The Food and Drug Administration (FDA) recently posted an advance notice of proposed rulemaking (ANPRM) to set a maximum nicotine content in cigarettes to minimize their addictiveness.1 This policy would aim to help dependent smokers be more successful in attempts to quit smoking, as well as minimize risks of becoming dependent among youth who initiate tobacco smoking.2 Recent research has estimated the potential public health benefits of such a policy but did not provide data to establish what that level should be.3 In the major issues raised, the ANPRM states that “FDA is particularly interested in comments about the merits of nicotine levels like 0.3, 0.4, and 0.5 mg nicotine/g of tobacco filler, as well as other levels of nicotine.” Similarly, the World Health Organization (WHO) notes the threshold for addiction is likely to be at or below a cigarette nicotine content of 0.4 mg/g.4 A wide array of research is likely necessary to document a nonaddictive level of nicotine in smoked tobacco.5 Among the four study “types” of interest to FDA in addressing such a nicotine standard are “indirect estimates of an addiction threshold.” Although few data are available, our recent research provides indirect support on the potential for nonaddictive nicotine levels at or below 0.5 mg/g. We recently conducted studies with Spectrum research cigarettes obtained from NIDA that allow different fixed amounts of moderate and very low filler nicotine contents (ranging from 0.4 to 13 mg/g), to assist FDA by indirectly estimating an addiction threshold. After developing and evaluating a procedure for assessing ability to discriminate nicotine via tobacco cigarettes,6 our research assessed the threshold for ability to discriminate moderate to low nicotine cigarettes from the lowest available nicotine cigarette content, or 0.4 mg/g (“ultra-low”). Discrimination testing involved comparing this lowest content cigarette, 0.4 mg/g, with each of the higher nicotine content cigarettes, followed by a “choice” test as to which cigarette they preferred to smoke (ie, self-administered). Note the 0.4 mg/g was the lowest available because a policy to decrease content to zero, that is “placebo” cigarette, is currently prohibited by law.1 Such formal drug discrimination research, used in preclinical and clinical studies, objectively tests whether individuals can reliably perceive differences between psychoactive drug doses based solely on the resulting acute interoceptive stimulus effects.7 This assessment is potentially very relevant to helping identify a threshold dose for addiction, as it is unlikely that a very low dose that cannot be discriminated by smokers will support the onset or persistence of dependence2,5; smoked products virtually free of nicotine (eg, herbal) are not known to be reinforcing or cause dependence. In our studies, we found that the threshold nicotine cigarette able to be discriminated from the “ultra-low” 0.4 mg/g cigarette was also one reliably self-administered by smokers in the choice procedure, whereas the next lowest nicotine cigarette (“subthreshold”) was not self-administered more than chance. In other words, as hypothesized, cigarettes able to be discriminated were also reinforcing, and those unable to be discriminated were not reinforcing. Based on our research, only 5% of dependent smokers (and no nondependent smokers) were able to discriminate 1 mg/g from 0.4 mg/g nicotine (ie, Spectrum product codes NRC200/NRC201 vs. NRC102/NRC103,8 respectively), meaning 95% of smokers could not.9,10 Thus, because the “ultra-low” Spectrum research cigarette for comparison with this 1 mg/g contained 0.4 mg/g nicotine, not zero, a nicotine content below the threshold of virtually all smokers for discrimination and self-administration in comparison with a zero nicotine cigarette (which does not produce dependence) appears to be below 0.6 mg/g. Yet, further research explicitly assessing discrimination and self-administration of cigarettes at or below 0.6 mg/g versus zero nicotine is necessary to confirm a nicotine content that cannot be discriminated from a true “placebo” cigarette in at least 95% or more of dependent and nondependent smokers. If so, setting a maximum nicotine content at that level would greatly reduce the risk for nicotine addiction in the vast majority of smoked tobacco users. In sum, although further research is needed,5 our results from nicotine discrimination and self-administration studies support FDA’s interest in a possible threshold in cigarettes for dependence of “0.3, 0.4, and 0.5 mg nicotine/g.”1 Funding This study was supported by National Institutes of Health (NIH) research grant DA 035968. Views expressed are those of the author and do not represent the position of NIH or Food and Drug Administration (FDA). Declaration of Interests None declared. References 1. Food and Drug Administration. Tobacco Product Standard for Nicotine Level of Combusted Cigarettes: A Proposed Rule . 2018: 11818– 11843. Document citation 83 FR 11818. Document number no. 2018–05345. https://www.federalregister.gov/documents/2018/03/16/2018–05345/tobacco-product-standard-for-nicotine-level-of-combusted-cigarettes. Accessed March 16, 2018. 2. Benowitz NL, Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. Tob Control . 2013; 22( suppl 1): i14– i17. Google Scholar CrossRef Search ADS PubMed 3. Apelberg BJ, Feirman SP, Salazar E, et al. Potential public health effects of reducing nicotine levels in cigarettes in the United States. N Engl J Med . 2018; 378. doi:10.1056/NEJMsr1714617. 4. World Health Organization. Advisory Note: Global Nicotine Reduction Strategy. WHO Study Group on Tobacco Product Regulation . Geneva, Switzerland: WHO Press; 2015. 5. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK. Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev . 2009; 18( 12): 3241– 3262. Google Scholar CrossRef Search ADS PubMed 6. Perkins KA, Kunkle N, Michael VC, Karelitz JL, Donny EC. Assessing discrimination of nicotine in humans via cigarette smoking. Nicotine Tob Res . 2016; 18( 9): 1830– 1836. Google Scholar CrossRef Search ADS PubMed 7. Glennon RA, Young R. Drug Discrimination: Application to Medicinal Chemistry and Drug Studies . New York, NY: John Wiley & Sons; 2011. Google Scholar CrossRef Search ADS 8. Richter P, Pappas RS, Bravo R, et al. Characterization of SPECTRUM variable nicotine research cigarettes. Tob Reg Sci . 2016; 2( 2): 94– 105. Google Scholar CrossRef Search ADS 9. Perkins KA, Kunkle N, Karelitz JL, Perkins KA, Kunkle N, Karelitz JL. Preliminary test of cigarette nicotine discrimination threshold in non-dependent versus dependent smokers. Drug Alcohol Depend . 2017; 175(1): 36– 41. Google Scholar CrossRef Search ADS 10. Perkins KA, Kunkle N, Karelitz JL. Threshold dose for behavioral discrimination of cigarette nicotine content in menthol vs. non-menthol smokers. Psychopharmacology (Berl) . 2017; 234( 8): 1255– 1265. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Nicotine and Tobacco Research – Oxford University Press
Published: Apr 6, 2018
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