Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats

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.

Keywords: Abstinence; Addiction; CBD; Tobacco; Treatment; Withdrawal.

Figure 1.. CBD reduces nicotine cessation-induced somatic signs of withdrawal.

A) Experimental timeline and group design; B) Somatic signs of withdrawal during acute withdrawal. C) Somatic signs of withdrawal during protracted abstinence (***p < 0.001, from vehicle, #p < 0.05 from CBD 0). Error bars represent the SEM of the mean (n = 12 [6 male, 6 female]).

Figure 2.. CBD prevents nicotine cessation-induced hyperalgesia.

A) Experimental timeline and group design; B) Pain threshold as percent (g) of baseline during acute withdrawal. C) Pain threshold as percent (g) of baseline during protracted abstinence (*p < 0.001, from vehicle, #p < 0.05 from CBD 0). Error bars represent the SEM of the mean (n = 12 [6 male, 6 female]).

Figure 3.. CBD prevents weight gain during acute withdrawal but not protracted abstinence.

A) Experimental timeline and group design; B) Body weight as percent (g) of nicotine minipump timepoint from the minipump (M) to acute withdrawal (W) timepoints (*p < 0.05, from vehicle). C) Body weight as percent (g) of nicotine minipump timepoint from the acute withdrawal (W) to the protracted abstinence (A) timepoints (*p < 0.05 and ***p < 0.001, from vehicle). Data is represented as individual rats (n = 12 [6 male, 6 female]).

Figure 4.. CBD reduces serum nicotine metabolite levels.

A) Experimental timeline and group design; B) Serum nicotine concentration during the nicotine minipump timepoint for the CBD 0 and CBD 30 groups. C) Serum cotinine concentration during the nicotine minipump timepoint for the CBD 0 and CBD 30 groups (*p < 0.05). Error bars in B and C represent the SEM of the mean (n = 6 [3 male, 3 female]); D) Serum CBD concentration time course after a single injection (s.c.) of 30 mg/kg CBD in sesame oil. Error bars represent the SEM of the mean (n = 3 [1 male, 2 female]); E) Serum CBD concentration for the CBD 30 group during the acute withdrawal and protracted abstinence timepoints. Error bars represent the SEM of the mean (n = 12 [6 male, 6 female]).

Figure 5.. CBD does not alter the behavior in the saline minipump group.

A) Experimental timeline and group design; B) Somatic signs of withdrawal during acute withdrawal. C) Somatic signs of withdrawal during protracted abstinence. D) Pain threshold as percent (g) of baseline during acute withdrawal. C) Pain threshold as percent (g) of baseline during protracted abstinence. F) Body weight as percent (g) of nicotine minipump timepoint from the acute withdrawal (W) to the protracted abstinence (A) timepoints (*p < 0.05). All data is represented as individual rats (n = 12 [6 male, 6 female]). E) Serum CBD concentration for the CBD 30 group during the acute withdrawal and protracted abstinence timepoints. Error bars represent the SEM of the mean (n = 5 [3 male, 2 female]).