Accelerated Intermittent Theta Burst Stimulation in Smoking Cessation: A Randomized Controlled Study
Phase: NA
Conditions: Nicotine Dependence, Smoking Cessation
Sponsor: Cyprus rTMS Center

 
 
Repetitive Transcranial Magnetic 
Stimulation as a Treatment Option for 
Smoking Cessation 
 
 
NCT05271175 
 
Date: March 28, 2019 
 
 

Objectives 
This study aims to investigate whether repetitive transcranial magnetic (rTMS) stimulation over 
the left dorsolateral prefrontal cortex (DLPFC) decreases craving and increases quitting success 
from smoking in tobacco smokers who wish to quit. This project will also examine whether 
presentation of provocative visual cues during brain stimulation may produce improved results in 
reducing craving of smoking as compared to brain stimulation alone. 
 
Introduction 
The World Health Organisation (WHO) suggests that smoking is responsible for approximately 
six million deaths each year1. Smokers are at greater risk for heart and blood vessel diseases2,3. In 
addition, smoking causes strokes and coronary heart disease which are the leading causes of death 
in the United States2,3. Additionally, individuals smoking less than 5 cigarettes per day could be 
affected by early signs of cardiovascular diseases2,3. Lung diseases caused by smoking include 
emphysema and chronic bronchitis2,3. Further, smoking causes different types of cancer such as 
lung, bladder, oesophagus, liver, pancreas and stomach cancer2,3. Individuals who quit smoking 
sharply, cut their cardiovascular risk after one year and decrease the risk of a heart attack3. Within 
2-5 years of quitting, the risk of stroke may reduce to about the same for non-smokers3. Smoking 
cessation decreases the risk for cancers of the mouth, throat, oesophagus, and bladder drop by half 
within 5 years3. Ten years after smoking cessation, the risk for lung cancer drops by half3. Due to 
these and other health risks which were shown to be directly linked to smoking, a global target 
was announced aiming to reduce the current prevalence of tobacco use in individuals aged 15 and 
above, by 30%. In Cyprus, the estimated rate of smoking reached 31% in 2005, making it one of 
the countries with the highest rates in tobacco consumption. While many smokers desire to quit 
smoking, only 4-7% of them succeed in quitting smoking without supportive treatment5. 
 
Several studies have proposed different therapies for quitting smoking. Such therapies include 
counselling therapies6,7,8 and pharmaceutical treatments with the use of products such as the 
nicotine replacement therapy bupropion (Zyban) and varenicline (Chantix)9,10,11,12,13,14. However, 
the majority of those attempting to quit smoking are most likely to relapse, as success of such 
methods is deemed modest. Due to the failure of the current licensed therapies offered for smoking 
cessation to sustain the initial effect and the fact that patients present high chances of relapse, there 
is a need to identify new therapeutic approaches. It is essential that such approaches should be 
related to physiological brain processes, with the aim of understanding, and therefore 
implementing therapies that are successful beyond immediate behavioural change. Such therapies 
should ideally directly target brain networks associated with nicotine craving and addiction such 
as cognitive control and reward processing brain regions.  
 
Tobacco addiction has been linked with the mesolimbic dopaminergic system since the early 90s’ 
in studies that tried to elucidate the role of tobacco addiction in vitro31. Later studies indicated that 
brain stress systems play a critical role in tobacco addiction. Smoking as well as smoking cessation 
affect the regulation of the HPA axis. On one hand, smoking leads to increased release of cortisol 
and adrenocorticotropic hormone, (a hormone which is produced in the frontal, anterior and 
pituitary gland of the brain), as well as upregulation and desensitization of nicotinic acetylcholine 
receptors (nAChRs). It is suggested that the excessive number of responsive nAChRs may 
contribute to cigarettes’ craving and relapse31. However, it is important to note that the effects of 
nicotine in the brain at the molecular level differ from the effects that amphetamines and cocaine 

addictions have, and it is vital to understand such differences which may contribute in their better 
understanding and in potential therapies. At the cellular and system level, tobacco addiction is 
highly associated with excessive dopamine projections and overflow specifically in structures of 
the nucleus accumbens, namely the core and the median shell32.   
 
