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Cited by 70Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyInhalation and Respiratory Drug Delivery

A Randomised Study to Investigate the Nicotine Pharmacokinetics of Oral Nicotine Pouches and a Combustible Cigarette

Open access
McEwan, Michael, Azzopardi, David, Gale, Nathan, Camacho, Oscar M., Hardie, George, Fearon, Ian M., Murphy, James·2022·European Journal of Drug Metabolism and Pharmacokinetics
DOI 10.1007/s13318-021-00742-9PMC PMC8917032
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Abstract

Nicotine pouches (NPs) are a relatively new type of oral smokeless tobacco-free nicotine product. Currently, few data are available on the nicotine pharmacokinetics or subjective effects of NP use. The objective of this study was to determine and compare the pharmacokinetics of nicotine absorption into the blood from different NP variants and a combustible cigarette. In a randomised, controlled, crossover clinical study, nicotine pharmacokinetics and subjective effects were compared among commercially available NPs (five different brands; 6–10 mg nicotine/pouch) and a combustible cigarette. During an 8-day confinement period, 35 healthy adult participants who were current dual users of snus and combustible cigarettes used one study product each day for a defined period following overnight nicotine abstinence. Nicotine maximum plasma concentration ( C max ) and area under the plasma concentration-time curve between 0 and 6 h (AUC 0–6h ) were significantly greater for the Lyft 10 mg NP than for the cigarette (both p < 0.0001), while the other NPs had C max and AUC 0–6h values that were either greater than or similar to those of the cigarette. Plasma nicotine concentration was not associated with the nicotine contents of the NPs. Time to reach maximum plasma concentration ( T max ) was higher for all NPs (60–65 min) than for the cigarette (7 min). Regarding subjective effects, liking and intent to use product again scores were higher for the cigarette than for any NP and were lowest for the NP with the lowest nicotine content. This study provides important insight into nicotine pharmacokinetics and subjective effects during NP use, and demonstrates that NPs can provide nicotine in amounts sufficient to replicate cigarette smokers' nicotine uptake following a switch from conventional cigarettes to these potentially less harmful NP products. Further studies are required to ascertain how physical characteristics of NPs other than nicotine content may affect nicotine delivery, pharmacokinetics and subjective responses. ISRCTN17828518.

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized crossover study of 35 dual snus/cigarette users, oral nicotine pouches (6–10 mg) delivered nicotine with slower Tmax (60–65 min) than a combustible cigarette (7 min), while Cmax and AUC0–6h were greater than or similar to the cigarette. Liking and intent-to-use-again scores were higher for the cigarette than for any NP and were lowest for the 6 mg NP.

Key findings

  • Nicotine Cmax for the NPs ranged from 11.9 to 18.4 ng/mL versus 13.9 ng/mL for the cigarette; AUC0–6h ranged from 35.8 to 53.7 ng·h/mL for the NPs versus 25.2 ng·h/mL for the cigarette. Median Tmax was 60–65 min for all NPs versus 7 min for the cigarette.
  • The Lyft 10 mg NP had significantly greater Cmax and AUC0–6h than the cigarette (p = 0.0084 and p < 0.0001, respectively, in Table 3), and significantly greater Cmax and AUC0–6h than Zyn 10 mg and Skruf 8 mg. No significant differences were reported between Lyft and Nordic Spirit 9 mg or On! 6 mg for these parameters.
  • Plasma nicotine concentration was not associated with NP nicotine content: the 10 mg Zyn NP had the lowest NP Cmax and AUC0–6h (11.9 ng/mL and 35.8 ng·h/mL), while the 9 mg Nordic Spirit NP had the highest Cmax (18.4 ng/mL) and the 10 mg Lyft NP had the highest AUC0–6h (53.7 ng·h/mL). Relative bioavailability versus Zyn was 1.37 for Skruf, 1.44 for Lyft, 1.72 for Nordic Spirit, and 2.45 for On!.
  • Subjective scores were highest for the cigarette: liking >5 was reported by 21/35 (60.0%) for the cigarette versus 10–19/35 (28.6–54.3%) for the NPs, and intent-to-use-again >5 by 20/35 (57.1%) for the cigarette versus 5–13/35 (14.3–37.1%) for the NPs. The 6 mg On! NP had the lowest scores and significantly lower liking than the cigarette (p = 0.0216) and Zyn (p = 0.0392), and significantly lower intent-to-use-again than the cigarette (p = 0.0030) and Lyft (p = 0.0363).
  • There were 27 product use-emergent adverse events; 26 were mild, 1 was moderate, none were severe, and there were no serious AEs or withdrawals due to AEs.

