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Cannabidiol Reduces Withdrawal Symptoms in Nicotine Dependent Rats Lauren C. Smith,1, 2 Lani Tieu,2 Ray Suhandynata,3 Brent Boom

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Cannabidiol Reduces Withdrawal Symptoms in Nicotine Dependent Rats Lauren C. Smith,1, 2 Lani Tieu,2 Ray Suhandynata,3 Brent Boom Cannabidiol reduces withdrawal symptoms in nicotine dependent rats Lauren C. Smith,1, 2 Lani Tieu,2 Ray Suhandynata,3 Brent Boomhower, 2 Melissa Hoffman,3 "adira Sepulveda,$ Jeremiah D. Momper,$ Robert Fitzgerald,3 Kate Hanham,+ Joseph &owling,+ Marsida Kallupi, *1, 2 and Olivier George., 1, 2 1Department of Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La ol!a, CA 92037 %Department of Psychiatry, University of Ca!ifornia, San Diego School of Medicine, San Diego, "# 92093 &Department of Pathology, University of Ca!ifornia, San Diego School of Medicine, San Diego, "# 92093 ,Division of Pharmaceutica! Sciences, University of Ca!ifornia, San Diego Skaggs School of Pharmacy and Pharmaceutica! Sciences, La Jol!a, CA 92093 5". Sciences, Inc., 10070 Barnes Canyon Road, San Diego, CA 92121 *Correspondence to: mka!!upi1hea!th.ucsd.edu and olgeorge1hea!th.ucsd.edu 'unding and Disclosure This work was supported by the Nationa! Institute on Drug Abuse (grant no. 1F31D#047113-01 to L.C.S.), Nationa! Institute on A!cohol Abuse and A!coholism (grant no. ##022977 and A#006420 to O.G.), Tobacco-Re!ated Disease Research Program (grant no. 27IR-0047 to O.G.), Tobacco-Re!ated Disease Research Program (grant no. T31KT1859 to 1 +.K.) and CV science (9.G.). Joseph Dow!ing and Kate Hanham are CE9 and Acting Sr. VP of Deve!opment of C. Sciences, Inc. The authors would like to thank Mol!y Brennan, Sharona Sedighim, Liese!ot Carrete, Hassiba Be!djoud and Nathan Ve!arde for providing he!p with the study. /uthor Contributions +;, O:, K=, and JD designed the experimentA LCS and LT performed the behaviora! experiments, nicotine and cotinine blood extraction. LCS and M; ana!yzed the data and prepared the manuscript and figures. YS performed L"+S ana!ysis of nicotine and cotinine serum leve!s, JD+ supervised and interpreted nicotine and cotinine serum leve! determinationsA RS, M=, and R5 deve!oped the isotope di!ution L"E+SE+S assay for quantifying CBD in blood specimensA M; and O: edited the manuscript and figures. A!! authors approve the fina! version of the manuscript. 2 /bstract Rationale: Cannabidiol (CBD) reduces craving in anima! mode!s of a!cohol and cocaine seeking and is kno2n to modulate nicotinic receptor function, suggesting that it may a!!eviate symptoms of nicotine withdra2a!A however, prec!inica! eva!uation of its eGcacy is sti!! lacking. Objectives: The goa! of this study was to test the prec!inica! eGcacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdra2a! symptoms inc!uding somatic signs, hypera!gesia, and weight gain during acute and protracted abstinence. Methods: Ma!e and fema!e Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 m*E-*Eday) for t2o weeks, after which minipumps were removed to induce spontaneous withdra2a!. Three groups received CBD injections at doses of 7.5, 15, and 30 m*E-*Eday for t2o weeks, starting one wee- into chronic nicotine infusion. The control groups inc!uded rats with nicotine minipumps that received vehic!e injections of sesame oi! instead of CBDA rats implanted with sa!ine minipumps that received sesame oi! injections (double vehic!e7 or the highest dose of CBD 30m*E-*Eday. Throughout the experiment, serum was col!ected for determination of CBD and nicotine concentrations, mechanica! sensitivity threshold and 2ithdra2a! scores were measured, and body weight was recorded. Results: CBD prevented rats from exhibiting somatic signs of withdra2a! and hypera!gesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a cei!ing eIect at the doses used and the potentia! for lower eIective doses of CBD. The sa!ine minipump group did not show either somatic signs of withdra2a! or hypera!gesia during acute and protracted abstinence, and the highest dose of CBD used (30m*E-*Eday) did not a!ter these results. 3 Conclusions: This prec!inica! study suggests that using CBD as a strategy to a!!eviate the 2ithdra2a! symptoms upon nicotine6cessation may be beneCcia!. *eywords: CBD, tobacco, addiction, treatment, abstinence, withdra2a! 1ntroduction Nicotine abuse through tobacco smoking is the leading cause of preventa3!e death in the (nited States, with an annua! loss of life of about 500,000 4Harren, A!berg et a!. 2014). Despite the dec!ining rates of combusti3!e cigarette smoking in the last 50 years, the use of e!ectronic cigarettes containing nicotine is drastica!!y increasing 4Harren, A!berg et a!. 2014). In addition to the rise in e!ectronic cigarette use, the popularity of ora! smoke!ess tobacco products, such as che2a3!e tobacco, or "snuff," remains high in some parts of the world, such as South East Asia 4;han, Farooq et