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Behavioural Neurology 00 (2013) 1–13 1DOI 10.3233/BEN-130337IOS Press

rTMS in the treatment of drug addiction: Anupdate about human studies

Elisa Bellamolia,b,∗, Paolo Manganottib, Robert P. Schwartzc, Claudia Rimondod,Maurizio Gommaa and Giovanni SerpellonieaAddiction Department, ULSS 20, Verona, ItalybDepartment of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona,Verona, ItalycFriends Research Institute, Baltimore, MarylanddNational Coordination Centre for NIDA Collaborations, Verona, ItalyeDepartment for Anti-Drug Policies, Presidency of Ministers’ Council of Italy, Italy

Abstract. Drug addiction can be a devastating and chronic relapsing disorder with social, psychological and physical conse-quences, and more effective treatment options are needed. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasivebrain stimulation technique that has been assessed in a growing number of studies for its therapeutic potential in treating addic-tion. This review paper offers an overview on the current state of clinical research in treating drug addiction with rTMS. Becauseof the limited research in this area, all studies (including case reports) that evaluated the therapeutic use of rTMS in nicotine,alcohol or illicit drug addiction were included in this review. Papers published prior to December 2012 were found through anNCBI PubMed search (http://www.ncbi.nlm.nih.gov). A total of eleven studies were identified that met review criteria. Thereis nascent evidence that rTMS could be effective in reducing cocaine craving, and nicotine and alcohol craving and consump-tion, and might represent a potential therapeutic tool for treating addiction. Further studies are needed to identify the optimalparameters of stimulation for the most effective treatment of drug addiction, to improve our comprehension of the treatmentneurophysiological effects, and to conduct rigorous, controlled efficacy studies with adequate power.

Keywords: Repetitive transcranial magnetic stimulation (rTMS), addiction, nicotine, alcohol, cocaine

1. Introduction1

Psychoactive drugs act on the central nervous sys-2

tem and recurring drug intoxication can result in addic-3

tion, a complex disease process of the brain which can4

be treated [1]. Addiction can be described as a persis-5

tent state in which there is reduced capacity to control6

compulsive drug-seeking, regardless of whether it in-7

volves risk of negative consequences [2,3]. It is often8

a devastating and chronically relapsing disorder with9

social, psychological and physical consequences. Drug10

∗Corresponding author: Elisa Bellamoli, Dipartimento delleDipendenze ULSS 20, Via Germania 20 – 37136 Verona, Italy.Tel.: +39 045 8076246; Fax: +39 045 8622239; E-mail: [email protected].

addiction incurs enormous medical, economic and so- 11

cial costs. The currently available treatment options for 12

addiction remain somewhat limited and long-term suc- 13

cess rates are modest [4]. 14

Brain stimulation allows modulation of activity in 15

specific brain regions. Recently, non-surgical brain 16

stimulation techniques have been utilized in examining 17

the effects of drug administration on cortical activity 18

in order to further explore the effects of repeated drug 19

use on cortical excitability. Furthermore, several novel 20

studies have begun to assess brain stimulation as a po- 21

tential treatment for reducing addictive behaviours [5]. 22

This review paper offers an overview on the cur- 23

rent state of research in treating addiction in humans 24

with Transcranial Magnetic Stimulation (TMS), a non- 25

ISSN 0953-4180/13/$27.50 c© 2013 – IOS Press and the authors. All rights reserved