Methods

  • Randomized, controlled, crossover clinical study at a single site in Uppsala, Sweden. Thirty-five healthy adults aged 19–55 were enrolled; all were current daily snus users (pouch weight ≥0.8 g, ≥8 mg nicotine, ≥6 months) and current smokers (≥5 cigarettes/week for ≥1 year). The study included an ~8-day confinement period with overnight nicotine abstinence before each product use session.
  • Products were a combustible cigarette (Pall Mall Red; 0.66 mg ISO nicotine yield) and five mint NPs: Lyft 10 mg, Zyn (Wet) 10 mg, Nordic Spirit 9 mg, Skruf Super White Fresh Stark 8 mg, and On! 6 mg. NPs were placed between the upper lip and gum for 60 min; the cigarette was smoked ad libitum for 5 min.
  • Venous blood was sampled at –5, 3, 5, 7, 10, 20, 45, 60, 65, 75, 120, 240, and 360 min relative to product use. Plasma nicotine was analyzed by UPLC-MS/MS with an LLOQ of 0.4 ng/mL. Cmax, AUC0–6h, and Tmax were calculated by non-compartmental methods; geometric mean Cmax and AUC0–6h were compared using mixed-effects ANOVA on ln-transformed data. Subjective effects were assessed with 0–10 liking and intent-to-use-again questionnaires.

Limitations

  • The paper states that the study was carried out among combustible cigarette users in Sweden, so findings may not be generalizable to other cohorts or countries with different tobacco use patterns.
  • The paper states that product use was limited to a single time-controlled NP use on a single day, so it cannot infer whether nicotine pharmacokinetics change with continued use or with shorter/longer use than the 60-min protocol period.
  • The paper states that the cohort comprised current snus users who also smoked cigarettes, so it provides no information on NP nicotine pharmacokinetics or subjective effects in current non-users of oral tobacco products. It also notes that the 60-min NP use period is longer than the manufacturers’ commonly recommended ~30 min, so real-world Cmax and AUC0–6h may be lower than observed.
  • Evident from the text: the sample was small (n = 35), predominantly male (77.1%) and white (94.3%), from one Swedish site, and all participants were dual snus/cigarette users, further limiting broader generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s13318-021-00742-9

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 43 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In vitro studies indicate that extracts from nicotine pouches are significantly less biologically active than extracts from Swedish snus or cigarette smoke.

    “In vitro studies also indicate that extracts from NPs are significantly less biologically active than extracts from Swedish snus or cigarette smoke [22], supporting a potential role of NPs in tobacco harm reduction.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Bishop E, East N, Bozhilova S, Santopietro S, Smart D, Taylor M, Meredith S, Baxter A, Breheny D, Thorne D, Gaca M. An approach for the extract generation and toxicological assessment of tobacco-free ‘modern’ oral nicotine pouches. Food Chem Toxicol. 2020;145:111713. source
  • Premisecitation

    A 60-min usage time was selected based on prior snus pouch nicotine pharmacokinetic studies that had a 60-min mouth hold time based on product use data.

    “In this study, a 60-min usage time was selected based on prior snus pouch nicotine pharmacokinetic studies that had a 60-min mouth hold time based on product use data [24, 25].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] Digard H, Errington G, Richter A, McAdam K. Patterns and behaviors of snus consumption in Sweden. Nicotine Tob Res. 2009;11:1175–81. https://doi.org/10.1093/ntr/ntp118 (Epub 2009 Aug 17). source
    • cites [25] Digard H, Proctor C, Kulasekaran A, Malmqvist U, Richter A. Determination of nicotine absorption from multiple tobacco products and nicotine gum. Nicotine Tob Res. 2013;15:255–61. source
  • Findingown data

    No significant difference in Cmax and AUC0-6h between the Lyft 10 mg NP and the other NPs was observed.

    “No significant difference in Cmax and AUC0–6h between the Lyft 10 mg NP and the other NPs was observed.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The amount of nicotine blood plasma concentration (Cmax and AUC0-6h) was greater or similar to that seen with cigarette smoking for the NPs examined.

    “whereas the amount of nicotine blood plasma concentration (i.e. Cmax and AUC0–6h) was greater or similar to that seen with cigarette smoking for the NPs examined.”
    • Also stated in: § Discussion · plain
      “Our study, conducted among current smokers, found that both Cmax and AUC0–6h were generally higher for NPs than for a combustible cigarette”
    • Also stated in: § Conclusion · plain
      “Cmax and AUC values from these products match or exceed those of a combustible cigarette during smoking”
    Quote in the paperSubstantial claim
  • Findingown data

    Tmax was higher for all NPs (60-65 min) than for the combustible cigarette (7 min).

