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Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats

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Abstract

Rationale

Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking.

Objectives

The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence.

Methods

Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded.

Results

CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose–response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results.

Conclusions

This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.

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Acknowledgements

The authors wish to express their thanks to Molly Brennan, Sharona Sedighim, Hassiba Beldjoud, and Nathan Velarde for providing help with the study. The authors aknowledge the Preclinical Addiction Research Consortium at UCSD for supporting this project.

Funding

This work was supported by the National Institute on Drug Abuse (grant no. 1F31DA047113-01 to L.C.S.), National Institute on Alcohol Abuse and Alcoholism (grant no. AA022977 and AA006420 to O.G.), Tobacco-Related Disease Research Program (grant no. 27IR-0047 to O.G.), Tobacco-Related Disease Research Program (grant no. T31KT1859 to M.K.), and CV science (O.G.).

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Authors and Affiliations

  1. Department of Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, USA

    Lauren C. Smith, Marsida Kallupi & Olivier George

  2. Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA,, 92093, USA

    Lauren C. Smith, Lani Tieu, Brent Boomhower, Lieselot L. G. Carrette, Marsida Kallupi & Olivier George

  3. Department of Pathology, University of California, San Diego School of Medicine, San Diego, CA, 92093, USA

    Raymond T. Suhandynata, Melissa Hoffman & Robert L. Fitzgerald

  4. Division of Pharmaceutical Sciences, University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, 92093, USA

    Yadira Sepulveda & Jeremiah D. Momper

  5. CV Sciences, Inc., 10070 Barnes Canyon Road, San Diego, CA, 92121, USA

    Kate Hanham & Joseph Dowling

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  1. Lauren C. Smith
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  13. Olivier George
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Contributions

MK, OG, KH, and JD designed the experiment; LCS and LT performed the behavioral experiments, and nicotine and cotinine blood extraction. BB and LLGC performed the behavioral experiments, blood withdrawal, and data analysis. LCS and MK analyzed the data and prepared the manuscript and figures. YS performed LCMS analysis of nicotine and cotinine serum levels. JDM supervised and interpreted nicotine and cotinine serum level determinations; RS, MH, and RF developed the isotope dilution LC/MS/MS assay for quantifying CBD in blood specimens; MK and OG edited the manuscript and figures. All authors approve the final version of the manuscript.

Corresponding authors

Correspondence to Marsida Kallupi or Olivier George.

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Competing interests

Joseph Dowling and Kate Hanham are CEO and Acting Sr. VP of Development of CV Sciences, Inc.

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Smith, L.C., Tieu, L., Suhandynata, R.T. et al. Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats. Psychopharmacology 238, 2201–2211 (2021). https://doi.org/10.1007/s00213-021-05845-4

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