sustained abstinence at one year, underscoring that NRT primarily aids initial withdrawal but does not address underlying behavioral dependencies.[28] Key factors influencing outcomes include adherence to the gum regimen, which is often suboptimal and strongly predicts success; non-adherent users have quit rates approaching placebo levels.[35] Individual characteristics such as higher education (odds ratio up to 1.83 for college-educated versus less than high school), fewer prior quit attempts, lower body mass index, and reduced perceived stress correlate with better adherence and abstinence.[35][36] Treatment factors like concurrent behavioral counseling or follow-up appointments enhance efficacy, with one trial showing 22% 12-month abstinence for gum plus short follow-up versus 15% for counseling alone.[37] Conversely, high nicotine dependence, early smoking initiation, and lack of pharmacotherapy integration reduce success, as do external stressors overriding NRT's nicotine delivery.[38][39] Combination therapies (e.g., gum with patches) yield higher rates than monotherapy, per meta-analyses, but still fall short of 25% long-term abstinence without strong motivational support.[40]Comparisons to Alternative Cessation Methods
Nicotine replacement therapy (NRT), including Nicorette gum, approximately doubles the odds of sustained smoking abstinence at six months or longer compared to placebo or no pharmacological aid, with meta-analyses showing an odds ratio (OR) of about 1.55 (95% CI 1.49-1.61) across over 130 trials involving more than 64,000 participants. In contrast, unaided quitting attempts ("cold turkey") yield long-term success rates of 3-5% at one year, as evidenced by population-level data where the majority of self-quitters relapse within weeks due to unmanaged nicotine withdrawal and cravings.[41] While abrupt cessation without aids can succeed for highly motivated individuals, pharmacotherapy like NRT consistently outperforms unaided methods in randomized controlled trials (RCTs), reducing withdrawal severity through controlled nicotine delivery that mimics smoking pharmacokinetics without combustion toxins.[42] Among NRT formats, Nicorette gum—a fast-acting oral form—demonstrates quit rates comparable to transdermal patches or lozenges, with a 2023 Cochrane review of 296 studies finding no significant differences in six-month abstinence (OR 1.49 for gum vs. 1.64 for patches; moderate-certainty evidence).[43] Lozenges and gum both provide ad libitum dosing for acute cravings, achieving similar efficacy to steady-state patch delivery, though user adherence varies: gum requires proper "chew and park" technique to optimize absorption, with misuse linked to lower jaw soreness but not reduced effectiveness. Combination NRT, such as Nicorette gum paired with patches, boosts quit rates by 34% over single-form NRT (OR 1.34, 95% CI 1.14-1.57), per meta-analysis of 11 RCTs, by addressing both baseline and breakthrough cravings.[44] Compared to prescription pharmacotherapies, Nicorette and other single-form NRTs are less effective than varenicline, a partial nicotinic receptor agonist; a 2023 network meta-analysis ranks varenicline highest for abstinence at 6-12 months (OR 2.33 vs. placebo), outperforming NRT by about 25% (number needed to treat: 22 for one additional quitter). Varenicline also surpasses bupropion (OR 1.62 vs. placebo), an antidepressant that modulates dopamine and norepinephrine, with head-to-head trials showing varenicline's continuous abstinence rates at 52 weeks exceeding bupropion's by 10-15 percentage points.[45] Bupropion's efficacy aligns closely with NRT (OR ~1.6 for both), but adding it to NRT yields no clear benefit over NRT alone, based on limited evidence from four RCTs.[46] All pharmacological aids outperform placebo, yet real-world adherence limits gains, with NRT's over-the-counter availability potentially enhancing accessibility over prescription-only options like varenicline, despite the latter's superior receptor-targeted mechanism.[47]| Method | 6-12 Month Abstinence OR vs. Placebo (95% CI) | Key Evidence Source |
|---|---|---|
| Nicorette/Other NRT (single) | 1.55 (1.49-1.61) | Cochrane Review, 2023 |
| Combination NRT | 1.82 (1.60-2.07) | Meta-analysis of 11 RCTs[44] |
| Varenicline | 2.33 (2.02-2.68) | Network Meta-analysis, 2023 |
