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The Effects of Repetitive Transcranial Magnetic Stimulation in Reducing Cocaine Craving and Use

Protasio, Maria I.B. MD*; Da Silva, João P.L. PhD; Machado, Sergio PhD; Chagas, Silvana V. MD*; Murillo-Rodriguez, Eric PhD§; Cruz, Marcelo S. PhD*

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Addictive Disorders & Their Treatment: December 2019 - Volume 18 - Issue 4 - p 212-222
doi: 10.1097/ADT.0000000000000169
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Cocaine is considered the second most harmful drug to users, causing damage to their health, well-being, and social performance.1 Pharmacotherapy focusing on reducing cocaine use has been widely researched and despite showing good results in increased duration of abstinence and reduction of withdrawal symptoms, it has not yet proved effective in reducing consumption. In addition, there are restrictions to its use because of adverse effects, contraindications, and possible dependence.2,3 In this context, repetitive transcranial magnetic stimulation (rTMS) is a noninvasive alternative to reducing cocaine craving because of its capability to modulate the circuits involved in the cycle of psychoactive substance dependence.4,5

Research on TMS began in the mid-1980s. The studies focused mainly on its therapeutic use in neuromotor and neurological pathologies and in some psychopathologies,6 recommended by the Food and Drugs Administration for treat depression, headache, and compulsive obsessive disorder. Regarding cocaine addiction it is still an investigational product.6 Certain behavioral changes were of particular interest to researchers studying compulsive behavior. The first trial with cocaine addicts was published in 2007. However, a limited number of papers had been published by 2014.7,8 Since then, other studies have been published showing design and technique innovations. The aim of our work is to present aspects of clinical relevance to the treatment of compulsive cocaine use present in trials investigating the effects of TMS on cocaine (and cocaine-derived substance) addicts.


The use of rTMS to generate sensory and motor-evoked potentials (MEP) gave rise to investigations on the effects of rTMS on brain function.9,10 Other events were later observed, such as the increase and decrease of electrical activity in cortical areas with neuroplasticity and modulatory effects.4,11,12 The capability to alter synaptic strength is rTMS’ main therapeutic action.7,10 In this process, neurotransmitters such as dopamine (DA), glutamate and gamma aminobutyric acid (GABA) are involved.13 Increased DA14 and GABA15 secretion and release were observed following cortical stimuli produced by rTMS on the cortex of rats. In humans, rTMS in the medial prefrontal cortex caused DA to be released in the caudate nucleus16 and produced a higher concentration of GABA in the primary motor cortex.15 A lower stress response in the hypothalamic-pituitary-adrenocortical axis (HPA) was related to the effects of rTMS, which caused a decrease in the vasopressin released in the HPA axis.17

According to neurobiology of dependence studies, the glutamatergic facilitation from the prefrontal to accumbens causes loss of dopaminergic control in the accumbens activation.5 Related to higher anxiety and urgency of use, the HPA axis in this population also responds more rapidly and outside the norm of healthy physiological responses.18 Frequent and excessive use compromises the cortical functions of inhibitory control, decision-making and salience attribution, which contributes to making it difficult to control substance use, even when desired by the user.5 These findings, as well as the effects found from the previously described application of rTMS, have guided some of the hypotheses of the research on the effects of rTMS on chronic cocaine users. They have also motivated research on the effects of rTMS on people suffering from a compulsive use of other psychoactive substances, gambling, and eating disorders.19


Superficial rTMS—Figure-8 Coil

Figure-8 coil is also known as a double coil. Unlike a simple coil, which generates an electromagnetic field around the coil, its 8 shape guides the magnetic field from the 2 lateral wings, concentrating it in the central axis. This axis is known as the “hotspot” and is the place where the electromagnetic field reaches its highest value and where the coil has the greatest transmission power.20 With a focal characteristic, the figure-8 coil can reach a depth of transmission of 2 to 3 cm below the “hotspot,” depolarizing neurons closer to the surface.10