2 E. Bellamoli et al. / rTMS in the treatment of drug addiction: An update about human studies

invasive brain stimulation technique that may have26

therapeutic potential in treating addiction.27

Due to the limited amount of research in this area,28

all studies (including case reports) that were identified29

through an NCBI PubMed search (http://www.ncbi.30

nlm.nih.gov), were included in the review if published31

prior to December 2012 and if reporting on the eval-32

uation of the therapeutic use of rTMS in tobacco,33

alcohol or illicit drug addiction. Search terms in-34

cluded “repetitive transcranial magnetic stimulation”,35

“rTMS”, with adjoining terms “addiction”, “drug”,36

“nicotine”, “tobacco”, “alcohol”, “cocaine”, “opioids”,37

“heroin”, “cannabis”, “marijuana”, “MDMA”, “ec-38

stasy”. A total of 11 studies were identified and in-39

cluded in this review and were classified according to40

the system reported by Brainin et al. [67] for the Euro-41

pean Federation of Neurological Societies. In this sys-42

tem, individual studies are rated on a continuum based43

on the level of evidence, as follows: Class I requires a44

rigorously conducted randomized clinical trial (RCT);45

Class II requires a less rigorously conducted RCT or46

a prospective matched-group cohort study; Class III47

requires any other type of controlled trial (Class III);48

and, Class IV requires uncontrolled studies, case se-49

ries, case reports, or expert opinion. Based on the ev-50

idence, the approaches are then rated in three levels:51

Level A indicates the approach is effective, ineffec-52

tive, or harmful if there is at least one Class I study or53

two Class II studies; Level B indicates the approach is54

probably effective, ineffective, or harmful if there is at55

least one convincing Class II study or overwhelming56

Class III evidence; and, Level C indicates the approach57

is possibly effective, ineffective, or harmful if there are58

at least two convincing class III studies.59

2. Transcranial magnetic stimulation60

TMS is a non-surgical brain stimulation technique61

that is proving to be valuable for both its research62

and therapeutic potential within psychiatry [6]. TMS63

is able to modulate cortical excitability and it is used64

to facilitate functional brain mapping of cortical re-65

gions [7]. It uses a magnetic pulse of high intensity, fo-66

cused in a limited area, which is administered through67

a coil. The extremely fast passage of electric current68

in the coil induces a transient, high-intensity magnetic69

pulse that penetrates through the scalp and reaches70

the underlying cortex. In the targeted cortical area, the71

magnetic pulse generates an electric current that in-72

duces depolarization of superficial cortical neurons [8].73

In the region beneath the coil and interconnected ar- 74

eas occurs a stimulation or a disruption of local neural 75

activity [9,10]. 76

Repetitive TMS (rTMS) is used to induce longer 77

lasting alterations, facilitation or functional disrup- 78

tions. In rTMS, trains of several pulses are delivered 79

using various stimulation patterns [11]. It provides a 80

repeated stimulation of the scalp at the same point with 81

a frequency ranging from 1 to 20 Hz or more. The 82

parameters in rTMS include its intensity, frequency, 83

length of trains of pulses and time interval between 84

trains. The effects of rTMS are longer than TMS sin- 85

gle pulse. These long-term changes in the functioning 86

of the cortex produce effects that vary depending on 87

the frequency of stimulation, resulting in inhibition or 88

facilitation. 89

While the long-lasting neurophysiologic effects of 90

rTMS are poorly understood, several studies showed 91

that rTMS can induce significant and long-lasting be- 92

havioural alterations, including reduction in craving 93

and consumption of drugs of abuse. 94

The safety of TMS has been reported in a number 95

of studies [12–14] and the most recent guidelines for 96

its use have been published in 2009 by Rossi and col- 97

leagues [15]. The use of TMS is generally not recom- 98

mended with patients who have a history of epilepsy, in 99

carriers of pacemaker, hearing aids, metal in any part of 100

the body, and in pregnant women. Single pulses or low 101

frequency stimulation appears to carry little risk be- 102

yond occasionally causing local discomfort at the site 103

of stimulation. In some circumstances, especially when 104

the intensity of the magnetic pulse is high, the effect 105

of current induced by the magnetic field can spread to 106

the surrounding muscles on the head and neck, causing 107

contractions. Occasionally, mild or moderate transient 108

headache have been reported. Long-term effects of re- 109

peated rTMS sessions are as yet unknown. Based on 110

existing data, rTMS appears safe when administered 111

according to recommended guidelines, and its safety 112

record supports its further development as a clinical 113

treatment [14,16]. 114

3. TMS and cortical excitability in addiction: 115

Physiopathological mechanisms 116

There were some reports of using TMS to mea- 117

sure cortical inhibition in the cerebral cortex of sub- 118

jects with substance dependence [17–27]. These stud- 119

ies found that chronic exposure to various addictive 120

drugs induces alterations in cortical excitability in 121


E. Bellamoli et al. / rTMS in the treatment of drug addiction: An update about human studies 3

the motor, occipital and prefrontal cortex (PFC). Cor-122

tical conductivity has been evaluated in individuals123

with exposure to alcohol [17–21], with nicotine de-124

pendence [22], with chronic cannabis exposure [23],125

with chronic ecstasy exposure [24], and cocaine addic-126

tions [25–27].127

Decreased excitability in the motor cortex was found128

in individuals who are cocaine [25–27] and nicotine129

dependent [22]. Chronic cannabis use is associated130

with a reduction in cortical inhibition [23]. Increased131

excitability of the visual cortex was found in individu-132

als with chronic MDMA use, abstinent for 3 days [24].133

Acute alcohol exposure was found to be associated134

with decreased excitability in the motor cortex [17,18]135

and the PFC [19]. Moreover, Conte et al. [20] proposed136

that while acute ethanol administration seemed to af-137

fect GABA neurotransmission, chronic administration138

appeared to alter the glutamate mechanisms involved139

in cortical excitability. Nardone and colleagues [21]140

found that TMS showed a selective increase in in-141

tracortical facilitation after ethanol withdrawal which142

supported the theory that altered glutamatergic recep-143

tor function plays an important role in the pathogene-144

sis of human alcohol withdrawal [21]. Impaired corti-145

cal inhibition has been reported in persons exposed to146

substances of abuse, suggesting that abnormal cortical147

excitability may reflect changes in the brain systems of148