| Bupropion | 1.62 (1.40-1.88) | Cochrane Review, 2023[46] |
| Unaided (Cold Turkey) | 1.00 (reference) | Population data synthesis[41] |
Product Formats
Chewing Gum
Nicorette chewing gum, the inaugural formulation of the nicotine replacement therapy brand, originated in Sweden during the late 1970s through research by pharmaceutical firm AB LEO, with initial market introduction in Switzerland in 1978.[2] This product pioneered controlled nicotine delivery via oral absorption to mitigate withdrawal symptoms, marking the first widely accessible NRT and facilitating gradual reduction in cigarette dependence by substituting inhaled nicotine with masticated doses.[2] The gum's active component is nicotine polacrilex, an ion-exchange resin binding nicotine for pH-dependent release, available in 2 mg or 4 mg strengths per piece to match varying dependency levels.[49] Inactive constituents typically encompass gum base, sodium carbonate and bicarbonate for alkalization to enhance mucosal uptake, sweeteners like sorbitol and acesulfame potassium, flavors, and stabilizers such as butylated hydroxytoluene and carnauba wax.[50] Upon chewing, the resin liberates nicotine, which diffuses across the buccal lining into the bloodstream, peaking absorption slower than smoking to curb acute cravings without the combustion byproducts of tobacco.[50] Product variants include the 2 mg dose for individuals smoking fewer than 25 cigarettes daily and 4 mg for heavier users, offered in flavors such as original, mint, fresh fruit, and fruit chill to boost palatability and compliance.[51] Sugar-free formulations predominate to minimize dental risks, with packaging in counts like 100 or 200 pieces supporting extended regimens.[52] Usage protocol emphasizes intermittent chewing: masticate slowly until a tingling or peppery sensation emerges, signaling nicotine release, then "park" the gum between cheek and gingiva for 20-30 minutes to promote trans-mucosal absorption while avoiding rapid swallowing that could induce gastrointestinal irritation.[16] Recommended schedule starts at one piece every 1-2 hours for weeks 1-6 (up to 24 daily), tapering to every 2-4 hours in weeks 7-9 and 4-8 hours in weeks 10-12, with discontinuation after 12-24 weeks to prevent prolonged reliance.[53] Adherence to this technique maximizes bioavailability, estimated at 50-70% of the nominal dose depending on chew-park cycles.[16] Randomized trials and meta-analyses affirm the gum's role in elevating quit rates, with one review of 33 studies reporting odds ratios of 1.5-2.0 for abstinence versus placebo at 6-12 months, though real-world general practice yields approximately 17% success at 4-6 months with gum versus 13% without.[30][29] Higher doses like 4 mg demonstrate superior efficacy in dependent smokers, tripling short-term quit rates over placebo in targeted populations.[54]Lozenges and Other Oral Forms
Nicorette lozenges contain nicotine bound to polacrilex resin in compressed tablet form, designed to dissolve in the mouth for buccal absorption of nicotine without swallowing.[55] They are available in 2 mg and 4 mg strengths, with mini-lozenges (1 mg) introduced for faster dissolution and discreet use; the 4 mg dose is recommended for smokers consuming more than 20 cigarettes daily.[56] Users place one lozenge between the cheek and gum, allowing it to dissolve over 20-30 minutes while occasionally moving it, with initial dosing of 1 lozenge every 1-2 hours up to a maximum of 20 per day for 6 weeks, followed by tapering.[56] FDA approval for nicotine lozenges occurred in 2002 under NDA 21-330, establishing them as an over-the-counter aid for smoking cessation in adults. Clinical evidence supports lozenges' efficacy in promoting abstinence, with randomized trials showing they increase continuous quit rates at 6-12 months compared to placebo, roughly doubling success odds when used as directed.[57] A multicenter double-blind trial of 2 mg and 4 mg mint lozenges in adult smokers reported biochemically verified abstinence rates of 18-22% at 12 weeks versus 10% for placebo, with higher doses benefiting heavier smokers.[58] Meta-analyses of nicotine replacement therapies, including lozenges, confirm a 50-60% relative increase in quitting efficacy over placebo, though absolute long-term success remains modest at 15-20% without behavioral support.