a!. 2020). To date, the most eIective pharmacologica! approach to smoking cessation is the administration of varenic!ine (Chantix), a nicotinic acetylcholine receptor agonist, which has a ~23% cessation rate in c!inica! studies (Prochaska and BenowitB 2016) (StitBer and Gross 1988). Nicotine withdra2a! is characteriBed by somatic (tremors, bradycardia, gastrointestina! discomfort, s!eep disturbances, and increased appetite7, aIective (craving, insomnia, anxiety, anhedonia, depression, dysphoria, hypera!gesia, and irritabi!ity) and cognitive symptoms (StitBer and Gross 1988, Cohen, Pic-2orth et a!. 1991, McLaughlin, Dani et a!. 2015). Other methods of cessation approved by the U.S. Food and Drug Administration (FD#) inc!ude nicotine replacement therapy and bupropion (Prochaska and BenowitB 2016). 4 Cannabidiol (CBD) is one of the phytocannabinoids found in the cannabis plant and is be!ieved to be non-psychoactive whi!e producing anxiolytic, antipsychotic, and neuroprotective, eIects 4#!vareB, Lafuente et a!. 2008, Zuardi 2008). CBD a!so decreases neurona! hyperexcita3i!ity in epi!epsy, and in 2018, the FD# approved the use of Epidiolex, a CBD oi! extract administered ora!!y, for the treatment of Dravet and Lennox-Gastaut syndromes, t2o rare forms of epi!epsy (2018). In both epi!epsy and nicotine withdra2a!, there is prominent neurona! hyperexcita3i!ity, a!beit lower with withdra2a!, suggesting that CBD may potentia!!y improve 2ithdra2a! symptoms. CBD has a!so been found to modulate the nicotinic, opioid, serotonin, and endocannabinoid systems (Russo, Burnett et a!. 2005, Kathmann, F!au et a!. 2006, Thomas, Bai!!ie et a!. 2007). When nicotine dependent rats undergo spontaneous withdra2a! and protracted abstinence, they exhibit dysregulation of endocannabinoids in the amygda!a, hypotha!amus, and hippocampus (Cippite!!i, Astarita et a!. 2011). Severa! studies have sho2n that chronic administration of cannabinoid receptor modulators like CBD can a!ter endocannabinoid receptor leve!s in the centra! nervous system 4:onza!eB, Cebeira et a!. 2005). 5urthermore, CBD has been found to inhibit the 7 nicotinic acetylcho!ine receptor 4+ahgoub, ;eun-Hang et a!. 2013), which plays a role in the reinforcing eIects of nicotine 4+arkou and Paterson 2001). Interactions of endocannabinoids with the CB1 receptor are essentia! in mediating behaviors associated with addiction (S!oan, Gowin et a!. 2017). Fina!!y, chronic CBD treatment prevents re!apse to cocaine and a!cohol6seeking in rodents (Liput, Hamme!! et a!. 2013, :onza!eB6Cuevas, Martin-5ardon et a!. 2018, ViudeB6+artineB, Garcia6:utierreB et a!. 2018), and there is pre!iminary c!inica! observation suggesting that CBD may he!p reduce the number of cigarettes smoked in a day 4+organ, Das et a!. 2013). 5 =owever, there has been no eva!uation of CBD in a prec!inica! mode! of nicotine dependence, so here we sought to test the eIect of chronic CBD treatment on somatic signs of 2ithdra2a!, hypera!gesia, weight, and nicotine metabolite leve!s. Rats made dependent on nicotine using subcutaneous minipumps (3.15 m*E-*Eday) were treated dai!y with CBD for t2o 2eeks0 during the last week of nicotine exposure, and the first wee- of a3stinence. Rats were tested for symptoms of acute and protracted withdra2a! upon nicotine cessation, inc!uding physica! signs of withdra2a!, hypera!gesia, and body weight gain. Varying doses of CBD (0, 7.5, 15, and 30 m*E-*Eday) were tested to identify the lowest eIective dose and blood leve!s of CBD, nicotine, and cotinine were examined throughout the study. Materials and Methods Animals Histar rats (n = 84 [42 ma!es, 42 fema!esP7 weighing 250-275g (Charles River) 2ere purchased at seven weeks old. Rats 2ere housed t2o per cage 2ith (Te-!ad 7090, La36:rade Sani6chios, Envigo, WI) bedding and maintained on a 12/12h lightEdark cyc!e with ad libitum access to (Te-!ad 8604, La3 Rodent Diet, Envigo, WI) food and tap 2ater. Rats were handled for ten minutes dai!y for three days by the experimenter. A!! the procedures 2ere performed t2o hours into the dark cyc!e and 2ere approved by the University of Ca!ifornia, San Diego Institutiona! Anima! Care and Use Committee. Drugs Nicotine hydrogen tartrate (Sigma7 was dissolved in sa!ine (nicotine dose 3.15 m*E-*Eday) and brought to pH 7.4 with Na9= 1+. Osmotic minipumps (A!Bet AP 2ML2) were 6 C!!ed with 2 m! of the nicotine solution the night before surgery was performed. Cannabidiol (Noramco Inc) was dissolved in sesame oi! (Sigma7 for dai!y subcutaneous injection at the doses 0, 7.5, 15, and 30 m*Ekg. The higher dose of CBD used (30 m*E-*7 trans!ates to ~200 m*E-* in humans, which is recommended for CBD treatment of epi!epsy (P+ID0 30681657). Other groups have reported successful results of CBD at doses 15 and 30 m*E-* in anxiety like behavior in rats 4P+ID0 29686308) Treatment with CBD was performed for 14 consecutive days using sesame oi! (Sigma7 as a control.
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