    “Tmax was higher for all NPs (60–65 min) than for the cigarette (7 min).”
    • Also stated in: § Discussion · plain
      “We found that the increase in nicotine blood plasma concentration from NP use was slower (i.e. a longer Tmax) than that seen when participants smoked combustible cigarettes”
    • Also stated in: § Conclusion · plain
      “Tmax is slower.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 33

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    It has been proposed that smokers who switch completely to alternative nicotine delivery products instead of continuing to smoke could potentially reduce their relative risks of disease.

    “In the past decade, alternative nicotine delivery products such as e-cigarettes or tobacco heating products have been developed, and it has been proposed that smokers who switch completely to these products instead of continuing to smoke could potentially reduce their relative risks of disease [16, 17].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [16] Murphy J, Gaca M, Lowe F, Minet E, Breheny D, Prasad K, Camacho O, Fearon IM, Liu C, Wright C, McAdam K, Proctor C. Assessing modified risk tobacco and nicotine products: description of the scientific framework and assessment of a closed modular electronic cigarette. Regul Toxicol Pharmacol. 2017;90:342–57. source
    • cites [17] McNeill A, Brosen LS, Calder R, Bauld L, Robson D. Evidence review of e-cigarettes and heated tobacco products 2018. A report commissioned by Public Health England. London: PHE Publications; 2018. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/684963/Evidence_review_of_e-cigarettes_and_heated_tobacco_products_2018.pdf. Accessed 08 Jul 2021.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nicotine pouches contain lower levels than snus of 10 harmful and potentially harmful tobacco constituents and undetectable levels of a further 13 such constituents.

    “The comparatively simple composition of NPs relative to snus is reflected in a recent toxicant analysis, which showed that NPs contain lower levels than snus of 10 harmful and potentially harmful tobacco constituents (HPHCs) and undetectable levels of a further 13 HPHCs [20].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Azzopardi D, Liu C, Murphy J. Chemical characterization of tobacco-free “modern” oral nicotine pouches and their position on the toxicant and risk continuums. Drug Chem Toxicol. 2021;25:1–9. source

      Supplementary Table S3 (page not given) compares snus and nicotine pouches and shows lower estimated exposure for some constituents, including NNN and NNK, while marking many pouch results “NQ” (not quantified). It does not establish the claimed counts of 10 lower-level constituents and 13 undetectable constituents; “not quantified” is not necessarily “undetectable.” (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The harmful effects of cigarette smoking are caused by exposure to some of the 8700 or more identified chemical constituents, some of which contribute to disease development.

    “It is now generally accepted that the harmful effects of cigarette smoking are caused by exposure to some of the 8700 or more identified chemical constituents [6–11], some of which contribute to disease development.”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [6] Farsalinos KE, Le Houezec J. Regulation in the face of uncertainty: the evidence on electronic nicotine delivery systems (e-cigarettes). Risk Manag Healthc Policy. 2015;8:157–67. source

      The Tobacco harm reduction section says cigarette smoke contains toxic substances produced by combustion and that most cigarette toxicity is related to burning. The Introduction links smoking to chronic diseases. Neither passage supports the specific figure of 8,700 or more identified chemical constituents; a search for that figure found no supporting passage in our copy. Page numbers were not provided. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Food and Drug Administration. Harmful and potentially harmful constituents in tobacco products and tobacco smoke; established list. Docket no. FDA-2012-N-0143. Federal Register 2012;77.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8] International Agency for Research on Cancer. Reversal of risk after quitting smoking. IARC Handbooks of Cancer Prevention, vol. 11. Lyon: IARC; 2007.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9] Institute of Medicine. Clearing the smoke—assessing the science base for tobacco harm reduction. Washington, DC: The National Academies Press; 2001.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10] Rodgman A, Perfetti T. The chemical components of tobacco and tobacco smoke. Boca Raton: CRC Press; 2013.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [11] Stratton K, Shetty P, Wallace R, Bondurant S. Clearing the smoke: the science base for tobacco harm reduction—executive summary. Tob Control. 2001;10:189–95. source

      The section on exposure to whole tobacco smoke says that many smoke chemicals are toxic and that a few causative constituents have been identified, supporting the claim that some constituents contribute to disease. It reports more than 4,000 chemicals, however, and does not substantiate the specific figure of 8,700 or more. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was more variability in the T1/2 for Zyn, based on an inexplicably high result from one subject.

