Nicotine - Addiction/Dependence

Addiction: "A mental disposition towards repeated episodes of abnormally high levels of motivation to engage in a behaviour, acquired as a result of engaging in the behaviour, where the behaviour results in risk or occurrence of serious net harm."

Dependence: "A bodily disposition which is realised as impaired functioning following reduction or termination of use of a psychoactive substance. This is distinguished from addiction. The two are often correlated but distinct. Dependence is a disposition to experience impaired functioning, which includes withdrawal symptoms, while addiction is a distinction to experience powerful motivation. The motivation can, but need not be caused by impaired functioning."

Abuse Liability: The potential to develop a dependence or addiction to a substance.

Smoking - Combustible Tobacco

2010 Nicotine Addiction

• Conslusions: "Nicotine sustains tobacco addiction, a major cause of disability and premature death, by acting on nicotinic cholinergic receptors in the brain to trigger the release of dopamine and other neurotransmitters. Release of dopamine, glutamate, and GABA is particularly important in the development of nicotine dependence, and CRF may play a key role in withdrawal. Neuroadaptation and tolerance involve changes in nicotinic receptors and neural plasticity. Nicotine addiction occurs when smokers come to rely on smoking to modulate mood and arousal, relieve withdrawal symptoms, or both. Light or occasional smokers smoke mainly for positive reinforcement in specific situations.
• Genetic studies indicate that nicotinic receptor subtypes and the genes involved in neuroplasticity and learning play a part in the development of dependence.
• People with psychiatric or substance-abuse disorders, who account for a large proportion of current smokers, have an increased susceptibility to tobacco addiction.
• Nicotine is metabolized primarily by the enzyme CYP2A6, and variation in the rate of nicotine metabolism contributes to differences in vulnerability to tobacco dependence and the response to smoking-cessation treatment. An increased understanding of the mechanisms of nicotine addiction has led to the development of novel medications (e.g., varenicline) that act on specific nicotinic receptor subtypes. The development of other drugs that act on nicotinic receptors and other mediators of nicotine addiction is likely to further enhance the effectiveness of smoking-cessation pharmacotherapy.
• Citation: Benowitz NL. Nicotine addiction. N Engl J Med. 2010 Jun 17;362(24):2295-303. doi: 10.1056/NEJMra0809890. PMID: 20554984; PMCID: PMC2928221.
• Acknowledgment: Supported by grants from the Flight Attendants Medical Research Institute and the National Institute on Drug Abuse (U.S. Public Health Service grants DA02277 and DA20830).

ENDS/E-Cigarettes/NVP/Vaping

• ENDS = Electronic Nicotine Delivery System
• NVP = Nicotine Vapor Product

2020 Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers

• Conclusions: Controlled use of JS among adult smokers resulted in nicotine delivery, product liking, and satisfaction that were less than that of combustible cigarettes but generally greater than nicotine gum. These results support the conclusion that JS has lower abuse liability than combustible cigarettes, higher abuse liability than nicotine gum, and may provide sufficient nicotine delivery and satisfying effects to support substitution for combustible cigarettes among adult smokers.
• Citation: Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Henningfield JE. Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers. Drug Alcohol Depend. 2020 Dec 1;217:108395. doi: 10.1016/j.drugalcdep.2020.108395. Epub 2020 Nov 4. PMID: 33176942.
• Acknowledgment: The study was funded by Juul Labs, Inc. NIG, EMA and MLR are full-time employees of Juul Labs, Inc., JEH and ARB are full-time employees of PinneyAssociates, Inc. PinneyAssociates provides consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Within the last two years, PinneyAssociates has consulted for British American Tobacco and Reynolds American Inc and subsidiaries on tobacco harm reduction. JEH co-holds a patent for a novel nicotine medication that has not been developed or commercialized. There are no other interests declared by authors.