[6] Direct comparisons indicate lozenges perform similarly to nicotine gum in adherence and outcomes, with potentially better tolerability for some users due to passive dissolution.[57] Common adverse events with lozenges include mouth or throat irritation (affecting up to 20% of users), hiccups, dyspepsia, and nausea, typically mild and transient, resolving with proper "parking" technique to minimize swallowing. Serious risks are rare, but overuse can lead to nicotine toxicity symptoms like vomiting or palpitations; contraindications include recent myocardial infarction or hypersensitivity.[56] No significant differences in safety profiles were noted between lozenge and gum in comparative studies, though pediatric use is not approved due to insufficient data.[59]Other oral forms include Nicorette QuickMist, a metered-dose mouth spray delivering 1 mg nicotine per activation directly onto the oral mucosa for rapid absorption and craving relief within minutes.[24] Administered as 1-2 sprays inside the mouth up to 2 sprays per minute (maximum 64 daily), it targets breakthrough urges and is used alongside other NRT for up to 6 months with tapering.[60] A randomized placebo-controlled trial demonstrated QuickMist's superiority, with continuous abstinence rates of 23% at 6 weeks, 18% at 24 weeks, and 14% at 52 weeks versus 11%, 7%, and 6% for placebo, respectively.[61] Side effects of the spray primarily involve local irritation, including throat/mouth burning (up to 10% of users), cough, hiccups, and dysgeusia, with systemic effects like headache or nausea from overuse.[24] Allergic reactions such as urticaria occur rarely; it shares contraindications with other NRT forms, emphasizing avoidance in non-smokers or pregnant individuals without medical advice.[62] Efficacy data position oral sprays as comparable to lozenges in speed of delivery but with potentially higher adherence due to ease of use, though direct head-to-head trials are limited.[61]
Transdermal Patches and Inhalers
Nicorette transdermal patches deliver nicotine through the skin to provide a steady release, helping to alleviate withdrawal symptoms during smoking cessation. Available in stepwise decreasing strengths such as 21 mg, 14 mg, and 7 mg for 24-hour wear or 25 mg, 15 mg, and 10 mg for 16-hour application, users apply one patch daily to a clean, dry, non-hairy area of the upper body or outer arm, rotating sites to avoid irritation.[13][63][64] The patches are approved for over-the-counter use by the FDA for adults aged 18 and older, with a typical regimen starting at the highest dose for heavy smokers (more than 10 cigarettes per day) and tapering over 8-12 weeks.[65] Nicorette inhalers consist of a plastic mouthpiece with replaceable cartridges containing 10-15 mg of nicotine, designed to mimic the hand-to-mouth action of smoking while delivering vapor absorbed primarily through the oral and pharyngeal mucosa rather than deep lung inhalation.[66][67] Users insert a cartridge, puff shallowly and frequently (up to 20 puffs per cartridge, 6-16 cartridges daily initially), with each puff providing about 4 mg of absorbed nicotine, and the device is often prescription-required in markets like the United States.[68][13] Treatment duration typically spans 3-6 months, with gradual reduction in usage to minimize cravings without tobacco combustion products.[69]Combination Therapies
Combination nicotine replacement therapies (NRT) typically pair a long-acting form, such as the Nicorette transdermal patch, which delivers a steady nicotine dose over 16–24 hours to alleviate baseline withdrawal symptoms, with a short-acting oral form like Nicorette chewing gum, which provides rapid nicotine absorption to address acute cravings. This dual approach addresses both sustained nicotine dependence and episodic urges, potentially improving adherence and outcomes for moderate-to-heavy smokers (≥10 cigarettes per day). Guidelines from public health authorities, including the U.S. Centers for Disease Control and Prevention, endorse combination NRT for individuals who have failed monotherapy, recommending starting with a patch in the morning followed by ad libitum use of gum as needed, up to 15–20 pieces daily depending on dosage strength.