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Threshold dose for intravenous nicotine self-administration in young adult non-dependent smokers

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Abstract

Rationale

Reducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies.

Objectives

The current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure.

Methods

Young adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo.

Results

Mixed effect models revealed a significant effect of nicotine dose for positive (i.e., “stimulatory” and “pleasurable”; p < .0001) effects, but not “aversive” effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03–.05).

Conclusions

Using our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

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Acknowledgements

The authors thank Ms. Haleh Nadim for measurements of nicotine and cotinine.

Funding

This work was funded by a US Department of Veteran Affairs Career Development Award, Mental Illness Research Education Clinical, Centers (MIRECC), and NIDA/NIH and FDA Center for Tobacco Products (CTP) R01 DA042528 (MS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the FDA.

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA

    R. Ross MacLean, Elise E. DeVito, Suprit Parida & Mehmet Sofuoglu

  2. VA Connecticut Healthcare System, 950 Campbell Ave., Bldg. 36/116A4, West Haven, CT, 06516, USA

    R. Ross MacLean, Suprit Parida & Mehmet Sofuoglu

  3. Department of Laboratory Medicine, School of Medicine, Yale University, New Haven, CT, USA

    Tore Eid

  4. Department of Biostatistics, Yale University School of Public Health and School of Medicine, New Haven, CT, USA

    Ralitza Gueorguieva

Authors
  1. R. Ross MacLean
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  2. Elise E. DeVito
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  3. Tore Eid
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  4. Suprit Parida
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  5. Ralitza Gueorguieva
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  6. Mehmet Sofuoglu
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Correspondence to Mehmet Sofuoglu.

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MacLean, R.R., DeVito, E.E., Eid, T. et al. Threshold dose for intravenous nicotine self-administration in young adult non-dependent smokers. Psychopharmacology 238, 2083–2090 (2021). https://doi.org/10.1007/s00213-021-05833-8

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  • DOI: https://doi.org/10.1007/s00213-021-05833-8

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