2020 Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum and comparator electronic nicotine delivery system

• Conclusions: These results suggest that the abuse liability of both 5.0 % and 3.0 % JS is: (1) substantially lower than UB cigarette; (2) somewhat lower than comparator ENDS; and (3) higher than nicotine gum. Additionally, the abuse liability of JS 5.0 % is somewhat higher than JS 3.0 %.
• Acknowledgment: The study was funded by Juul Labs, Inc. NIG, EMA, DVH and MLR are full-time employees of Juul Labs, Inc., JEH and ARB are full-time employees of PinneyAssociates, Inc. PinneyAssociates provides consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Within the last two years, PinneyAssociates has consulted for British American Tobacco and Reynolds American Inc and subsidiaries on tobacco harm reduction. JEH co-holds a patent for a novel nicotine medication that has not been developed or commercialized. There are no other interests declared by authors.

Evaluating More Than One Product Type

2021 Dependence on nicotine in US high school students in the context of changing patterns of tobacco product use

• Among US high school students, increases in the prevalence of nicotine product use from 2012 to 2019 do not appear to have been accompanied by a similar increase in the population burden of nicotine dependence. This may be at least partly attributable to a shift in the most common product of choice from cigarettes (on which users are most dependent) to e-cigarettes (on which users are least dependent).
• PDF Version
• Citation: Jackson, S. E., Brown, J., and Jarvis, M. J. (2021) Dependence on nicotine in US high school students in the context of changing patterns of tobacco product use. Addiction, 116: 1859– 1870. doi: 10.1111/add.15403
• Acknowledgement: Cancer Research UK (C1417/A22962) supported S.J. andJ.B.’s salaries.

2020 Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers

• Conclusions: Controlled use of JS among adult smokers resulted in nicotine delivery, product liking, and satisfaction that were less than that of combustible cigarettes but generally greater than nicotine gum. These results support the conclusion that JS has lower abuse liability than combustible cigarettes, higher abuse liability than nicotine gum, and may provide sufficient nicotine delivery and satisfying effects to support substitution for combustible cigarettes among adult smokers.
• Citation: Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Henningfield JE. Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers. Drug Alcohol Depend. 2020 Dec 1;217:108395. doi: 10.1016/j.drugalcdep.2020.108395. Epub 2020 Nov 4. PMID: 33176942.
• Acknowledgment: The study was funded by Juul Labs, Inc. NIG, EMA and MLR are full-time employees of Juul Labs, Inc., JEH and ARB are full-time employees of PinneyAssociates, Inc. PinneyAssociates provides consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Within the last two years, PinneyAssociates has consulted for British American Tobacco and Reynolds American Inc and subsidiaries on tobacco harm reduction. JEH co-holds a patent for a novel nicotine medication that has not been developed or commercialized. There are no other interests declared by authors.

2018 Assessment of the abuse liability of three menthol Vuse Solo electronic cigarettes relative to combustible cigarettes and nicotine gum

• These findings are concordant with our previous results and provide evidence that menthol Vuse Solo ECs have abuse liability that is lower than menthol cigarettes and potentially greater than that of nicotine gum.
• PDF Version
• Citation: Stiles MF, Campbell LR, Jin T, Graff DW, Fant RV, Henningfield JE. Assessment of the abuse liability of three menthol Vuse Solo electronic cigarettes relative to combustible cigarettes and nicotine gum. Psychopharmacology (Berl). 2018 Jul;235(7):2077-2086. doi: 10.1007/s00213-018-4904-x. Epub 2018 May 3. PMID: 29725702; PMCID: PMC6015619.
• Acknowledgement: ClinicalTrials.gov identifier: NCT02664012. MF Stiles, LR Campbell, and T Jin are full-time employees of RAI Services Company. RAI Services Company is a wholly owned subsidiary of Reynolds American Inc., which is a wholly owned subsidiary of British American Tobacco plc. DW Graff is a full-time employee of Celerion and provided the original draft of the manuscript. RV Fant and JE Henningfield are full-time employees of PinneyAssociates, which provides consulting services on smoking cessation and tobacco harm minimization (including nicotine replacement therapy and electronic vapor products) to Niconovum, USA, Inc., RJ Reynolds Vapor Company, and RAI Services Company (all subsidiaries of Reynolds American Inc.). JE Henningfield also owns an interest in intellectual property for a novel nicotine medication. Through PinneyAssociates, Fant and Henningfield provide consulting services to pharmaceutical companies on abuse potential assessment, and the regulation of substances with a potential for abuse.

