Augmenting varenicline treatment with transcranial direct current stimulation (tDCS) increases smoking abstinence rates at end of treatment

Tobacco smoking relapse is often associated with neuroadaptations such as desensitization of nicotine acetylcholine receptors [[1]Picciotto M.R. Addy N.A. Mineur Y.S. Brunzell D.H. It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.Prog Neurobiol. 2008; 84: 329-342Crossref PubMed Scopus (366) Google Scholar]. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, is currently the most effective pharmacotherapy for smoking cessation, however, long-term abstinence rates remain low [[2]Livingstone-Banks J. Fanshawe T.R. Thomas K.H. Theodoulou A. Hajizadeh A. Hartman L. et al.Nicotine receptor partial agonists for smoking cessation.Cochrane Database Syst Rev. 2023; 5: CD006103Google Scholar]. Given the emphasis of neuroplasticity in chronic tobacco use, the adjunctive use of neuromodulation techniques such as transcranial direct current stimulation (tDCS) can potentially target and reverse select neuroadaptations associated with tobacco smoking relapse. Previous studies show tDCS to modulate synaptic plasticity in human models of addictive motivation [[3]Kuo M.F. Chen P.S. Nitsche M.A. The application of tDCS for the treatment of psychiatric diseases.Int Rev Psychiatr. 2017; 29: 146-167Crossref PubMed Scopus (0) Google Scholar]. Further, studies of low (0.1 mg) and high (1 mg) single doses of varenicline combined with short-term adjunct tDCS over the left dorsolateral prefrontal cortex (DLPFC) demonstrate prolonged inhibitory plasticity in the motor cortex of healthy smokers under nicotine withdrawal [[4]Batsikadze G. Paulus W. Grundey J. Kuo M.F. Nitsche M.A. Effect of the nicotinic alpha4beta2-receptor partial agonist varenicline on non-invasive brain stimulation-induced neuroplasticity in the human motor cortex.Cerebr Cortex. 2015; 25: 3249-3259Crossref PubMed Google Scholar,[5]Batsikadze G. Paulus W. Hasan A. Grundey J. Kuo M.F. Nitsche M.A. Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic alpha4beta2-receptor partial agonist varenicline.Sci Rep. 2017; 7: 1387Crossref PubMed Scopus (0) Google Scholar]. Thus, there is a potential therapeutic additive effect of varenicline and adjunct tDCS through synergies affecting α4β2 neuroplasticity, however, this theory has not been investigated under the clinical treatment guidelines of varenicline for smoking cessation. In this pilot study, we examined the efficacy of tDCS to the left DLPFC as an adjunct to standard varenicline treatment (1 mg BID for 12 weeks) for smoking cessation. Participants (n = 41) were randomly assigned to active tDCS (n = 20) or sham tDCS (n = 21). In brief, participants received acute sessions (10 daily sessions over 2 weeks) of tDCS to the left DLPFC followed by five biweekly booster sessions over the remainder of varenicline treatment. Twenty-eight participants completed all study procedures: n = 12 in active tDCS group and n = 16 in sham tDCS group. Participant drop-out was attributed to COVID-19 restrictions. Full details of the study protocol have been previously published [[6]Zawertailo L. Zhang H. Rahmani N. Rajji T.K. Selby P. Active versus sham transcranial direct current stimulation (tDCS) as an adjunct to varenicline treatment for smoking cessation: study protocol for a double-blind single dummy randomized controlled trial.PLoS One. 2022; 17e0277408Crossref Scopus (0) Google Scholar]. Here we report several key findings on smoking quit rates, smoked cigarettes per day (CPD), and cigarette craving. First, the addition of active tDCS to standard varenicline treatment was associated with higher quit rates at the end of treatment compared to sham tDCS. Out of completers, the 7-day abstinence rates were significantly higher in the active tDCS group (n = 9/12) compared to sham (n = 6/16) (X2 [[1]Picciotto M.R. Addy N.A. Mineur Y.S. Brunzell D.H. It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.Prog Neurobiol. 2008; 84: 329-342Crossref PubMed Scopus (366) Google Scholar] = 2.7, p = 0.04) (Cohen's h = 0.6, 95% CI: −0.0012 to 0.61). Using last observation carried forward (LOCF) analysis, there was a trend for higher 7-day abstinence rates in the active tDCS group (n = 9/20) compared to sham (n = 6/21) (X2 [[1]Picciotto M.R. Addy N.A. Mineur Y.S. Brunzell D.H. It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.Prog Neurobiol. 2008; 84: 329-342Crossref PubMed Scopus (366) Google Scholar] = 1.2, p = 0.1) (Fig. 1a). Out of completers, a trend for higher 30-day continuous abstinence was also observed for the active tDCS group (n = 8/12) compared to sham (n = 6/16) (X2 [[1]Picciotto M.R. Addy N.A. Mineur Y.S. Brunzell D.H. It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.Prog Neurobiol. 2008; 84: 329-342Crossref PubMed Scopus (366) Google Scholar] = 1.5, p = 0.12). Using LOCF analysis, there was no significant difference in 30-day continuous abstinence between the groups (X2 [[1]Picciotto M.R. Addy N.A. Mineur Y.S. Brunzell D.H. It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.Prog Neurobiol. 