Deep rTMS—H-1 Coil

Deep repetitive transcranial magnetic stimulation (dTMS) reaches deeper areas of the brain with a lower rate of decline of the electric field.21 The H1 coil is composed of a rectangular network of parallel lines through which electrical current pulses generate a summation of magnetic fields with the same direction. dTMS is less focal than rTMS with the figure-8 coil and includes both hemispheres. Its effects are bilateral. However, as with the figure-8 coil, the summation of the magnetic fields is more potent in a coil “hotspot,” which determines a side of preference.21 It may be effective up to a depth of 5.5 cm. There is a slow decline of the field magnitude. It is believed to reach deeper regions of the brain as well as the cortical region closer to the coil.21

Theta Burst rTMS

Another rTMS modality is theta burst stimulation, which adds another device to the rTMS already described, allowing for a different frequency with each rTMS pulse. Theta burst stimulation (TBS) rTMS protocols in humans associate theta frequencies (5 Hz) with the gamma frequency (50 Hz), known as the theta gamma frequency.15 This frequency is either intermittent or continuous.15

The intermittent form—iTBS—is considered excitatory while the continuous form (cTBS) is inhibitory, the figure-8 coil being the most commonly used.4,15


Database search through Pubmed/Medline, Scopus, and Web of Science with descriptors referring to rTMS treatments and compulsive use disorders, such as those shown in Figure 1.

Search descriptors related to compulsive use paired with descriptor “transcranial magnetic stimulation” and the descriptor “treatment.”

The chosen articles were predominantly in English. However, a study in Portuguese, one in German, and one in Dutch were also included. In an initial screening, a study in Farsi was excluded, along with duplicated documents and those not in agreement with the topic. The criteria for exclusion were as follows: trials on animals; trials on Transcranial Magnetic Stimulation (TMS) related to pathologies other than compulsive psychoactive substances (PASs) use disorders or other compulsive behaviors; TMS trials with obsessive compulsive disorder; trials that did not deal with either TMS or disorders; trials on TMS for diagnosis or paired pulse; trials on TMS and compulsions focusing on neurobiology and cortical excitability; and trials on PASs disorders or other compulsive behaviors without TMS.

After the first selection, a complementary search was made in Google Scholar using names of authors cited in previous reviews not found in the first search. This sequence of selections is illustrated in the flowchart below (Fig. 2). Only trials on cocaine-dependents and rTMS were included for analysis in this review.

Flowchart showing result of the search selection in 2 steps. The 7 studies with cocaine dependents are the final selection.

Trials on cocaine-dependents were analyzed according to the 5 following topics. The first 3—area of intervention; hemisphere; and number of pulses and intensity of irradiation—describe different techniques and studied reduction of craving and consumption as outcomes. The 2 last ones analyze adverse effects and safety as well as other outcomes researched by the authors. Frequency and intensity parameters were not emphasized as a topic. In order to unify irradiation parameters, we multiply the number of pulses by the intensity of the irradiation, as frequency and intensity are connected parameters. Thus, when the frequency is increased, it is common to lower the intensity and vice versa, which is related to the safety and effect of the treatment.

All the trials included users who had been diagnosed with cocaine dependence or cocaine use disorders according to DSM-IV and DSM-V criteria. A publication in the form of a letter to an editor8 was included here as it was an innovative trial appearing in previous reviews on this topic.19,22,23 A previously unpublished single blind randomized controlled trial whose study was cited in a previous review22 was selected. However, it was not included in the tables and analysis. This trial was conducted in a master thesis and we consider it to be relevant because of the rigor in its design, method and data analysis. Ribeiro (unpublished), led the trial in 2012 and observed reduction in cocaine craving intensity after 20 sessions of rTMS over the left DLPFC. The active group was significantly different when compared to the sham one rTMS (P≤0.001). Moreover, a decrease in cocaine use was observed between 5 and 7 weeks, after the end of the treatment, which may suggest a transitory reduction in consumption. The trial is available at A summary of the published trial results is shown in Table 1.

