Cigarette smoking is one of the foremost causes of preventable disease and premature death (1–5). According to the World Health Organization (WHO), in 2020, 22.3% of the global population used tobacco (6). Nicotine is a highly addictive chemical compound (7) in tobacco and is released directly in the mesolimbic dopamine pathways where reward processing takes place (8). In 2014, 68% of US adult smokers wanted to quit smoking and in 2017, 55.1% of US adult smokers had made an attempt to quit smoking (9–11). However, only a small percentage of adult smokers (7.4%) actually achieved to quit smoking (11). To support smokers in smoking cessation, behavioral, psychological and pharmacological interventions as well as nicotine replacement therapy are some of the most used interventions (12) with medium to low success rates (12, 13). Recently, there has been growing interest in new, alternative, and effective treatments for smoking cessation.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation therapy (14, 15) that delivers magnetic pulses to a brain region, inducing an electric current that can depolarize neurons and induce action potentials (14). Repetitive (r)TMS protocols have been found to have lasting effects on excitability that can either be (generally) inhibitory (1 Hz) or excitatory (10 Hz) in nature by engaging synaptic plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD) (16). Theta Burst Stimulation (TBS) is a more recent TMS protocol that delivers a comparable number of pulses in a very short time (17, 18). Two different patterns of TBS were developed: intermittent TBS (iTBS) and continuous TBS (cTBS) which generally increases and decreases cortical excitability, respectively (17).

The dorsolateral prefrontal cortex (DLPFC) is a frontal brain region that plays a crucial role in meso-cortico-limbic and serotonergic systems (19) and is involved in executive functions such as inhibitory control, as well as emotion regulation and decision making; processes modified by substance use and dependence (19–21). Mesolimbic dopamine reward circuits and frontoparietal networks are associated with craving and are activated by addictive drugs (22). Exposure to cigarette-related cues has been associated with activation in the DLPFC (23, 24). Smoking related cues provoke activation of these brain circuits of smokers (24, 25). The combination of rTMS with smoking related cues has been found to be more effective compared to the combination of rTMS alone (26).

Several lines of evidence support the efficacy of high frequency (HF)-rTMS over the left DLPFC in the reduction of nicotine craving and cigarette consumption (21, 24, 27) and cue-induced smoking craving (28). A recently published double blind RCT showed that HF-rTMS (20 Hz) over the left DLPFC for 10 daily sessions is effective in reducing cigarette consumption, craving, dependence as well as in improving anxiety and depressing symptoms (29). According to a recent systematic review, multiple target HF-rTMS may be effective in smoking cessation (21). Accelerated TMS (aTMS), is used increasingly in research and clinical practice and has been shown to be as effective as a standard TMS procedure (30–32). Recently, an accelerated, high-dose, iTBS protocol has shown promising results in patients with treatment resistant depression (33).

A growing body of research highlights the importance of determining the efficacy of TMS in neuropsychiatric disorders using randomized controlled trials (RCT) with placebo-controlled groups. Placebo effects in TMS are a very common phenomenon (34–37) and can have a big influence on the results of a study (38). Several studies indicated that the placebo effect may be a component of the therapeutic response to rTMS in neuropsychiatric disorders like major depressive disorder, and stroke rehabilitation (35, 37).

Considering current knowledge of the efficacy of iTBS in substance use disorders, we investigated in a double-blind randomized control trial efficacy of four iTBS sessions per day during five consecutive days over the left DLPFC in smoking cessation, using the Cool-B65 Active/Placebo (A/P) coil, an advanced coil that is designed to support true “double blinded” clinical trials. Moreover, we wanted to investigate whether the exposure to smoking-related cues during the rTMS treatment, compared to neutral cues impacts cigarette craving. We hypothesized that 20 sessions of accelerated theta burst simulation over the left DLPFC while exposed to smoking-related cues, would reduce cigarette consumption and cigarette cravings, accompanied by reduced stress and motivation to quit smoking to a greater extent than active stimulation combined with neutral cues and sham stimulation with smoking-cues.

The current study investigated the efficacy of a rapid accelerated iTBS therapy (four sessions per day for five consecutive days) combined with smoking related cues in smoking cessation. We hypothesized that an active TMS group that is exposed to smoking related videos during stimulation (TMS&S group) shows more improvement with regard to reducing their cigarette consumption and smoking craving compared to the group that receives sham stimulation while watching smoking-related videos (sham group), and to the group receiving active TMS while watching neutral videos (TMS&N group).

In contrast to these expectations, we however found that all conditions, including sham stimulation, were equally effective in reducing cigarette consumption, CO levels, smoking craving and nicotine dependence. Contrary to our expectations and to what is reported in the literature, active TMS combined with smoking related cues was not more effective than active TMS combined with neutral cues, not sham stimulation.

Most interestingly was the fact that our TMS intervention was highly effective in facilitating smoking cessation. Our participants in the active TMS conditions showed 80.7 and 82.59% decrease in cigarette consumption in TMS &N Group and TMS&S group respectively, and 56.38 and 47.59% reduction in nicotine craving in TMS &N Group and TMS&S group respectively. The number of cigarettes smoked per day was statistically significantly lower over time, from the baseline to the End of treatment of the fifth day. These results are consistent with previous TMS trials, which show that rTMS can significantly reduce cigarette consumption and nicotine craving (21, 24, 26). Surprisingly, our advanced placebo coil technology condition specifically designed to support true “double blinded” clinical trials showed to be equally effective in treating smoking cessation. Our participants in Sham group showed 79.1% decrease in cigarette consumption and 59.34% reduction in nicotine craving. A similar reduction in cigarette consumption was found in a recent RCT, where the reduction in the active group was 76.19% (27), although, contrary to our findings, a much smaller reduction in cigarette consumption was found in the sham group (35.29%). Similarly, participants in all conditions showed huge reductions in CO scores (TMS&N group: 62.01%, TMS&S group: 53.42%, Sham group: 61.29%).