GABA and glutamate [5].149

These findings are important as they indicate altered150

cortical excitability in drug dependent populations and151

suggest that TMS can be utilized as an investigative152

tool to better understand the pathophysiology of ad-153

diction. Nevertheless, these studies have several limi-154

tations. First, these were exploratory studies with small155

samples. Second, it is difficult to determine whether al-156

terations in the corticospinal measures are a direct re-157

sult of chronic drug administration, or rather, occur due158

to pre-existing vulnerabilities, or perhaps even a com-159

bination of both. Finally, poly-substance use and/or a160

comorbid psychiatric condition could also exacerbate161

these alterations in cortical excitability.162

4. rTMS as a therapeutic tool163

Repetitive TMS can modulate the excitability of164

stimulated cortex and interconnected brain regions,165

even after the period of stimulation [10,11,28]. It has166

been reported that high frequency rTMS (> 5 Hz) tran-167

siently increases cortical excitability [29,30]. Changes168

in neurotransmission induced by rTMS have been ob-169

served in both animal [31,32] and human studies [33, 170

34]. rTMS over the PFC seems to have modulator ef- 171

fect on mesolimbic and mesostriatal dopaminergic sys- 172

tems. Strafella et al. [33] found that high frequency 173

rTMS on the prefrontal cortex in humans induces sub- 174

cortical release of dopamine in caudate nucleus. Cho 175

and Strafella [34] showed that rTMS over the left 176

DLPFC modulates the release of dopamine in anterior 177

cingulated cortex and orbitofrontal cortex in the same 178

hemisphere. 179

The effect of rTMS on dopaminergic neurotransmis- 180

sion and cortical excitability suggests that this tech- 181

nique can be used in the study and treatment of vari- 182

ous neuropsychiatric disorders associated with abnor- 183

mal dopamine activity and altered cortical excitabil- 184

ity, such as depression [35–38], obsessive-compulsive 185

disorder [39,40], schizophrenia [41–44] and drug ad- 186

diction [45–55]. The efficacy of administering TMS 187

protocols, to frontal brain areas, as a potential non- 188

pharmacological candidate for increasing dopamine 189

levels in the mesocorticolimbic circuitry and altering 190

neuroadaptations induced by chronic drug use has been 191

assessed with animal studies [5]. 192

5. rTMS in the treatment of addiction: The 193

rationale and experimental evidence 194

Recent studies have begun to assess the effects of 195

rTMS on addictive behaviours in humans. Repeated 196

exposure to drugs can cause long-term neural adap- 197

tations in some systems. These neuroadaptations are 198

partly associated with altered dopamine activity in 199

the mesocorticolimbic circuitry [56,57], and lead to 200

an alteration of glutamate neurotransmission [58] and 201

cortical excitability [59,60], which have been impli- 202

cated in the persistence of drug-seeking behaviours, in- 203

creased difficulties regulating drug-seeking behavior, 204

and a heightened likelihood of relapse [61]. 205

Because rTMS can affect cortical excitability and 206

increase the release of dopamine in the mesolimbic 207

dopaminergic system, it is thought that repeated appli- 208

cations of rTMS may affect neuroadaptation induced 209

by the chronic use of substances. In addition, rTMS 210

can modulate neuronal activity and, thus, at least in- 211

duce acute effects on circuitries that mediate differ- 212

ent behaviours. Repeated sessions of rTMS of the 213

PFC are, therefore, suggested to reduce drug craving, 214

drug-seeking and eventually drug consumption and re- 215

lapse [47]. 216

There is accumulating evidence that stimulating the 217

dorsolateral part of the prefrontal cortex (DLPFC) 218



may be of use in addiction treamtent. DLPFC is in-219

volved in the decision-making processes [62] and these220

processes can be altered by rTMS [63]. Addiction221

is associated with increased impulsivity and willing-222

ness to take risks, which in turn can lead to impaired223

decision-making [64]. rTMS on the DLPFC could224

modulate these decision-making processes in addic-225

tion and thereby reduce impulsivity and enhance in-226

hibitory control, which may lead to a reduction in227

the use of substances. Therefore, the neuropsychologi-228

cal assumption underlying research using rTMS in the229

treatment of addiction is that exciting the DLPFC by230

high frequency pulses, should increase its activity and231

increase its inhibitory control function. In particular,232

with drug-addicted subjects, this treatment should in-233

crease DLPFC function to cope with drug craving. In234

fact, to date, several human studies have evaluated the235

effects of rTMS protocols on drug craving, a major236

component determining relapse, and consumption in237

nicotine [45–49], alcohol [50–53] and cocaine [54,55]238

dependent groups.239

The following section describes studies which have240

explored the therapeutic potential of rTMS in reducing241

addictive behaviours within substance dependent pop-242

ulations.243

5.1. rTMS and nicotine244

Five papers which examined rTMS and nicotine de-245

pendence are summarized below and in Table 1.246

Johann et al. [45] and Eichhammer et al. [46] investi-247

gated with exploratory studies whether high frequency248

rTMS of DLPFC could decrease nicotine-seeking re-249

lated behaviours. In the first pilot double-blind cross-250

over study, Johann et al. [45] investigated whether251

rTMS of the DLPFC could modulate levels of to-252

bacco craving. Eleven treatment-seeking smokers un-253

der 12 hour abstinent conditions were administered ei-254

ther one active or one sham session of 20 Hz rTMS255

over the left DLPFC at 90% of MT. The session con-256

sisted of 20 trains of stimuli of 2.5 s. The levels of257

tobacco craving were assessed using a 100-point vi-258

sual analogue scale (VAS) both 30 minutes prior to and259

following the rTMS treatment. rTMS significantly re-260

duced the level of tobacco craving reported 30 minutes261

following the treatment [45]. These findings, therefore,262

motivated further investigation on the efficacy of rTMS263

as a potential treatment in nicotine dependence to re-264

duce not only the level of craving but also of smoking265

consumption.266

Following this pilot study, the same research gro-267

up [46] investigated the effects of two sessions of268

active and sham rTMS at the same parameters with 269

a double-blind cross-over design study. Participants 270

consisted of 14 treatment-seeking tobacco dependents. 271

All participants were required to abstain from smok- 272

ing 12 hours before the rTMS sessions. In a random- 273

ized order, each participant received 2 active trials and 274

2 sham stimulation sessions over 4 consecutive days. 275

Smoking craving was measured at baseline and 30 min 276

after the rTMS session using a VAS. In addition, the 277