Over the last ten years, neuroscience has advanced in a level that has allowed researchers to 
implement methods for diagnosis and treatment of various disorders on brain system level. 
Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive safe treatment option for 
a variety of neuropsychiatric disorders which has received FDA approval for Depression15 and 
Obsessive Compulsive Disorder16. Neuromodulation interventions with the use of TMS also 
appear as a promising approach in treating addictions29. The effect of TMS would ideally be to 
affect brain circuits by inducing neuroadaptations in the cortico-mesolimbic dopamine system, and 
in the glutamatergic corticolimbic circuitry where dopamine projections are entrenched19,20,21. A 
review on nine studies focussing on addictions (tobacco, alcohol, cocaine and methamphetamine) 
investigated outcomes of TMS treatment. Most of the studies applied high frequency (5-20 Hz) 
rTMS over the left DLPFC. While the underlying mechanism was poorly understood, it was 
suggested that it may involve dopamine and glutamate function in the cortico-mesolimbic brain 
circuits and modulation of neuronal activity that mediate cognitive process related to addiction. In 
this review, support of craving was suggested for nicotine, and in some participants, significant 
reduced cigarettes consumption was observed. However, changes in craving were not always 
consistent with decreased smoking30. 
 
A study by Amiaz and colleagues in 2009, suggested that applying TMS on the left DLPFC at high 
frequency, could offer an innovative treatment option for tobacco dependency22. The intervention 
included ten daily sessions over the left DLPFC, 20 trains per day at 100% of motor threshold. 
Each train consisted of 50 pulses at 10 hz with an inter-train interval of 15 seconds. Amiaz 
investigated the presentation of smoking cues on cigarette consumption, dependence and cravings. 
A series of 14 pictures were presented to the subjects immediately before the administration of the 
TMS. Cigarette consumption was measured subjectively through self-report. Craving levels were 
assessed with the visual analogue scale prior and following the presentation of the visual cues 
every day. Active TMS was found to signiﬁcantly reduce both cigarette consumption and nicotine 
dependence compared to sham stimulation. Additionally, it has been suggested that if rTMS is 
delivered to the left dorsolateral prefrontal cortex, it could affect decision making which 
corresponds to addiction and craving18. On high frequency at 10 hz (24 trains, 5s per train, 25s 
inner train-interval 1200 pulses with 11.6 minutes, 90% MT) rTMS stimulation of the DLPFC, 
Jürgen Pripfl33 and colleagues demonstrated in 14 healthy smokers on cue-induced nicotine 
craving and resting-state EEG that the rTMS stimulation had an effect on reducing nicotine craving 
in short term abstinent smokers, with changes in delta activity. This study has supported the idea 
that stimulation induce effects are mediated by the dopaminergic brain reward system making it a 
potentially promising treatment for smoking cessation. The DLPFC of addicted individuals has 
been associated with the experience of craving23,24,25, induced by substance-related cues for 
nicotine26,27,28. For instance Brody and colleagues (2002) found activation in the DLPFC in “heavy 
smokers” when exposed to cigarette-related cues compared with non-smokers. Xingbao Li35 has 
suggested that even one session of high-frequency rTMS (10 Hz) on the left DLPFC can 
significantly reduce subjective craving induced by smoking cues in nicotine-dependent 
participants. Further, an fMRI study has suggested that expectancy of smoking following the brain 

scan, induced activation in areas that usually correspond to arousal, attention and cognitive control 
while in participants where smoking was not allowed after the brain scan, such activation was non-
existent in response to smoking cues26. It is therefore important that craving induced cues are 
present; however most studies use such cues prior to the task or treatment. Further, there is no 
systematic study comparing a condition of rTMS without an external craving cue, versus a 
condition of rTMS in combination with a smoking craving cue at the time of treatment. So, it 
would be interesting to investigate whether craving induced cues during rTMS treatment could 
produce similar results to studies that used a smoking craving cue prior to treatment, comparing it 
with rTMS at rest, without a smoking craving cue, where treatment will not be dependent to the 
smoking cue. Finally, across studies on smoking cessation, it has been reported that researchers 
have used breath carbon monoxide (CO) cut-off values ranging from 4 to 10 ppm to define 
abstinence in cigarette-smoking cessation. It has been furtherly demonstrated by Murray Jarvik34 
that there is a negative correlation between blood nicotine levels and craving for cigarettes while 
carbon monoxide has shown to correlate significantly with nicotine blood levels.  
 