We were thus able to show, that, especially when using such an advanced double blind placebo stimulation technology, the placebo effect of TMS in clinical context can be considerably large and even equal to the effect achieved with active TMS stimulation. Placebo effects in TMS are known to be playing a certain role on the clinical results obtained with TMS and have been documented before (35–38). There are several factors that contribute to the enhancement of placebo effect in rTMS studies (38, 48). A systematic review and meta-analysis by Razza et al. (37) evaluated the efficacy of rTMS for depression using data from a sham group of 61 RCTs, concluding that placebo effect sizes in depression trials are rather large (g = 0.8). Previous studies also demonstrated that placebo effects may be a component of the therapeutic response to rTMS (35, 37). The placebo effect was also shown to be larger in more intense TMS protocols [HF rTMS (48)] and especially accelerated protocols (49).

We therefore support that several specific factors not directly associated with rTMS treatment have contributed to the enhanced placebo effect found in the present study. First, our participants were highly motivated to quit smoking. Our data clearly indicate that already at day 1 and 2 during the treatment cycle, a strong effect of both, active and placebo TMS, was revealed. The timeline of these effects indicate that this is likely driven more by the motivation and expectation of our participants rather than by actually induced neuroplastic changes. Second, we used an intensive and state-of-the art TMS design, applying accelerated TMS with multiple sessions per day using theta burst stimulation sequences. It has been shown before that placebo effects scale with the intensity and complexity of the used TMS technology (48, 49). Finally, we used an advanced placebo coil technology capable of creating a true double blind clinical trial and an undistinguishable experience for each participant whether or not to be in a placebo or active stimulation condition. Unlike previous TMS studies, we did not use a simple coil tilting procedure (50), or a standard sham coil (51) to achieve our placebo condition. Instead, we used a novel and advanced placebo coil technology capable of mimicking not only the visual and auditory experience of active TMS, but also the somatosensory skin sensation using a low intensity current stimulator built into the A/P coils and a pair of surface electrodes placed just below the hairline on the scalp of each participant. These factors likely contributed to the fact that we do find our accelerated TMS intervention to be highly effective in reducing cigarette consumption and smoking craving, but not significantly more effective than placebo. The actual effect of our active rTMS had to show statistically to be on top of the highly effective placebo condition, which turned out to be not the case in our trial due to the factors mentioned above.

Additionally, our results demonstrated a statistically significant difference in perceived stress over time. However, due to the absence of a significant effects of the Group and the interaction effect between Time and Group, these results are inconclusive regarding the efficacy of active TMS in reducing perceived stress. Nevertheless, previous findings have shown that left DLPFC is a principal target of noninvasive brain stimulation techniques in regulating stress-related cognitive processes (52). It was reported in the literature that perceived stress may be a barrier to smoking cessation (53), and thus further investigation on the association of perceived stress and smoking cessation during rTMS treatment is required.

The follow up assessment proved that these positive effect in nicotine dependence and perceived stress, as measured by FTND, TCQ-SF and PSS-4, lasts at least 1 week after the End of treatment. The findings of this study have to be seen in light of some limitations. Firstly, we did not measure self-reported cigarette consumption after the fifth day of treatment and during the 1-week follow up. Another potential limitation is the absence of a fourth group receiving sham stimulation while watching neutral videos. Finally, we did not use any formal assessment of blinding efficacy.

Although future RCTs are necessary to validate these conclusions, the present study highlights the importance of placebo effects and the role of specific placebo coil technologies in evaluating the efficacy of TMS in any psychiatric and psychological contexts. This could be used to further improve the administration of TMS based interventions, both for designing better placebo conditions in clinical trials, as well as for utilizing TMS placebo for enhancing coping and other psychological strategies of patients during rTMS treatment (48).

Our findings show that active aiTBS combined with smoking related cues, is as effective as active aiTBS combined with neutral cues as well as placebo aiTBS in smoking cessation. These findings extend the results of previous studies indicating that rTMS therapy is associated with considerably large placebo effects and that these placebo effects may be further increased when using advanced placebo coil technology. These beneficial effects in reducing cigarette consumption and craving for smoking in this and previous studies are likely a combination between the active rTMS effect and the placebo TMS effect. Future RCTs using advanced placebo coil technology are needed to confirm these results. Finally, future studies should emphasize on how to minimize placebo effect on TMS treatment.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Cyprus National Bioethics Committee (EEBK/EΠ/2019/08). The patients/participants provided their written informed consent to participate in this study.

GM: conceptualization, methodology, formal analysis, data curation, writing—original draft, and project administration. PM: formal analysis, data curation, and writing—original draft. LP: formal analysis, data curation, and writing—review and editing. AS: conceptualization, methodology, participant recruitment, data collection, formal analysis, data curation, and writing—review and editing. TS: supervision and writing—review and editing. ATS: conceptualization, supervision, and writing—review and editing, and project administration. All authors agree with the contents of the manuscript and were fully involved in the study and preparation of the manuscript and have read the final version of the manuscript and have approved the submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.