Human Abuse Liability Assessment of Tobacco and Nicotine Products: Approaches for Meeting Current Regulatory Recommendations

Abstract

Many regulatory bodies now recommend tobacco product manufacturers provide information regarding new tobacco products’ abuse liability, to inform regulatory authorization of currently marketed tobacco products or new product applications (including premarket tobacco product applications in the US). In addition, the US Food and Drug Administration (FDA) recommends including this information as part of modified risk tobacco product applications. Regulators, including FDA, and many public health officials and researchers consider abuse liability assessment a model which predicts the likelihood that use of the tobacco product would result in addiction and be used repeatedly or even sporadically resulting in undesirable effects. Abuse liability of a new, potentially reduced harm product can also inform its ability to substitute completely for more harmful tobacco products. While many methods exist, no standard tobacco product abuse liability assessment has been established. The purpose of this paper is to provide background information and practical recommendations for human abuse liability testing methods to meet tobacco regulatory needs. A combination of nicotine test product pharmacokinetic, subjective effect and/or behavioral response, and physiological response data relative to comparator products with known abuse liability satisfies some regulatory requirements. Implications This review provides a practical inspection of the current, international regulatory recommendations for abuse liability assessment of tobacco, regulatory review of such information within the U.S., and recommends study designs and methods for abuse liability testing of tobacco products based on scientific and regulatory knowledge. Given that tobacco product abuse liability testing is of increasing interest to regulatory bodies globally, especially with the emergence of novel tobacco products, this timely work provides background and functional recommendations for tobacco product abuse liability testing.

A randomised, open-label, cross-over clinical study to evaluate the pharmacokinetic, pharmacodynamic and safety and tolerability profiles of tobacco-free oral nicotine pouches relative to cigarettes

“…In understanding the potential abuse liability of a nicotine product, a combination of nicotine pharmacokinetics, subjective effects and behavioural responses, relative to a comparator product with known abuse liability, can be informative. Based on the pharmacokinetic outcomes reported here, which demonstrate lower and slower levels of nicotine delivery compared to cigarettes, coupled with the absence of the hand-to-mouth behaviour associated with smoking, and the reported subjective response data, it is likely that based on the outcomes generated under the study conditions, the assessed nicotine pouches may have lower abuse potential than cigarettes for adult smokers (Vansickel et al, 2022 ). This is consistent with the findings and conclusions reported (i.e.…”

Nicotine pharmacokinetics and subjective responses after using nicotine pouches with different nicotine levels compared to combustible cigarettes and moist smokeless tobacco in adult tobacco users

“…Nonetheless, these limitations may restrict the generalizability to all tobacco/nicotine product users, particularly since differences in male and female nicotine PK have been reported by Benowitz et al ( 2006 ). Despite these limitations, the nicotine PK analysis and the subjective measures used in this study are well-established methods for evaluating the abuse potential of tobacco/nicotine products (Carter et al 2009 ; Cobb et al 2010 ; Cox et al 2001 ; Gray et al 2008 ; Hanson et al 2009 ; Henningfield and Keenan 1993 ; Lunell and Curvall 2011 ; Lunell et al 2020 ; Vansickel et al 2010 , 2021a , b ).…”

Human abuse liability assessment of e‐cigarettes: Why, what and how?

“…Various guidances exist for the human abuse liability assessment of many drugs that act on the central nervous system. [61][62][63] In reality, however, there is no defined and consensual methodology with which to assess the abuse liability of nicotine products such as e-cigarettes, although a recent paper provided a proposed framework. 61 Clinical abuse liability studies of nicotine products in humans have variously examined outcome measures that together may form an assessment of abuse liability, although the amalgamated measures are put together in a somewhat subjective manner.…”

“…These include domains such as satisfaction, intent to use again, product liking, and effects on withdrawal symptoms such as urge to smoke a cigarette, and a plethora of different tools are able to assess these and contribute to an abuse liability assessment. 53,61 A number of routinely used questionnaires are multifactorial, such as the product evaluation scale (PES) that assesses subjective satisfaction, psychological reward, aversion and relief. 74 Although no two studies are identical, a useful starting point for an abuse liability study design would be administration of the PES, a single-question liking scale and a single-question intent to use again scale, each assessed at a single timepoint following e-cigarette use.…”