    “However, it should be noted that there was more variability in the T1/2 for Zyn, based on an inexplicably high result from one subject.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both product liking and intent to use the product again scores were lowest for the NP with the lowest nicotine content (6 mg On! NP).

    “Both the product liking and the intent to use the product again scores were lowest (i.e. the greatest number of participants reported a score of < 5) for the NP with the lowest nicotine content (6 mg On! NP).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Product liking and intent to use the product again scores were highest for the combustible cigarette; more participants reported an intent to use the product again (score > 5) for the cigarette (n = 21) than for the NPs (n = 14-19).

    “Broadly speaking, scores for product liking and intent to use the product again were highest for the combustible cigarette; that is, more participants reported an intent to use the product again (i.e. a score > 5) for the cigarette (n = 21) than for the NPs (n = 14–19).”
    • Also stated in: § Discussion · hedged
      “We note that the proportion of participants reporting a positive response in the product liking questionnaire was lower for the NPs than for the cigarette”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Relative bioavailability of nicotine from Skruf, Lyft, Nordic Spirit, and On! NPs was 1.37, 1.44, 1.72, and 2.45 times that of Zyn NP, respectively.

    “Skruf was the next highest and was 1.37 times higher than Zyn, Lyft was 1.44 times higher, and then Nordic Spirit and On! were 1.72 and 2.45 times higher than Zyn, respectively.”
    • Also stated in: § Discussion · boosted
      “This is supported by the relative bioavailablity of nicotine from the NPs used in this study, which showed that Zyn had the lowest level, followed by Skruf, Lyft, Nordic Spirit and On!, with the latter three products having relative bioavailabilities ranging from 1.37 to 2.45 times higher than Zyn.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nicotine Cmax and AUC0-6h were significantly greater for the Lyft 10 mg nicotine pouch than for the combustible cigarette (both p < 0.0001).

    “Nicotine maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between 0 and 6 h (AUC0–6h) were significantly greater for the Lyft 10 mg NP than for the cigarette (both p < 0.0001)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On! showed significantly lower scores for intent to use again than the combustible cigarette (p = 0.0030) and the Lyft product (p = 0.0363).

    “In addition to this, On! showed significantly lower scores for intent to use again than the combustible cigarette (p = 0.0030) and the Lyft product (p = 0.0363).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cmax and AUC0-6h were highest for the 9 mg Nordic Spirit (18.4 ng/mL) and 10 mg Lyft (53.7 ng·h/mL) NPs, respectively, but were lowest for the 10 mg Zyn NP (11.9 ng/mL and 35.8 ng·h/mL, respectively).

    “For example, Cmax and AUC0–6h were highest for the 9 mg Nordic Spirit (18.4 ng/mL) and 10 mg Lyft (53.7 ng·h/mL) NPs, respectively, but were lowest for the 10 mg Zyn NP (11.9 ng/mL and 35.8 ng·h/mL, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Liking and intent-to-use-again scores were higher for the combustible cigarette than for any nicotine pouch and were lowest for the nicotine pouch with the lowest nicotine content.

    “Regarding subjective effects, liking and intent to use product again scores were higher for the cigarette than for any NP and were lowest for the NP with the lowest nicotine content.”
    • Also stated in: § Key Points · plain
      “Liking and intent-to-use-again scores were higher for the cigarette than for any NP and were lowest for the NP with the lowest nicotine content.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cmax and AUC0-6h were significantly higher for the Lyft 10 mg NP compared with the Zyn 10 mg NP (both p < 0.0001).

    “In addition, Cmax and AUC0–6h were significantly higher (both p < 0.0001) for the Lyft 10 mg NP as compared with the Zyn 10 mg NP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Although the 10 mg Zyn NP had the lowest Cmax and AUC0-6h values of all the NPs, it was one of the best-performing NPs for the subjective effect liking score.

    “Furthermore, although the 10 mg Zyn NP had the lowest Cmax and AUC0–6h values of all the NPs, it was one of the best-performing NPs for the subjective effect liking score.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cmax and AUC0-6h were significantly higher for the Lyft 10 mg NP than for the Skruf 8 mg NP (p = 0.0005 and p < 0.0001, respectively).

    “Similarly, Cmax and AUC0–6h were significantly higher (p = 0.0005 and p < 0.0001, respectively) for the Lyft 10 mg NP than for the Skruf 8 mg NP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The NP with the lowest nicotine content (6 mg On!) had one of the highest Cmax values (17.5 ng/mL) and the highest nicotine bioavailability, while the subjective effects scores (liking and intent to use again) were lowest for this NP, whereas there were no major differences among the other four NP products with differing nicotine contents.