2012 Determinants of Tobacco Use and Renaming the FTND to the Fagerström Test for Cigarette Dependence

• More recently, it has been found that, although nicotine is the most important addictive component of tobacco smoke, it is probably not the only substance involved in the development of tobacco dependence. In light of what is now known about what determines cigarette smoking, it seems timely to propose a renaming of the Fagerstrom Test for Nicotine Dependence (FTND) to the Fagerstrom Test for Cigarette Dependence (FTCD).
• PDF Version
• Citation: Karl Fagerström, Ph.D., Determinants of Tobacco Use and Renaming the FTND to the Fagerström Test for Cigarette Dependence, Nicotine & Tobacco Research, Volume 14, Issue 1, January 2012, Pages 75–78, doi: 10.1093/ntr/ntr137
• See Also: 2013: Dependence on tobacco and nicotine

Nicotine Pouches

2024 Evaluating the Role of Nicotine Stereoisomer on Nicotine Pouch Abuse Liability: A Randomized Crossover Trial

• "Implications: Little is known about the effects of racemic (vs. S-) nicotine in humans. In a sample of adults who smoke cigarettes, we identified that oral nicotine pouches containing racemic nicotine exposed participants to less nicotine than oral nicotine pouches containing only S-nicotine, but both types of oral nicotine pouches held similar, moderate appeal. Additional research evaluating the roles that flavorings, total nicotine concentration, and freebase nicotine play in the abuse liability of oral nicotine pouches would inform comprehensive product regulations to support public health."
• Citation: Keller-Hamilton B, Curran H, Alalwan M, Hinton A, Brinkman MC, El-Hellani A, Wagener TL, Chrzan K, Atkinson L, Suraapaneni S, Mays D. Evaluating the Role of Nicotine Stereoisomer on Nicotine Pouch Abuse Liability: A Randomized Crossover Trial. Nicotine Tob Res. 2024 May 7:ntae079. doi: 10.1093/ntr/ntae079. Epub ahead of print. PMID: 38713545.
• Acknowledgment: Grants: U54CA287392/DA/NIDA NIH HHS/United States, CA/NCI NIH HHS/United States

2024 Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study

• "Conclusions: Among adult smokers, using 6-mg nicotine concentration oral nicotine pouches (ONPs) was associated with greater plasma nicotine delivery at 30 minutes than 3-mg ONPs or cigarettes, but neither ONP relieved craving symptoms at 5 minutes as strongly as a cigarette. Accelerating the speed of nicotine delivery in ONPs might increase their misuse liability relative to cigarettes."
• Citation: Keller-Hamilton B, Alalwan MA, Curran H, Hinton A, Long L, Chrzan K, Wagener TL, Atkinson L, Suraapaneni S, Mays D. Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study. Addiction. 2024 Mar;119(3):464-475. doi: 10.1111/add.16355. Epub 2023 Nov 14. PMID: 37964431; PMCID: PMC10872395.
• Acknowledgment: This study was funded by the Addiction Innovation Fund at The Ohio State University's College of Public Health. This research was also partially supported by The Ohio State University Comprehensive Cancer Center—The James and the National Cancer Institute of the National Institutes of Health (grant number P30CA016058). BKH was supported by grant number K01DA055696 from the National Institute on Drug Abuse. BKH, AH, TLW, and DM were supported by grant number U54CA287392 from the National Cancer Institute. The sponsors had no role in the study design; in the collection, analysis or interpretation of the data; in the writing of the report; or in the decision to submit the manuscript for publication.

Nicotine Replacement Therapy (NRT)

2013 Modifications To Labeling of Nicotine Replacement Therapy Products for Over-the-Counter Human Use

• We also note that although any nicotine-containing product has the potential to be addicting, based on the available evidence, currently marketed OTC NRT products do not appear to have significant potential for abuse or dependence. A 2010 review of historical reports made to the Agency's Adverse Event Reporting System and to the Substance Abuse and Mental Health Services Administration's Drug Abuse Warning Network between 1984 and 2009 suggested that NRT products have a low potential for abuse. Several published studies have also found that the abuse liability and dependence potential of NRT products is low, especially compared to cigarettes.
• PDF Version
• Citation: Food and Drug Administration, 78 FR 19718

2003 Subjective effects of the nicotine lozenge: assessment of abuse liability

• Results suggest that the nicotine lozenge has low abuse liability, both in adults and young adults.
• PDF Version
• Citation: Houtsmuller EJ, Henningfield JE, Stitzer ML. Subjective effects of the nicotine lozenge: assessment of abuse liability. Psychopharmacology (Berl). 2003 Apr;167(1):20-7. doi: 10.1007/s00213-002-1361-2. Epub 2003 Mar 4. PMID: 12616334.
• Acknowledgement: This research was supported by SmithKline Beecham Consumer Healthcare.