number of cigarettes freely smoked in a 6-hour time 278

period following treatment was recorded. During this 279

6 hour time period, the number of cigarettes smoked 280

following high frequency rTMS applied to the left 281

DLPFC was significantly decreased, but craving lev- 282

els remained unchanged. The authors have suggested 283

that the evaluation of craving may have not been sen- 284

sitive enough and that the sample size was probably 285

too small to detect alterations in craving [46]. Treat- 286

ment with high-frequency rTMS was, therefore, found 287

to decrease craving level for tobacco in the pilot study, 288

although this finding was not replicated in the second 289

study. The second study demonstrated reduced smok- 290

ing consumption following rTMS session, thus con- 291

tributing to the preliminary evidence of the utility of 292

rTMS treatment in nicotine dependence [65]. Based 293

on these findings, the authors propose that high fre- 294

quency rTMS could have potential therapeutic value 295

in the treatment of nicotine dependence through a re- 296

duction in the levels of craving [45] and its consump- 297

tion [46]. 298

Amiaz et al. [47] were also interested in evaluating 299

the effects of high frequency rTMS of the left DLPFC, 300

combined with either smoking or neutral cues, on 301

cigarette consumption, dependence and craving. The 302

researchers expanded on the previous two studies by 303

assessing whether exposure to smoking cues (prior to 304

the stimulation) could modulate the effect of rTMS. 305

They postulated that in addition to the effect of rTMS 306

on dopamine transmission and cortical excitability, 307

rTMS over the PFC may disrupt craving-related cir- 308

cuitries and that this effect would be prominent when 309

rTMS is applied immediately after activation of such 310

circuitry by smoking cues. Forty-eight heavy smok- 311

ers motivated to quit smoking were recruited for the 312

study. Participants were randomly divided into real and 313

sham stimulation groups. Each group was subdivided 314

randomly into two subgroups presented with either 315

smoking-related or neutral cues just before the daily 316

TMS intervention. Thus, there were four experimen- 317

tal groups: active TMS with smoking pictures, active 318

TMS with neutral pictures, sham TMS with smoking 319



pictures and sham TMS with neutral pictures. The au-320

thors assessed the effects of 10 days of treatment with321

either active or sham 10 Hz rTMS treatment applied to322

the left DLPFC. Daily rTMS sessions were applied ev-323

ery week-day and then a maintenance phase was con-324

ducted in which rTMS sessions were less frequent.325

Ten daily sessions of high frequency (10 Hz) rTMS326

over the left DLPFC were administered in an attempt327

to induce long-lasting effects. Stimulation included328

20 trains/day at 100% of MT and each train consisted329

of 50 pulses at 10 Hz with an inter-train interval of 15 s.330

Prior to the rTMS, participants were exposed to either331

smoking or neutral visual cues. Cigarette consump-332

tion was evaluated objectively by measuring cotinine333

(a metabolite of nicotine) urine levels before the first334

and the 10th treatment, and participants were admin-335

istered standard questionnaires on nicotine consump-336

tion, craving and dependence. VAS was used to evalu-337

ate levels of nicotine craving before and after the pre-338

sentation of the smoking or the neutral cues and af-339

ter rTMS administration. rTMS, independent of expo-340

sure to smoking pictures, reduced subjective and ob-341

jective measures of cigarette consumption and nico-342

tine dependence. It also reduced cue-induced craving343

and blocked the development of general craving in-344

duced by repeated presentation of smoking-related pic-345

tures. However, these effects tended to dissipate after346

the 10 daily sessions and the reduction in cigarette con-347

sumption was not significant 6 months after treatment348

termination. Interestingly, there was a trend for lower349

cigarette consumption in the active rTMS-smoking350

picture group at 6 month follow-up. Overall, results351

from this study suggested that high frequency rTMS352

over the DLPFC reduced cigarette consumption and353

nicotine dependence [47].354

Wing et al. [48] examined the efficacy of high355

frequency rTMS for smoking cessation in treatment-356

seeking individuals with schizophrenia, a population of357

smokers who are typically highly nicotine-dependent.358

These authors completed a 10-week, randomized, dou-359

ble-blind, sham-controlled trial of rTMS (20 sessions;360

5 treatments/week in Weeks 1–4) as an adjunct to361

weekly group therapy and transdermal nicotine (TN;362

21 mg) provided in Weeks 3–9 in 15 heavily-dependent363

smokers ages 18 to 60 with schizophrenia or schizoaf-364

fective disorder. They were motivated to quit within365

the next month and the target quit date was the start366

of Week 3. Subjects were randomly assigned to re-367

ceive active (N = 6) or sham (N = 9) rTMS. Bi-368

lateral rTMS (randomized and counterbalanced) was369

administered to the DLPFC. 20 Hz stimulation was370

administered at 90% of the resting motor threshold 371

for 25 trains (30 pulses/train; 30 s intertrain interval; 372

750 pulses/hemisphere). Sham stimulation was admin- 373

istered in the single-wing tilt position. Smoking (self- 374

report and breath carbon monoxide [CO] levels), psy- 375

chiatric measures (Positive and Negative Syndrome 376

Scale [PANSS]), and adverse events were assessed 377

weekly. Craving, using the Tiffany Questionnaire for 378

Smoking Urges (TQSU), and withdrawal, using the 379

Minnesota Nicotine Withdrawal Scale, were assessed 380

pre- and post-rTMS once during each treatment week. 381

Consistent with findings in non-psychiatric smok- 382

ers [45], pre- and post-rTMS data collected in Week 383

1 showed that treatment with rTMS significantly re- 384

duced craving. While there was a robust increase in 385

craving following the rTMS session in the sham group 386

(due to abstinence from smoking), post-treatment crav- 387

ings in the active group were the same or lower than 388

the pre-treatment assessment. rTMS did not alter crav- 389

ing in Weeks 2–4. As short-term smoking abstinence 390

did not increase craving in these weeks, data obtained 391

in Week 1 likely provides the most sensitive measure- 392

ment of rTMS effects on craving. Despite attenuation 393

of tobacco craving, rTMS did not increase abstinence 394

rates. An increased number of rTMS sessions may be 395

needed for the effects on craving to translate to effects 396

on smoking [48]. 397

Rose et al. [49], instead, investigated the rTMS ef- 398

fects over Superior Frontal Gyrus (SFG), a specific 399

prefrontal cortex region, which supports cue-induced 400

craving. They implemented a within-subject design to 401

examine subjective responses to smoking versus neu- 402