[70] Randomized controlled trials demonstrate that adding nicotine gum to patch therapy increases biochemically verified abstinence rates. In a 1995 multicenter trial involving 812 smokers, the combination of active 21 mg/24-hour nicotine patches plus active 2 mg gum yielded a 6-month continuous abstinence rate of 27%, compared to 19% for patch plus placebo gum (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.12–2.11; p=0.008), with benefits persisting among heavier smokers. A 2019 Hong Kong primary care trial of 1,002 participants found combined 21 mg patch plus 2–4 mg gum over 8 weeks resulted in 26-week abstinence rates of 20.5% versus 13.9% for patch alone (relative risk [RR] 1.47, 95% CI 1.08–2.01; p=0.02), with sustained effects at 52 weeks (RR 1.43, 95% CI 0.92–2.22). These gains are attributed to complementary pharmacokinetics: patches maintain plasma nicotine levels at 10–15 ng/mL, while gum spikes levels by 5–10 ng/mL within minutes, mimicking cigarette pharmacokinetics more closely than monotherapy.[71][72] Meta-analyses confirm the broader efficacy of patch-plus-oral NRT combinations. A 2008 systematic review of 10 trials (n=4,909) reported combination therapy increased 12-month abstinence odds by 1.42-fold (95% CI 1.20–1.69) over single NRT, with patch-gum pairings showing consistent short-term (3–6 months) superiority (OR 1.34–1.56) and moderate long-term benefits, though absolute quit rates remain 15–25% due to multifactorial relapse drivers like behavioral cues. A 2020 meta-analysis of 7 studies focused on patch-plus-short-acting NRT echoed this, finding 6-month abstinence ORs of 1.58 (95% CI 1.28–1.95) versus patch monotherapy, with no significant increase in serious adverse events beyond mild oral irritation or skin reactions. Nicorette's product lineup, including combo packs of 21 mg patches and 2–4 mg gum, aligns with these regimens, though real-world adherence varies, with oral forms often underused due to chewing fatigue.[73][74][44] For subpopulations, combinations may offer tailored benefits; heavier smokers (>20 cigarettes/day) derive greater relative gains (OR up to 1.8 at 6 months), while evidence for light smokers is weaker, favoring monotherapy to minimize nicotine overload risks. Manufacturer-supported data indicate patch-plus-gum regimens achieve 30% higher 12-month success than patch alone in motivated users, but independent trials emphasize integrating counseling for optimal results, as pharmacotherapy alone yields diminishing returns beyond 6 months.[75][76]Safety Profile
Common Side Effects and Adverse Events
The most frequently reported side effects of Nicorette gum, the primary formulation, include mouth soreness, hiccups, dyspepsia (indigestion), and jaw ache, which are typically mild and transient in nature.[77] These local effects arise from the mechanical chewing action and nicotine release in the oral cavity, with clinical observations indicating they often resolve with proper usage technique, such as avoiding rapid chewing.[13] Gastrointestinal disturbances such as nausea, heartburn, belching, diarrhea, and upset stomach are also common, particularly with oral forms like gum and lozenges, affecting a notable proportion of users during initial treatment phases.[78][10] A meta-analysis of randomized controlled trials found orally administered nicotine replacement therapy (NRT) associated with elevated odds of mouth and throat soreness (odds ratio 1.87, 95% CI 1.36-2.57) and mouth ulcers (odds ratio 1.49, 95% CI 1.05-2.20) compared to placebo.[79] Systemic effects like headache, dizziness, and mild increases in heart rate or blood pressure can occur due to nicotine's pharmacological actions, though these are generally less severe and less frequent than those from cigarette smoking.[78][80] For other Nicorette formats, such as lozenges, similar oral irritation profiles predominate, while transdermal patches may cause localized skin erythema or pruritus in up to 20-50% of users, resolving upon discontinuation.[27][13] Adverse events leading to discontinuation are rare, occurring in fewer than 5% of trial participants across NRT studies.[79]- Mouth and jaw-related: Soreness, ache, ulcers (common in gum/lozenge users).[79][13]
- Gastrointestinal: Nausea, hiccups, dyspepsia, diarrhea (dose-dependent, often early-onset).[78]
- Neurological: Headache, dizziness (transient, nicotine-mediated).[10]
- Other: Throat irritation, cough (with inhaler variants).[13]