2002 Flavor improvement does not increase abuse liability of nicotine chewing gum

• Mint-flavored nicotine gum was rated as more palatable than the original nicotine gum, but the improvement in flavor did not increase abuse liability in adults (22 – 50 years old) or young adults (18 –21 years old).
• PDF Version
• Citation: Houtsmuller EJ, Fant RV, Eissenberg TE, Henningfield JE, Stitzer ML. Flavor improvement does not increase abuse liability of nicotine chewing gum. Pharmacol Biochem Behav. 2002 Jun;72(3):559-68. doi: 10.1016/s0091-3057(02)00723-2. PMID: 12175452.
• Acknowledgement: This study was supported by SmithKline Beecham Consumer Healthcare.

VLNC - Very Low Nicotine Cigarettes

• WARNING! It is still smoking and has all the harms of smoking, even if less addictive.

2024: Perceptions of the Addictiveness of Low-Nicotine Cigarettes Versus Typical Cigarettes and Exposure to Tobacco Industry-Sponsored Corrective Campaign

• 'In the overall population, 4.1% reported that low-nicotine cigarettes were much more addictive than typical cigarettes, 67.5% said they were equally addictive, while 28.4% reported they were slightly/much less addictive."

2021: Reactions to reduced nicotine content cigarettes in a sample of young adult, low-frequency smokers

• Reducing nicotine content will likely lower the abuse liability of cigarettes for most young, low-frequency smokers. Additional work is needed to determine if compensatory smoking may lead to increased toxicant exposure, and if a subset of individuals choosing lower nicotine cigarettes may continue to smoke regardless of nicotine content.

2021: "I actually finally feel like the cigarettes aren't controlling me." - Interviews with participants smoking very low nicotine content cigarettes during a residential study

• Several participants expected, prior to trying VLNC cigarettes, to compensate for the reduced nicotine levels by smoking more cigarettes but were surprised when they did not increase their smoking. A subset of participants reported experiencing minor withdrawal symptoms, such as irritability and fatigue. Several participants reported feeling less dependent after exclusively smoking VLNC cigarettes. Most participants said they would smoke VLNC cigarettes if they were the only cigarettes available to purchase. Some also said that smoking VLNC cigarettes could help people taper down or quit smoking.

2020: Changes in Cigarette Consumption With Reduced Nicotine Content Cigarettes Among Smokers With Psychiatric Conditions or Socioeconomic Disadvantage

• These 3 randomized clinical trials including 775 participants with affective disorders, opioid use disorder, or socioeconomic disadvantage found that reducing nicotine content significantly decreased total cigarettes smoked daily and nicotine dependence severity.

2020 Abuse liability of cigarettes with very low nicotine content in pregnant cigarette smokers

• Ten pregnant smokers in Burlington, VT and Baltimore, MD participated in 2017–2018.
• Reducing the nicotine content of cigarettes may decrease their abuse liability in pregnant smokers without causing untoward craving/withdrawal or compensatory smoking. Studies of extended exposure to VLNCs in pregnant women are warranted.

2015: Randomized Trial of Reduced-Nicotine Standards for Cigarettes

• In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked.

2010: Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation

• "Unlike the 0.3 mg cigarettes, 0.05 mg cigarettes were not associated with compensatory smoking behaviors. Furthermore, the 0.05 mg cigarettes and nicotine lozenge were associated with reduced carcinogen exposure, nicotine dependence and product withdrawal scores. The 0.05 mg cigarette was associated with greater relief of withdrawal from usual brand cigarettes than the nicotine lozenge. The 0.05 mg cigarette led to a significantly higher rate of cessation than the 0.3 mg cigarette and a similar rate as nicotine lozenge."