    “while the NP with the lowest nicotine content (6 mg On!) had one of the highest Cmax values (17.5 ng/mL) and the highest nicotine bioavailability, the subjective effects scores (liking and intent to use again) were lowest for this NP, whereas there were no major differences among the other four NP products with differing nicotine contents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean elimination half-life (T1/2) for plasma nicotine decay was similar for all study products, ranging from 2.15 ± 0.31 h for the 6 mg On! nicotine pouch to 2.82 ± 3.29 h for the 10 mg Zyn nicotine pouch.

    “The mean elimination half-life (T1/2) for the plasma nicotine decay ± SD was similar for all study products, ranging from 2.15 ± 0.31 h for the 6 mg On! NP to 2.82 ± 3.29 h for the 10 mg Zyn NP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cmax and AUC0-6h were significantly greater for the Lyft 10 mg NP than for the combustible cigarette (p < 0.0084 and p < 0.0001, respectively).

    “Cmax and AUC0–6h were significantly greater for the Lyft 10 mg NP than for the combustible cigarette (p < 0.0084 and p < 0.0001, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On! showed significantly lower scores for product liking than the combustible cigarette (p = 0.0216) and the Zyn product (p = 0.0392).

    “On! showed significantly lower scores for product liking than the combustible cigarette (p = 0.0216) and the Zyn product (p = 0.0392).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    While liking and intent-to-use-again scores were lower for the studied NPs than for combustible cigarettes, significant numbers of subjects reported positive liking and strong intent-to-use-again scores for NPs.

    “while liking and intent-to-use-again scores were lower for the studied NPs than for combustible cigarettes, significant numbers of subjects reported positive liking and strong intent-to-use-again scores for NPs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Like snus, nicotine pouches are placed between the user's upper lip and the gum, where the nicotine released is absorbed into the blood through the oral mucosa.

    “Like snus, NPs are placed between the user’s upper lip and the gum [19], where the nicotine released is absorbed into the blood through the oral mucosa.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Plurphanswat N, Hughes JR, Fagerström K, Rodu B. Initial information on a novel nicotine product. Am J Addict. 2020;29:279–86. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The health risks associated with cigarette smoking are correlated with duration of smoking and degree of daily cigarette consumption.

    “The health risks associated with cigarette smoking are correlated with duration of smoking and degree of daily cigarette consumption [8, 14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] International Agency for Research on Cancer. Reversal of risk after quitting smoking. IARC Handbooks of Cancer Prevention, vol. 11. Lyon: IARC; 2007.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14] Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years’ observations on male British doctors. Brit Med J. 1994;309:901–11. source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Premisecitation

    The harmful effects of cigarette smoking are not substantially caused by nicotine, which is considered by some prominent regulatory and healthcare bodies to be relatively harmless at the levels of uptake during cigarette smoking.

    “These effects are not substantially caused by the addictive compound nicotine, which is considered by some prominent regulatory and healthcare bodies to be relatively harmless at the levels of uptake during cigarette smoking [12, 13].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Public Health England. Health matters: stopping smoking—what works?. London: PHE Publications; 2019. https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction. Accessed 08 July 2021.

      Not checked in the free run.

    • cites [13] Royal College of Physicians. Nicotine without smoke. Tobacco harm reduction. A report by the Tobacco Advisory Group of the Royal College of Physicians. London: Royal College of Physicians; 2016.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Between-run accuracy ranged from 98.71 to 105.97% of the nominal concentration, and the between-run CV was 1.90-4.90%.

    “Between-run accuracy ranged from 98.71 to 105.97% of the nominal concentration, and the between-run CV was 1.90–4.90%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was registered in the ISRCTN registry (ISRCTN17828518).

    “The study was registered in the ISRCTN registry (ISRCTN17828518).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Analyte recoveries for the low-, medium-, and high-quality control samples were 98.04, 99.00, and 100.62%, respectively, and the recovery of the internal standard was 100.56%.

    “Analyte recoveries for the low-, medium-, and high-quality control samples were 98.04, 99.00, and 100.62%, respectively, and the recovery of the internal standard was 100.56%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was a randomised, controlled, crossover clinical study carried out at a single clinical site in Uppsala, Sweden.

    “This was a randomised, controlled, crossover clinical study carried out at a single clinical site in Uppsala, Sweden.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Within-run accuracy ranged from 98.22 to 102.93% of the nominal concentration, and the within-run CV was 0.55-3.26%.