Data Experimental Trials Using rTMS on Cocaine Addicts


Topic I—Area of Intervention: Dorsolateral and Medial Prefrontal

The two areas of choice for stimulation in the trials were the dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (MPFC). The trials which stimulated the DLPFC were based on certain hypotheses, for example, that the changes in the activation of the stimulated area cause improvements in executive control functions, resulting in a reestablishment of the capability to make rational choices.26 The authors also believe that the indirect transynaptic effects modulate and reorganize the neurotransmitter systems in the mesolimbic pathway, which reflects in healthier reward responses.7,8,24,25

Hanlon et al4 observed reduced craving in cocaine abusers when the left MPFC was inhibited. The area was allocated as a target for rTMS application because of the anatomical connection between the MPFC, ventral striatum and amygdala.4 Thus, the authors suggest that the MPFC structures, including the orbitofrontal cortex, are a “cortical input to the ventral striatum,” and that an intervention with rTMS in the area would cause a direct response in the ventral striatum. Therefore, MPFC inhibition could modulate the dysfunctional activity in the ventral striatum, observed during the anticipation of substance use,5,27 improving the reward functions and reducing craving.4 The main areas of intervention are represented in Figure 3.

From the left to right DLPFC as intervention. Higher activation on DLPFC with TMS, modulate and reorganize the neurotransmitter systems in the mesolimbic pathway, which reflects on healthier reward responses7,8,28 MPFC as intervention area. MPFC inhibition could act by modulating the dysfunctional activity in the ventral striatum, observed during the anticipation of substance use,5 improving the reward functions and reducing craving4 (illustrated by Leonardo Caldi). DLPFC indicates dorsolateral prefrontal cortex; DS, dorsal striatum; MPFC, medial prefrontal cortex; NA, nucleus accunbens; OFC, orbitofrontal córtex; VS, ventral striatum.

Topic II—Choice of Hemisphere: Right and Left

The choice of the hemisphere to be stimulated is commonly related to variations in cortical activity found in individuals with certain pathologies. For example, it is assumed that individuals with depression possess an increased dorsolateral prefrontal cortical metabolism on the right side and reduced on the left,6,28 which leads researchers to choose to stimulate the left and/or inhibit the right.6,29 Psychoactive substances cause alterations in prefrontal cortical metabolic activation.5 In the case of stimulants such as cocaine, a rise in cortical activity occurs after use, and during abstinence the prefrontal region is hypoactive. However, during the anticipation of use there is a rise in activity both in the prefrontal and reward areas.5,27 Among cocaine abusers, it is not yet clear which of the hemispheres shows greater or less activation.5,25

Camprodon et al7 compared the effects of rTMS on the left and right DLPFC in individuals with smokable cocaine dependence. Reduced craving was observed with rTMS on the right side but not on the left, with ratings returning to the baseline after four hours. The authors suggest that when applying high frequency rTMS on the right DLPFC, there is improved control over seductive choices, consequently reducing craving, and that this result is likely a reflection of the suppression of contralateral neuronal activity.7

Politi et al8 observed the effect of rTMS on the left DLPFC. Participants were given 10 rTMS sessions on the left DLPFC. Given the modulatory properties of rTMS, different from Camprodon et al,7 they found significantly reduced craving from session 7, showing that rTMS on the left DLPFC brought about a gradual reduction of cocaine craving, because of a probable interference in the biological processes of dependence8

Terraneo et al24 stimulated the left DLPFC in a randomized pilot trial with 2 experimental stages. In it, the control group used the standard pharmacological treatment, whereas the stimulated group was given 8 rTMS sessions. The authors observed differences regarding reduced craving and use in the stimulated group in comparison to the control group. In the second stage of the trial, the same procedure was used with the control group—without the standard treatment used in the first stage (one week of wash-out). In both stimulated groups (stages 1 and 2), there was a reduction of craving and consumption, confirming the efficacy of high-frequency rTMS on the left DLPFC.24 On the basis of previous findings,30 the authors believe that high-frequency rTMS on the left DLPFC improves local inhibitory function, helping to control craving and reduce cocaine use.24