On the bases of previous research findings, in this study, we are going to compare tobacco cravings 
between three groups (two experimental and one control) of tobacco smokers that wish to quit 
smoking, after a five-day treatment of five 3-minute theta burst repetitive transcranial magnetic 
stimulation which will be applied over the left DLPFC. We hypothesize that: 
(A) The two experimental groups (group A that will receive real rTMS, four sessions per day of 
intermitted theta burst, for three minutes per session, for five consecutive days, while watching a 
smoking video as a cue for craving, and group B group that will receive real rTMS, four sessions 
per day of intermitted theta burst, for three minutes per session, for five consecutive days, with no 
presentation of the smoking video as a cue for craving, but presentation of a neutral video) will 
present lower craving scores in relation to their baseline measures, 
(B) The two experimental groups, (groups A and B) will present lower craving scores in relation 
to the placebo group (group C will receive sham rTMS four sessions per day of intermitted theta 
burst, for three minutes per session, for five consecutive days, while watching a smoking video as 
a cue for craving) after the end of rTMS treatment, 
(C) We investigate the difference between the presentation or absence of visual cue among the two 
experimental groups (group A and B that will both receive real rTMS, with the difference that 
group B will not be presented a smoking video as cue for craving) as to whether presentation or 
absence of stimuli influences outcome of craving scores. 
 
Method 
Participants 
 
Recruitment of participants will be done through public advertisements of the study, as participants 
belong in the healthy population. Individuals who agree to participate in this study will be 
volunteers. The minimum number of participants required was determined by an a priori power 
analysis where at least a sample size of 100 participants was suggested. (*Measures that suggested 
this sample size were determined by the mixed model, a small to medium effect size (0.4), at an 
alpha level of probability of 0.05).   
Inclusion criteria of participants will be: (a) to be native speakers of the Greek language, (b) to be 
over the age of 18, (c) to be tobacco dependent users that wish to quit smoking.  

Exclusion criteria of participants will be: (a) individuals with metallic parts inside or near the skull, 
(b) dependency of any other substances apart from nicotine and caffeine. 
For the purposes of this study, participants will be formed into three groups. The groups will be as 
described below:  
 
(A) An experimental group of 34 participants that satisfy all criteria for inclusion. This group will 
receive real rTMS, four sessions per day of intermitted theta burst, for three minutes per session, 
for five consecutive days, while watching a smoking video as a cue for craving; 
(B) An experimental group of 34 participants that satisfy all criteria for inclusion. This group will 
receive real rTMS, four sessions per day of intermitted theta burst, for three minutes per session, 
for five consecutive days, with no presentation of the smoking video as a cue for craving, but a 
neutral video; 
(C) A control group of 34 participants that satisfy all criteria for inclusion. This group will receive 
sham rTMS four sessions per day of intermitted theta burst, for three minutes per session, for five 
consecutive days, while watching a smoking video as a cue for craving. 
 
Design 
 
This is a randomized, double‐blind, sham‐controlled study. 
 
Procedure 
 
Prior to the study 
 
After advertisement of the study, potential participants will be able to contact the researcher via 
contact details that will be given on the advertisement. The researcher will then perform a 
screening interview (either by phone or email correspondence) regarding the eligibility of 
participants. The questions will include demographics and contact details: a) telephone number, b) 
email address, c) sex, d) education and occupation, e) age; and the screening will involve questions 
regarding eligibility: f) “how many cigarettes do you smoke per day?”, g) “for how long have you 
been a smoker?”, h) “has there been any period in your life that you managed to quit smoking; if 
yes for how long and how did you manage to do it?”, i) “are you dependant on any other substances 
e.g. alcohol/drugs/benzodiazepines apart from caffeine and nicotine”. These questions will be 
asked in Greek. If individuals meet the criteria and wish to continue, the researcher will arrange 
with participants details regarding their visit to the site.   
 
 
At the research site 
 
Participants will arrive at the Cyprus rTMS Centre, will receive all the required information about 
their participation, and if agreed, they will sign the consent form and will be led to the testing 
room. Participants will then complete three questionnaires on a PC, prior to the beginning of the 
experiment. The questionnaires are all described in Materials section and they are attached in the 
Appendix. All participants will undergo a breath carbon monoxide (CO) measure prior to each 
TMS session of each day with the use of a smokerlyzer. Further information about its use is 
described in the section below.  