tral cues and to controlled presentations of cigarette 403

smoke. Fifteen smokers were recruited for study par- 404

ticipation and were exposed to three conditions on dif- 405

ferent days: 1) high frequency rTMS (10 Hz) over Su- 406

perior Frontal Gyrus (SFG), a specific prefrontal cor- 407

tex region, which supports cue-induced craving; 2) low 408

frequency (1 Hz) rTMS over the SFG; 3) low fre- 409

quency (1 Hz) rTMS over the motor cortex (control 410

condition). In each condition, subjects were stimulated 411

for three periods of 2 minutes and 30 seconds at 90% 412

MT. The researchers evaluated craving for cigarettes 413

and they found that compared to 1 Hz rTMS to the SFG 414

or motor cortex, 10 Hz to the SFG resulted in increased 415

cue-induced craving but lower craving during presen- 416

tation of neutral cues. Craving after smoking cue pre- 417

sentations was elevated in the 10 Hz SFG condition, 418

whereas craving after neutral cue presentations was re- 419

duced. Ratings of immediate craving reduction as well 420

as the intensity of interoceptive airway sensations were 421



also attenuated upon smoking in the 10 Hz SFG condi-422

tion. These findings support the idea that SFG plays a423

role in modulating craving reactivity, and that the SFG424

plays a role in both excitatory and inhibitory influences425

on craving but do not provide evidence for the utility426

of rTMS of the SFG for the treatment of tobacco ad-427

diction [49].428

In summary, as shown in Table 1, the first four429

studies described above showed that high frequency430

rTMS of the DLPFC can attenuate nicotine consump-431

tion [46,47] and craving [45,48]. Rose et al. [49], in-432

stead, highlighted the excitatory and inhibitory influ-433

ence of SFG on tobacco cravings but did not provide434

evidence for the utility of rTMS of the SFG for the435

treatment of tobacco addiction. However, the signif-436

icance and duration of these effects are limited and437

further investigation is required to identify the ap-438

propriate stimulation parameters and targets. While439

other types of brain stimulation techniques (transcra-440

nial direct current stimulation, cranial electrostimula-441

tion, deep brain stimulation) have been evaluated in the442

treatment of nicotine addiction, there is the most evi-443

dence to support rTMS’s potential to treat nicotine de-444

pendence [66]. According to the criteria suggested by445

Brainin et al. [67], the extant research on the thera-446

peutic use of rTMS for nicotine dependence has one447

study in Class II [47], three studies in class III [45,46,448

49] and one study in class IV [48] that showed reduc-449

tion in craving, consumption and dependence. Thus,450

according to the available evidence, rTMS falls within451

the Level B recommendation as probably effective in452

the treatment of nicotine addiction.453

5.2. rTMS and alcohol454

Studies of rTMS in alcohol dependent individuals455

are summarized below and in Table 2.456

Mishra et al. [50] published the first study about457

rTMS treatment of alcohol dependence. These authors458

studied the anti-craving efficacy of high frequency459

rTMS of the right DLPFC in a single-blind, sham-460

controlled study involved 45 patients with alcohol de-461

pendence. Participants were assigned to one of the462

two groups in which they received either real (N =463

30) or sham (N = 15) rTMS. They were admin-464

istered 10 daily sessions of high frequency (10 Hz)465

rTMS at 110% of MT over the right DLPFC. Each466

session consisted of 20 trains with 4.9 s per train and467

30 s inter-train interval. The Alcohol Craving Ques-468

tionnaire (ACQ-NOW) was administered in order to469

evaluate the extent of alcohol craving at baseline, im-470

mediately after the last rTMS and a month after the 471

last session. There was a significant reduction in the 472

post-rTMS ACQ-NOW total score and factor scores in 473

the group allocated to active rTMS compared to the 474

group allocated to sham stimulation. It was found that 475

10 daily sessions of high-frequency rTMS over right 476

DLPFC had significant anti-craving effects in alcohol 477

dependence. This study supports the therapeutic poten- 478

tial of rTMS which, especially when combined with 479

anti-craving drugs, could represent an effective strat- 480

egy in reducing craving and alcohol relapse among al- 481

cohol dependent subjects [50]. 482

Hoppner et al. [52] investigated the effect of high 483

frequency rTMS of the left DLPFC compared to sham 484

stimulation on craving and mood in alcohol depen- 485

dent women. Moreover, this study examined the im- 486

pact on an attentional blink (AB) paradigm to pictures 487

with neutral, emotional and alcohol-related contents. 488

Nineteen female detoxified participants were random- 489

ized either to a high frequency rTMS (20 Hz) over the 490

left DLPFC (N = 10) or a sham stimulations (N = 491

9) at 10 days. Alcohol craving was assessed with the 492

Obsessive Compulsive Drinking Scale and depressive 493

symptoms were assessed by the Hamilton Depression 494

Rating Scale and the Beck Depression Inventory. An 495

age-matched control group was investigated for the 496

AB paradigm. There were no significant differences in 497

clinical parameters such as alcohol craving or mood 498

after real rTMS compared to sham stimulation. In the 499

AB paradigm, real stimulated participants detected al- 500

cohol related T2 targets incorrectly in comparison to 501

the sham stimulated and control subjects. Although 502

there were no differences in craving and mood after 503

real high frequency rTMS compared to sham stimula- 504

tion, an interesting difference between the real and the 505

sham stimulated group and controls was found in the 506

AB paradigm, suggesting an increase of the AB effect 507

to alcohol-related pictures after real stimulation [52]. 508

Herremans et al. [69] performed a prospective, 509

single-blind, sham-controlled study in order to inves- 510

tigate the effect of single high frequency rTMS ses- 511

sion of the right DLPFC on alcohol craving in the 512

community. Participants (N = 36) were hospitalized 513

alcohol-dependent patients. After successful detoxifi- 514

cation, participants were allocated to receive one ac- 515

tive or one sham rTMS session. The rTMS session was 516

administered on Friday before the weekend at home. 517

The rTMS session consisted of 40 trains of 1.9 s at 518

20 Hz at 110% MT with a 12 s inter-train interval. 519

The obsessive–compulsive drinking scale (OCDS) was 520

administered to assess the intensity of alcohol crav- 521



Tabl

e1

Sum

mar

yof

the

stud

ies

onrT

MS

inth

etre

atm

ento

fnic

otin

ead

dict

ion

Stud

yN

subj

ects

Plac

eof

Num

bero

fL

engt

hFr

eque

ncy

Inte

nsity

ofSh

amA

sses

smen

tFi

ndin

gs(a

ctiv

e,sh

am)

stim

ulat

ion

sess

ions

stim

ulat

ion

stim

ulat

ion

Joha

nnet

al.