2008; 84: 329-342Crossref PubMed Scopus (366) Google Scholar] = 0.6, p = 0.4) (Fig. 1b). Second, there was a decrease in reported CPD over time in both groups (F = 595.32, p < 0.0001), with a main effect of tDCS group on CPD (F = 9.69, p = 0.02) but no group × time interaction (F = 2.16, p = 0.14) (Fig. 1c). Lastly, there was a decrease in nicotine craving, measured by the brief Questionnaire of Smoking Urges (QSU), over time in both groups (F = 1728.69, p < 0.0001), with a trend for main effect of tDCS group on craving (F = 3.26, p = 0.07), but no group × time interaction (F = 1.46, p = 0.23) (Fig. 1d). Findings from this pilot study support the use of adjunct tDCS to the left DLPFC with standard 12-week clinical treatment of varenicline for smoking cessation. One of the key strengths of the present study was its novel treatment paradigm of using pharmacotherapy with an adjunct brain stimulation technique as a more comprehensive treatment for tobacco dependence. The main neuroplastic effects of prolonged anodal tDCS is its ability to increase excitatory plasticity similar to long-term potentiation (LTP) across different cortical areas [[7]Kuo M. Nitsche M.A. tDCS-Pharmacotherapy Interactions.in: Brunoni A.R. Nitsche M.A. Loo C.K.e. Transcranial direct current stimulation in neuropsychiatric disorders. Springer, Cham2021Crossref Scopus (1) Google Scholar]. However, previous studies demonstrate diminished LTP-like plasticity of anodal tDCS and reduced cognitive abilities in smokers under nicotine withdrawal [[7]Kuo M. Nitsche M.A. tDCS-Pharmacotherapy Interactions.in: Brunoni A.R. Nitsche M.A. Loo C.K.e. Transcranial direct current stimulation in neuropsychiatric disorders. Springer, Cham2021Crossref Scopus (1) Google Scholar]. This withdrawal-related impaired plasticity can be reversed by activating nicotinic acetylcholine receptors through nicotine or varenicline [[7]Kuo M. Nitsche M.A. tDCS-Pharmacotherapy Interactions.in: Brunoni A.R. Nitsche M.A. Loo C.K.e. Transcranial direct current stimulation in neuropsychiatric disorders. Springer, Cham2021Crossref Scopus (1) Google Scholar]. This combination of varenicline and tDCS may help maintain smoking abstinence while addressing the neuroplastic changes produced by chronic tobacco use. Interestingly, we found no measurable effect of active tDCS on cigarette craving compared to sham, although there was a significant decrease of craving over the course of treatment. Since both active and sham tDCS groups received varenicline treatment, these findings may be attributed to the effectiveness of varenicline itself on craving reduction. Previous research highlights that 2 weeks of varenicline treatment is associated with about 40% reduction in craving [[8]Brandon T.H. Drobes D.J. Unrod M. Heckman B.W. Oliver J.A. Roetzheim R.C. et al.Varenicline effects on craving, cue reactivity, and smoking reward.Psychopharmacology (Berl). 2011; 218: 391-403Crossref PubMed Scopus (0) Google Scholar]. This craving reduction is similar to what was observed in the present study, suggesting tDCS may have little to no additive effects on craving reduction. Several of our findings were trending which can be partially attributed to the small sample size due to COVID-19 disruptions. One third of the sample were unable to complete the study, thus we were underpowered to detect significant differences in smoking quit rates at 30-day continuous abstinence and cigarette craving between the groups at end of treatment. Further, the current study did not have a varenicline monotherapy group to disentangle the effects of varenicline from the effects of tDCS. Future studies would address these limitations by including a varenicline monotherapy group and a larger sample size. In conclusion, findings of this pilot study suggest the superior efficacy of adjunct tDCS anodal stimulation to the left DLPFC with standard varenicline treatment for smoking cessation. The treatment combination was well-tolerated and significantly decreased cigarette consumption but did not have an effect on subjective nicotine craving. While the study was underpowered, our observed effect size between active vs sham (h = 0.6) strongly supports the need for future smoking cessation trials using adjunctive tDCS treatment paradigms for improving smoking cessation outcomes, thereby decreasing the burden of smoking-related diseases. Helena Zhang: Formal analysis, Investigation, Data curation, Writing – original draft, Visualization. Tarek Rajji: Methodology, Writing – review & editing. Peter Selby: Methodology, Writing – review & editing. Osnat Melamed: Resources, Writing – review & editing. Sophia Attwells: Writing – review & editing, Visualization. Laurie Zawertailo: Conceptualization, Methodology, Resources, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work. PS reports receiving funding and/or honoraria from Pfizer Inc./Canada, Shoppers Drug Mart, Bhasin Consulting Fund Inc., Patient-Centered Outcomes Research Institute, ABBVie, and Bristol-Myers Squibb; LZ receives support from Pfizer Global Research Awards in Nicotine dependence (GRAND) Award Program; there are no other relationships or activities that could appear to have influenced the submitted work. HZ, TK and OM have no conflicts of interests to declare. This research is funded by Global Research Awards for Nicotine Dependence (GRAND), a peer-reviewed research grant competition funded by Pfizer Inc (Zawertailo WS2391913). Pfizer Canada, the Canadian operation of Pfizer Inc, is located in Kirkland, Quebec, Canada (Telephone: 514-695-0500). The study sponsor did not have any role in the design, collection, management, data analysis, nor writing of the report. They did approve of the report for publication. The research personnel had the ultimate authority for all the aforementioned activities. The PI, delegates and investigators are completely independent from the funder and thus we do not have a Data Monitoring Committee. However, the CAMH Research Ethics Board will audit trials on a random basis.

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