 
The researcher will then take the appropriate head measures using the 10-20 system and then will 
place a cap on the participant’s head. The participant will sit on the TMS chair and the researcher 
will place the (real/sham) TMS coil on the participant’s left DLPFC and start the session. While 
participants will be receiving TMS, they will be presented with a smoking video as a cue for 
craving, throughout each TMS session (except for one group that they will not be presented with 
a cue craving video, but with a neutral video). There are two available videos, and those will be 
presented in a randomised manner for each participant. After each session, participants will have 
a forty-five minute break and then return for the next TMS session. Once done with all five days 
of TMS therapy, they will be again assessed with the three questionnaires.  
 
To protect personal data and for conditions to be double-blind (participants will not know whether 
they receive real or sham TMS and researcher will not know whether they administer real or sham 
TMS), participants will be pseudo-anonymised on an excel database and will be assigned in a 
randomised manner to each defined group. Demographic and personal data of participants will be 
confidential only to the researchers involved in the study and will be protected and handled 
according to the Data Protection Act 2018 and the ICH Good Clinical Practice for data protection. 
Recorded data of participants will include: demographic details, data of self-report questionnaires 
at baseline and follow up measures, and CO breath levels. 
   
Following TMS treatment  
Following the end of the rTMS treatment, participants will be contacted again to complete the 
three questionnaires. This will be done at one week, one month and six months post-TMS 
treatment.  
 
Materials 
 
Questionnaires 
 
The tools used in this study are three questionnaires: 
- The Fagerstrom Test of Nicotine Dependence (in Greek), 
- The Factor Structure of Tobacco Craving-Short Form (will be adjusted to Greek), 
- The Perceived Stress Scale (in Greek).  
These questionnaires will be administered to each participant prior to the first day of TMS 
treatment, after the last day of TMS treatment, after one week, after one month, and after six 
months. Participants will complete the questionnaires on a 14” laptop at baseline and first follow 
up, and then online during the remaining follow ups. The aim of the questionnaires will be to test 
for nicotine dependence, levels of craving, and screening for anxiety levels of participants at 
different time points. Those data will then be used for within and between participants’ analyses. 
Further, participants will be asked through a visual analogue scale ranked from 1-100 “How much 
do you want to smoke right now?”, prior and after each TMS session, as previously used by Revital 
Amiaz in similar methodology studies, to assess cue-induced craving of participants.  
 
 
Smokerlyzer 

 
Smokerlyzer is a non-invasive tool that measures the amount of CO on a smoker's breath and 
establishes smoking status biochemically. It will be used prior to each TMS session every day for 
each participant and its measures will be later used for analyses purposes.  
 
 
Craving Videos  
 
Two videos will be used during the TMS sessions, presented in a randomized manner. The first 
video is a smoking video which lasts for three minutes and its purpose is to be a cue for inducing 
craving. The other video used will be a neutral video, illustrating daily tasks that do not involve 
smoking. This video will be used as a control video.  
 
TMS Protocol 
 
This study will attempt to use accelerated theta burst stimulation of TMS, and specifically the 3-
minute FDA-approved protocol for depression. rTMS will be applied to each participant for a 
period of five consecutive days. Each day will consist of four sessions of the 3-minute theta-burst 
stimulation with a 45-minute gap (which is the optimal gap) between sessions. The protocol 
includes 2 seconds of stimulation on the left dorsolateral prefrontal cortex which is followed by an 
8 second pause. There will be 600 pulses in total for each 3-minute session. The site of stimulation 
will be the left DLPFC. It will be measured by using the 10-20 system, it will be determined by 
the Beam F3 software and it will be at 100% of the motor threshold.  
 
Planned Analysis 
The data will be analysed in SPSS. Analyses of hypotheses will be carried out with a mixed model 
(repeated measures within and between factors). Within factors will be determined from the 
craving scores in the baseline and follow ups from the three questionnaires, and CO measures. 
Between factors will be determined by the three experimental groups. Analyses will be adjusted 
for sex, age and visual stimuli.  
 
Expected outcomes & Benefits of the study 
Few studies have examined smoking cessation through a TMS treatment. Further, there is a 
question as to whether exposure to behavioural cues before or during TMS treatment may 
influence craving outcomes, which may improve our understanding in the mechanisms that 
influence successful outcome, while using induced plasticity methods. While we expect that 
experimental groups will have significantly decreased craving scores compared to control group, 
generally this study will aid in our understanding regarding potential options for smoking cessation 
and possibly for other addictions with similar physiological mechanisms.  
 
 
 
 
 
 
 

 
 
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