    “The within-run accuracy ranged from 98.22 to 102.93% of the nominal concentration, and the within-run CV was 0.55–3.26%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The pharmacokinetic profile of nicotine during cigarette smoking is a rapid rise and fall in plasma nicotine concentrations.

    “The pharmacokinetic profile of nicotine during cigarette smoking is a rapid rise and fall in plasma nicotine concentrations [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol. 2009;49:57–71. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The delivery of nicotine to the brain and the consequent pleasurable effects experienced by the smoker are rapid.

    “Correspondingly, the delivery of nicotine to the brain and the consequent pleasurable effects experienced by the smoker are also rapid [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Benowitz NL. Clinical pharmacology of nicotine. Annu Rev Med. 1986;37:21–32. source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    Nicotine delivery from alternative products is important in providing smokers with a satisfactory alternative to cigarette smoking.

    “Given the importance of nicotine delivery from alternative products in providing smokers with a satisfactory alternative to cigarette smoking [13, 23], studies assessing the delivery and pharmacokinetics of nicotine from NPs are required to inform our understanding of their harm reduction potential.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Royal College of Physicians. Nicotine without smoke. Tobacco harm reduction. A report by the Tobacco Advisory Group of the Royal College of Physicians. London: Royal College of Physicians; 2016.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [23] Hajek P, Pittaccio K, Pesola F, Myers Smith K, Phillips-Waller A, Przulj D. Nicotine delivery and users’ reactions to Juul compared with cigarettes and other e-cigarette products. Addiction. 2020;115:1141–8. source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nicotine is absorbed rapidly into the bloodstream during cigarette smoking.

    “Nicotine is absorbed rapidly into the bloodstream during cigarette smoking [3]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Lunell E, Molander L, Ekberg K, Wahren J. Site of nicotine absorption from a vapour inhaler—comparison with cigarette smoking. Eur J Clin Pharmacol. 2000;55:737–41. source

  • May combine two claims.

    Premisecitation

    Unlike snus, nicotine pouches typically do not contain tobacco but pharmaceutical grade nicotine absorbed onto a cellulose matrix in a porous pouch.

    “Unlike snus, however, NPs typically do not contain tobacco but pharmaceutical grade nicotine absorbed onto a cellulose matrix in a porous pouch [19–21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Plurphanswat N, Hughes JR, Fagerström K, Rodu B. Initial information on a novel nicotine product. Am J Addict. 2020;29:279–86. source
    • cites [20] Azzopardi D, Liu C, Murphy J. Chemical characterization of tobacco-free “modern” oral nicotine pouches and their position on the toxicant and risk continuums. Drug Chem Toxicol. 2021;25:1–9. source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [21] Lunell E, Fagerström K, Hughes J, Pendrill R. Pharmacokinetic comparison of a novel non-tobacco-based nicotine pouch (ZYN) with conventional, tobacco-based Swedish snus and American moist snuff. Nicotine Tob Res. 2020;22:1757–63. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was conducted in compliance with the study protocol, the Declaration of Helsinki, ICH GCP, FDA GCP, and EU regulation 536/2014, including regulations relating to protection of subjects' personal data.

    “The study was conducted in compliance with the study protocol, the Declaration of Helsinki, the International Council for Harmonisation (ICH) Guideline E6 for Good Clinical Practice (GCP), the Food and Drug Administration (FDA) GCP Code of Federal Regulations Title 21 (part 56) and the European regulation EU 536/2014, including regulations relating to the protection of subjects’ personal data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The plasma nicotine analysis had linearity for all runs with r ≥ 0.9981.

    “For the plasma nicotine analysis, the linearity for all runs was r ≥ 0.9981.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Swedish snus is one of the few products recognised by the US FDA as a contributor to tobacco harm reduction.

    “Swedish snus is one of the few products recognised by the US FDA as a contributor to tobacco harm reduction [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Clarke E, Thompson K, Weaver S, Thompson J, O’Connell G. Snus: a compelling harm reduction alternative to cigarettes. Harm Reduct J. 2019;16:62. https://doi.org/10.1186/s12954-019-0335-1. source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    There were no withdrawals during the study.

    “There were no withdrawals during the study, and none of the subjects utilised the opportunity to take a 1-day break after receiving at least four study products.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The randomisation code was not available to the bioanalytical facility personnel until the bioanalytical tables had been finalised and audited by quality assurance, and the statistician and pharmacokineticist were blind to the study product used on each study day until final analyses.