[45]

11L

eftD

LPF

C1

sess

ion

20tr

ains

of2.

5s

20H

z90

%M

TY

esC

ravi

ng,a

sses

sed

byVA

SR

educ

tion

incr

avin

g

Eic

hham

mer

etal

.[4

6]14

Lef

tDL

PFC

4se

ssio

ns(2

activ

ean

d2

sham

)

20tr

ains

of2.

5s

20H

z90

%M

TY

es(b

etw

een

the

grou

p)C

ravi

ng,a

sses

sed

byVA

S;ci

gare

ttes

num

ber

Red

uctio

nin

cons

umpt

ion

Am

iaz

etal

.[4

7]22

,26

Lef

tDL

PFC

10se

ssio

ns20

trai

nsof

5s

10H

z10

0%M

TY

esC

ravi

ng,a

sses

sed

VAS;

ciga

rette

snu

mbe

rR

educ

tion

incr

avin

g,co

nsum

ptio

nan

dde

pend

ence

Win

get

al.

[48]

6,9

Bila

tera

lDL

PFC

20se

ssio

ns50

trai

ns20

Hz

90%

MT

Yes

Cra

ving

,ass

esse

dby

TQ

SUR

educ

tion

incr

avin

g

Ros

eet

al.

[49]

15SF

G3

sess

ions

(1ac

tive

1H

z,1

activ

e10

Hz,

1M

OC

)

2.5

min

each

sess

ion

(tot

alpe

riod

ofst

imul

atio

n:7.

5m

in)

1H

zor

10H

z90

%M

TY

esC

ravi

ng,a

sses

sed

bySh

iffm

an-J

arvi

kqu

estio

nnai

rean

dci

gare

tteev

alua

tion

ques

tionn

aire

Red

uctio

nin

crav

ing

(10

Hz)

Abb

revi

atio

ns:

DL

PFC

=do

rsol

ater

alpr

efro

ntal

corte

x,SF

G=

supe

rior

fron

tal

gyru

s,M

OC

=m

otor

cort

ex,

MT=

mot

orth

resh

old,

VAS=

visu

alan

alog

uesc

ale,

TQ

SU=

Tiff

any

Que

stio

nnai

refo

rSm

okin

gU

rges

.



Tabl

e2

Sum

mar

yof

the

stud

ies

onrT

MS

inth

etre

atm

ento

falc

ohol

addi

ctio

n

Stud

yN

subj

ects

Alc

ohol

Plac

eof

Num

bero

fL

engt

hFr

eque

ncy

Inte

nsity

ofSh

amA

sses

smen

tFi

ndin

gs(a

ctiv

e,sh

am)

use

stat

usst

imul

atio

nse

ssio

nsst

imul

atio

nst

imul

atio

nM

ishr

aet

al.

[50]

30,1

5A

fter

deto

xific

atio

nR

ight

DL

PFC

10da

ilyse

ssio

ns20

train

sof

4.9

s10

Hz

110%

MT

Yes

Cra

ving

,ass

esse

dby

AC

Q-N

OW

Red

uctio

nin

imm

edia

tecr

avin

g;no

effe

cton

crav

ing

afte

r4w

eeks

Hop

pner

etal

.[5

2]10

,9(f

emal

es)

14da

ysaf

ter

deto

xific

atio

nL

eftD

LPF

C10

daily

sess

ions

1000

puls

es20

Hz

90%

MT

Yes

Cra

ving

,ass

esse

dby

OC

DS;

depr

essi

vesy

mpt

oms,

asse

ssed

byB

DI;

AB

forn

eutr

alan

dal

coho

lrel

ated

pict

ures

No

redu

ctio

nin

crav

ing

and

noef

fect

onm

ood;

incr

ease

AB

for

alco

holr

elat

edpi

ctur

es

Her

rem

ans

etal

.[6

9]36

Aft

erde

toxi

ficat

ion

Rig

htD

LPF

C1

sess

ion

40tr

ains

of1.

9s

20H

z11

0%M

TY

esC

ravi

ng,a

sses

sed

byO

CD

SN

oef

fect

onim

med

iate

and

long

term

crav

ing

De

Rid

der

etal

.[5

3]1

(fem

ale)

Act

ive

drin

king

perio

ddA

CC

daily

sess

ions

duri

ng5

wee

ks60

0pu

lses

1H

z50

%m

achi

neou

tput

No

Cra

ving

,ass

esse

dby

VAS

Red

uctio

nin

imm

edia

tecr

avin

gan

dco

nsum

ptio

n;re

laps

eaf

ter

3m

onth

sw

ithin

crea

sed

crav

ing

afte

r3m

onth

s

Abb

revi

atio

ns:

DL

PFC=

dors

olat

eral

pref

ront

alco

rtex,

dAC

C=

Dor

sala

nter

ior

cing

ulat

edco

rtex,

MT=

mot

orth

resh

old,

VAS=

visu

alan

alog

uesc

ale,

AC

Q-N

OW

=A

lcoh

olC

ravi

ngQ

uest

ionn

aire

,OC

DS=

Obs

essi

veC

ompu

lsiv

eD

rink

ing

Scal

e,B

DI=

Bec

kD

epre

ssio

nIn

vent

ory,

AB=

Atte

ntio

nalB

link.