    “The randomisation code was not available to the personnel of the bioanalytical facility until the bioanalytical tables had been finalised and audited by the quality assurance department. The statistician and pharmacokineticist were also blind to the study product used on each study day until the final analyses had been performed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    It has been suggested for other types of nicotine delivery products, such as e-cigarettes, that a higher nicotine delivery from these devices (closer to that of cigarette smoking) is likely to provide smokers with a more satisfactory alternative to conventional cigarettes.

    “It has been suggested for other types of nicotine delivery products, such as e-cigarettes, that a higher nicotine delivery from these devices (i.e. closer to that of cigarette smoking) is likely to provide smokers with a more satisfactory alternative to conventional cigarettes [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Hajek P, Pittaccio K, Pesola F, Myers Smith K, Phillips-Waller A, Przulj D. Nicotine delivery and users’ reactions to Juul compared with cigarettes and other e-cigarette products. Addiction. 2020;115:1141–8. source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The reported data correspond to the pharmacokinetic subject set, which excluded subjects who had relevant protocol violations or circumstances affecting evaluation of pharmacokinetic parameters.

    “The reported data correspond to the pharmacokinetic subject set, which was a subset of the full analysis set and excluded subjects who had relevant protocol violations (or circumstances) that affected the evaluation of pharmacokinetic parameters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Product liking and intent-to-use-again scores were greater for the higher nicotine content NPs, although these assessments of liking and intent were lower for all NPs than for combustible cigarettes.

    “the subjective questionnaire demonstrated that product liking and intent-to-use-again scores were greater for the higher nicotine content NPs, although these assessments of liking and intent were lower for all NPs than for combustible cigarettes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    A minimum of 32 subjects (4 per sequence) was calculated to be necessary to achieve a balanced design and a power of 0.825 with an α-level of 0.05, enabling detection of a 20% difference in the log scale with an intrasubject coefficient of variation of 0.3.

    “Based on two-sided pairwise comparisons, and using an eight-product and eight-sequence Williams design, we calculated that a minimum of 32 subjects (4 subjects per sequence) would be necessary to achieve a balanced design and a power of 0.825 with an α-level of 0.05. This would enable us to detect a difference of 20% in the log scale with an intrasubject coefficient of variation (CV) of 0.3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Previous studies have reported greater AUC and Cmax values for some types of snus than for cigarettes, probably due to the longer period of snus use relative to smoking a single cigarette.

    “previous studies have similarly reported greater AUC and Cmax values for some types of snus than for cigarettes [25–27], probably due to the longer period of snus use relative to smoking a single cigarette.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Digard H, Proctor C, Kulasekaran A, Malmqvist U, Richter A. Determination of nicotine absorption from multiple tobacco products and nicotine gum. Nicotine Tob Res. 2013;15:255–61. source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [26] Lunell E, Lunell M. Steady-state nicotine plasma levels following use of four different types of Swedish snus compared with 2-mg Nicorette chewing gum: a crossover study. Nicotine Tob Res. 2005;7:397–403. source
    • cites [27] Lunell E, Curvall M. Nicotine delivery and subjective effects of Swedish portion snus compared with 4 mg nicotine polacrilex chewing gum. Nicotine Tob Res. 2011;13:573–8. source

  • May combine two claims.

    Interpretationreasoning

    The study was carried out among combustible cigarette users in Sweden, and as such the findings may not be generalisable to other cohorts (e.g. current non-smokers using other nicotine products such as snus) or to populations of other countries in which tobacco product use patterns may differ.

    “First, it was carried out among combustible cigarette users in Sweden, and as such our findings may not be generalisable to other cohorts (e.g. current non-smokers using other nicotine products such as snus) or to populations of other countries in which tobacco product use patterns may differ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The cohort comprised current snus users who were also cigarette smokers, and as such the findings do not provide information on nicotine pharmacokinetics and subjective effects of NP use in current non-users of oral tobacco products.

    “Third, our cohort comprised current snus users who were also cigarette smokers, and as such our findings do not provide information on nicotine pharmacokinetics and subjective effects of NP use in current non-users of oral tobacco products.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Product use was limited to a single time-controlled use of an NP product on a single day, and as such we cannot infer whether nicotine pharmacokinetics will change over time following continued use or when individuals use NPs for shorter or longer time periods than the 60-min use period stipulated in this study protocol.

    “Second, product use was limited to a single time-controlled use of an NP product on a single day, and as such we cannot infer whether nicotine pharmacokinetics will change over time following continued use or when individuals use NPs for shorter or longer time periods than the 60-min use period stipulated in this study protocol.”
    Quote in the paperSubstantial claim
45 of 45

  • The paper relies on this without support.

    Smoking cessation substantially reduces the relative risks of developing smoking-related diseases.