Tabl

e3

Sum

mar

yof

the

stud

ies

onrT

MS

inth

etre

atm

ento

fcoc

aine

addi

ctio

n

Stud

yN

subj

ects

Plac

eof

Num

bero

fL

engt

hFr

eque

ncy

Inte

nsity

ofSh

amA

sses

smen

tFi

ndin

gsst

imul

atio

nse

ssio

nsst

imul

atio

nst

imul

atio

nC

ampr

odon

etal

.[5

4]6

Bila

tera

lDL

PFC

2se

ssio

ns20

trai

nsof

10s

10H

z90

%M

TN

oC

ravi

ng,a

nxie

ty,h

appi

ness

,sa

dnes

san

ddi

scom

fort,

asse

ssed

byVA

S

Red

uctio

nin

crav

ing

(with

righ

tDL

PFC

rTM

S);re

duct

ion

inan

xiet

yaf

ter

right

-si

ded

rTM

S;in

crea

sein

happ

ines

saf

terr

ight

-and

insa

dnes

saf

terl

eft-

side

drT

MS,

incr

ease

indi

scom

fort

equa

llyby

left-

and

right

-sid

edst

imul

atio

n

Polit

ieta

l.[5

5]36

Lef

tDL

PFC

10da

ilyse

ssio

ns20

train

sof

2s

15H

z10

0%M

TN

oC

linic

alas

sess

men

tof

crav

ing

rela

ted

sym

ptom

sR

educ

tion

incr

avin

g

Abb

revi

atio

ns:D

LPF

C=

dors

olat

eral

pref

ront

alco

rtex,

MT=

mot

orth

resh

old,

VAS=

visu

alan

alog

uesc

ale.



ing just before and after the rTMS session (on Fri-522

day), on Saturday and Sunday during the weekend at523

home, and on Monday (when the participants returned524

to the hospital). One high frequency rTMS session de-525

livered to the right DLPFC did not lead to changes in526

craving (neither immediately after the stimulation ses-527

sion, nor in participants’ natural environment during528

the weekend). This study found that application of a529

single rTMS session had no significant effect on alco-530

hol craving [51].531

In a case-report [53], a 48-year-old woman with532

a 23-years heavy drinking history was stimulated533

with low-frequency rTMS targeting the dorsal ante-534

rior cingulated cortex (dACC) using a double cone535

coil in an attempt to suppress very severe alcohol536

craving. 1 Hz rTMS (50% of the machine’s inten-537

sity, total of 600 pulses) was delivered for 3 weeks538

to the medial frontal cortex. It was a combined rTMS539

neuroimaging study: functional Magnetic Resonance540

Imaging (fMRI) and resting state electroencephalogra-541

phy (EEG) were performed before rTMS treatments,542

after successful rTMS and after unsuccessful rTMS543

with relapse. Blood alcohol volumes were acquired544

on random days during the treatment course. Alco-545

hol cravings were measured daily by a VAS during a546

cue exposure. Repetitive rTMS reduced alcohol con-547

sumption for the duration of the treatment. Symptoms548

of withdrawal and cravings were also reduced up to549

3 months. This reduction was also reflected with the550

change in fMRI and EEG activity. After 3 months, the551

patient relapsed and was treated with 1 week of rTMS.552

These effects lasted for 3 weeks until the patient re-553

lapsed again and the patient became unresponsive to554

the rTMS treatment [53].555

In conclusion, 10 daily sessions of high-frequency556

rTMS over right DLPFC had significant anti-craving557

effects in alcohol dependence [50], while a single558

rTMS session had no significant effect on immediate559

and long term craving; there were no reduction in crav-560

ing after high frequency rTMS over left DLPFC [52];561

repetitive rTMS targeting the dACC using a double562

cone coil reduced immediate alcohol craving and con-563

sumption [53]. These studies together suggest that564

rTMS may play a therapeutic role in alcohol depen-565

dence, though the evidence is still preliminary [68],566

and also indicate that one single session could be too567

short to alter alcohol craving in alcohol-dependent pa-568

tients. As we can see in Table 2, stimulation param-569

eters, such as frequency, % MT, train duration, in-570

tertrain interval and area of stimulation differ signif-571

icantly among studies. Based on these findings, Her-572

remans and Baeken [69] suggested the evaluation of 573

multiple rTMS sessions in larger, randomized, sham- 574

controlled population samples. Furthermore, random- 575

ized controlled studies should be done to evaluate 576

whether patients need stimulation with high or low fre- 577

quency [69]. 578

According to the criteria suggested by Brainin et 579

al. [67], rTMS therapy for alcohol dependence includes 580

one case report [53] (class IV) and three controlled 581

clinical trials (class III) [50–52], two of which reported 582

no effect on craving and one showed reduction in crav- 583

ing. Thus, there is inadequate evidence to confer a level 584

of recommendation for its effectiveness. 585

5.3. rTMS and cocaine 586

Camprodon and colleagues [54] conducted a prelim- 587

inary study to examine rTMS as a potential treatment 588

for the craving experienced by cocaine-dependent in- 589

dividuals. They investigated whether a single session 590

of rTMS over DLPFC could reduce cocaine craving 591

among six male participants with cocaine dependence. 592

Secondary endpoints were changes in anxiety, hap- 593

piness, sadness and discomfort. In this randomized 594

cross-over design, participants were administered two 595

sessions of high frequency (10 Hz) rTMS at 90% of 596

MT, to the right and left DLPFC, with a week break 597

between the two sessions. Patients were asked to com- 598

plete a set of 15 visual analogue scales (VAS) rang- 599

ing from “not at all” to “more than ever”. Each VAS 600

evaluated one of the primary or secondary endpoints 601

on three occasions: 10 minutes before the intervention, 602

immediately after, and 4 hours after rTMS session. 603

The authors found that a single session of high fre- 604

quency rTMS to the right DLPFC, but not to the left 605

DLPFC, decreased level of craving for cocaine. This is 606

a transient effect that resolves within 4 h after stimula- 607

tion. 608

Anxiety resulted significantly reduced after right- 609

sided stimulation. Happiness was increased after right- 610

and sadness after left-sided stimulation. Discomfort 611

was increased equally by left- and right-sided rTMS 612

and the interaction term was not significant, providing 613

a useful control for the non-specific effects of the stim- 614

ulation. 615

This research provided the first demonstration that 616

high frequency rTMS applied over the right DLPFC is 617

effective in reducing craving associated with chronic 618

use of cocaine [54]. Also Politi et al. [55] studied the 619

effects of rTMS over the DLPFC on cocaine cravings 620

among 36 cocaine dependent participants studied post- 621



detoxification. Ten daily sessions of high frequency622

(15 Hz) rTMS over the left DLPFC at 100% of MT623

were administered. The participants underwent daily624

clinical assessment of symptoms associated with co-625

caine craving. These authors found that the daily ses-626

sions of high frequency rTMS of the left DLPFC re-627

duced cocaine craving. Cocaine cravings reduced grad-628

ually throughout the sessions [55].629

As shown in Table 3, both these studies [54,55], us-630

ing different paradigms and assessment tools, suggest631

that rTMS over the DLPFC can potentially provide an632

effective therapeutic intervention for cocaine craving633

and addiction. There was a discrepancy in the laterality634

of the findings. Further research is required on the op-635

timal stimulation patterns and on the exact brain region636

to stimulate. Future studies that assess cocaine intake637

after treatment are also required. According to the cri-638

teria suggested by Brainin et al. [67], studies of rTMS639

therapy for cocaine dependence includes one clinical640

trial (class III) [54] and one study rated in class IV [55]641

that showed reductions in craving. Thus, there is inad-642

equate evidence to confer a level of recommendation643

for the effectiveness of this treatment.644

6. Conclusion and future studies645

In summary, in the research that evaluated the ther-646

apeutic use of rTMS in addiction we have one clini-647

cal trial classified in class II [47] that showed reduc-648

tion in craving, consumption and dependence, five tri-649

als classified in class III that support the effectiveness650

of rTMS [45,46,49,50,54] and two studies in the same651

class that reported the ineffectiveness of this treat-652

ment [51,52]. Thus, based on the available evidence,653

rTMS can be classified as probably effective in the654

treatment of addiction. At the moment, the best level655

of evidence of the effectiveness of rTMS is in the treat-656

ment of nicotine dependence.657

The effects of rTMS sessions on drug craving and658

consumption provide evidence and support for further659

TMS studies in the field of addiction research. Most660

of the studies that assessed the therapeutic potential661

of rTMS to treat alcohol, nicotine and cocaine addic-662

tion were performed using a figure-of-eight coil target-663

ing DLPFC. These studies show that high frequency664

rTMS over the DLPFC can reduce craving and con-665

sumption in nicotine, alcohol and cocaine-dependent666

populations. These studies are still few and have also667

methodological limitations: they were exploratory in668

nature and consist of relatively small sample sizes. Fu-669

ture research should identify the optimal parameters 670

(appropriate target, intensity, frequency and length) of 671

stimulation in rTMS studies for the most effective and 672

safe treatment of drug addiction. Future studies with 673

multiple rTMS sessions in larger, randomized, sham- 674

controlled population samples are required. 675

It is important to note that none of these studies 676

demonstrated complete abstinence from substance use 677

and few studies [46,52] evaluated craving in the nat- 678

ural environment of the patients. It also could be that 679

subjective craving assessment is not that reliable [52]. 680

In addition, the period of rTMS to maintain the gains 681

produced need to be examined with longer follow-up 682

studies. 683

Fitzgerald and colleagues review reported that high- 684

frequency rTMS applied to the left DLPFC is an ef- 685

fective treatment for patients with major depressive 686

disorder [70], although the review included only two 687

studies [52,54] that took in consideration that target- 688

ing the DLPFC might affect mood. Camprodon et 689

al. [54] found that in cocaine addicted individuals hap- 690

piness was increased after right-sided and sadness af- 691

ter left-sided stimulation [54]. These findings were in 692

contrast with those from studies of patients with de- 693

pression, who tend to show the opposite lateraliza- 694

tion [70,71]. Instead, Hoppner and colleagues [52] did 695

not find significant differences in mood after real rTMS 696

over the left DLPFC in individuals with alcohol de- 697

pendence [52]. Thus, more research is needed on the 698

impact of rTMS on mood in individuals with alco- 699

hol and drug dependence. More studies that measure 700

psychological and neurophysiological variables, such 701

as frontal activation tasks, quantitative EEG, evoked 702

potentials and functional Magnetic Resonance, along 703

with rTMS in addiction are required for more compre- 704

hensive assessment of the treatment effects. Given the 705

critical interaction between brain stimulation and cog- 706

nitive activation revealed in some studies (e.g. Amiaz 707

et al. [47]), it is possible that a combination of brain 708

stimulation and cognitive behavioural therapies would 709

produce a promising clinical outcome [5]. These find- 710

ings might translate across the spectrum of addictive 711

disorders [72]. 712

Acknowledgments 713

This work was supported by the Department of Anti- 714

Drug Policies of the Italian Presidency of the Coun- 715

cil of Ministers (DPA). We acknowledge all institu- 716

tions involved in this study, namely the Addiction De- 717



partment ULSS 20 of Verona and the Department of718

Neurological, Neuropsychological, Morphological and719

Movement Sciences, University of Verona. A special720

thanks is addressed to dr. Catia Seri and dr. Giuseppe721

Cuoghi (Addiction Department ULSS 20 of Verona)722

for their help in the preparation of the manuscript.723

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