    “Epidemiological studies have confirmed that smoking cessation substantially reduces the relative risks of developing smoking-related diseases.”

  • The paper relies on this without support.

    At present, there is little information concerning the ability of nicotine pouches to deliver nicotine to users or the impact the physical attributes of nicotine pouches, such as nicotine content, have on nicotine delivery and pharmacokinetics.

    “At present, however, there is little information concerning the ability of NPs to deliver nicotine to users or the impact the physical attributes of NPs, such as nicotine content, have on nicotine delivery and pharmacokinetics.”

  • The paper relies on this without support.

    The manufacturers' recommended usage time for these NP products is approximately 30 min, which is lower than the 60-min period used in this study.

    “we note that the 60-min period of use applied in this study is typically higher than the manufacturers' recommended usage time for these products. Commonly, manufacturers recommend a usage time of approximately 30 min”

  • The paper relies on this without support.

    At present, there are no other data comparing nicotine pharmacokinetics between cigarettes and this relatively new product category of NPs.

    “At present, there are no other data comparing nicotine pharmacokinetics between cigarettes and this relatively new product category of NPs”

  • The paper relies on this without support.

    Nicotine pouches are designed to be placed between the gum and the upper lip such that the nicotine released from the pouch is absorbed through the oral mucosa.

    “Nicotine pouches are designed to be placed between the gum and the upper lip such that the nicotine released from the pouch is absorbed through the oral mucosa.”

  • The paper relies on this without support.

    As yet, there is little information concerning the nicotine pharmacokinetic properties of NPs, their ability to deliver nicotine to users, and the effect of such nicotine delivery on the blood plasma concentration.

    “As yet, there is little information concerning the nicotine pharmacokinetic properties of NPs, their ability to deliver nicotine to users, and the effect of such nicotine delivery on the blood plasma concentration.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Intent-to-use-again counts are taken from the liking results

    Minor

    The stated counts of 21 for the cigarette and 14-19 for NPs match the product-liking scores above 5. For intent to use again, Table 4 instead gives 20 for the cigarette and 5-13 for NPs.

  • Relative-bioavailability range uses the wrong lower endpoint

    Minor

    "The latter three products" are Lyft, Nordic Spirit and On!, whose stated relative bioavailabilities run from 1.44 to 2.45 times Zyn's. The stated lower endpoint of 1.37 belongs to Skruf.

  • Abstract overstates the Cmax comparison's statistical significance

    Minor

    The abstract says both comparisons have p < 0.0001, but Table 3 reports p = 0.0084 for Cmax. The Cmax comparison remains significant, but the stated p-value is inconsistent.

  • Reported BMI standard deviation is impossible for its range

    Minor

    For 35 observations with a mean of 23.3 and a range of 22.6-29.8, the sample standard deviation cannot exceed about 2.17. The reported SD is 3.2; rounding of the displayed values cannot account for the gap.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Institute of Medicine. Clearing the smoke—assessing the science base for tobacco harm reduction. Washington, DC: The National Academies Press; 2001.
  2. Rodgman A, Perfetti T. The chemical components of tobacco and tobacco smoke. Boca Raton: CRC Press; 2013.

Cited by

Sorted by citations

Related

Authors
McEwan, M., Azzopardi, D., Gale, N., Camacho, O. M., Hardie, G., Fearon, I. M., & Murphy, J.
Affiliations
British American Tobacco (United Kingdom) (GB)
Corresponding author
McEwan, Michael
ORCID
Venue
European Journal of Drug Metabolism and Pharmacokinetics
Publisher
Springer Science and Business Media LLC
Published
2021-12-18
Volume
47
Issue
2
Pages
211-221
ISSN
  • 0378-7966 (ISSN-L)
  • 2107-0180
DOI
10.1007/s13318-021-00742-9
PMC
PMC8917032
OpenAlex
W4200390533
Semantic Scholar
7a0c07ad938382ddd7214957f0f3ce2281e4f1d4
Cited by
70
References
36
Citations by year
2026: 18 · 2025: 20 · 2024: 18 · 2023: 5 · 2022: 8 · 2021: 1
FWCI
4.89
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Drug Metabolism and Pharmacokinetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
British American Tobacco
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
Keywords
nicotine pouches, nicotine pharmacokinetics, combustible cigarettes, nicotine delivery, subjective effects, nicotine content, plasma nicotine concentration, nicotine abstinence
MeSH terms
Smokers, Adult, Humans, Nicotine, Cross-Over Studies, Tobacco Products, Electronic Nicotine Delivery Systems

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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