Bolloni et al25 applied bilateral deep rTMS (H-1) on the prefrontal cortex (PFC), with preference to the left. This trial in particular merited a more detailed description of its analyses in order to better understand the results. The authors found no significant difference between the active rTMS group and the sham group when they jointly analyzed the time and effect of treatment. However, reduced consumption when they only took the time factor into consideration was found. This reduction was described between the baseline and 3 months and the baseline and 6 months after the experiment. Later, it was observed that the reduced consumption occurred in the group that received the active rTMS but not in the sham group. Therefore, although it was not stated that the effects of treatment brought about a reduction of use, when analyzing only the timeline, a reduction in use was observed only in the actively stimulated group.

The authors highlighted the H-1 coil benefits because of its bilateral action and the inclusion of a greater area of the brain, impacting both the prefrontal cortical and subcortical areas. On the basis of previous findings,30 it is proposed that simultaneous bilateral application can produce greater improvement in the dopaminergic system.25

Rapinesi et al26 carried out a double-blind noncontrolled trial. A deeper H-1 rTMS on the bilateral DLPFC was targeted, with preference to the left, in order to reach the medial and lateral prefrontal areas and the orbitofrontal cortex.26 Results after four weeks of stimulation showed a progressive reduction of craving, with a greater effect in week 2, and craving ratings maintained for another four weeks after the end of the sessions. The authors’ hypothesis was that dTMS on the DLPFC causes improvement in the “connectivity strength” between the hippocampus and the PFC, and may re-establish functions in deeper areas accessed by pathways originating in the DLPFC.26

Hanlon et al4 used TBSc rTMS with a crossover design in 2 TBSc sessions—one active, on the left MPFC and a sham one on the right MPFC. The authors used 3 categories for assessing craving outcomes: reduced craving, no change, and increased craving. A difference in craving reduction appeared only in the active TBSc group. The authors believe that the results of the analysis were “propelled” mainly by the increased craving of 3 individuals of the sham group and no increase in the active group.4

Topic III—Number of Pulses and Intensity of Irradiation

The number of pulses changed from trial to trial, but all of them found favorable results in some of their analyses. To better compare the results, we have created an arbitrary unit multiplying the number of pulses by the intensity of the irradiation in the magnetic field, thus obtaining the stimulus power (pulses×intensity=stimulus power). The results for number and intensity of pulses used in the trials can be found in Table 2.

Relationship Between Pulses/Intensity Applied With rTMS and Reduced Cocaine Craving and Use

Topic IV—Safety and Adverse Effects

Only mild adverse effects were observed, such as pain in the stimulated area at the beginning of the process, discomfort in the first few sessions and mild cephalea with no seizure episodes. Four trials, including Ribeiro’s (unpublished), were conditioned to the subjects undergoing complete detoxification before the procedure, including hospitalized patients.4,7,8 The most recent trials24–26 did not require abstinence for inclusion and no difference in adverse effects was observed.

As safety measures Terraneo et al24 prescribed Disulfiram to avoid alcohol use,24 and Bolloni et al25 excluded 4 participants that reported excessive cocaine use.

Topic V—Other Outcomes

Hanlon et al4 observed changes in cortical activity based on cortical oxygen levels. A decrease of activity in a target area (MPFC) as well as in striatum connectivity was observed. Camprodon et al7 found reduced anxiety and increased joy when stimulating the right DLPFC, and increased sadness with stimulation on the left one.


The DLPFC was the target area used by most authors, with positive results for reduced cocaine craving and use outcomes.7,8,24–26 Research with rTMS and compulsive use of other PASs also used these areas with similar aims and results.31–50 Those studies were based mainly on the hypothesis that dorsolateral activation would bring about improvement in the functions of executive control and reestablishment of inhibitory action in the reward system.

In Hanlon et al4 the target area for rTMS application was the MPFC with an inhibitory frequency, much like the DLPFC activation used in other trials. This choice was based on the assumption that inhibiting the MPFC by a medial cortex direct pathway to the striatum because of the proximity of the areas could also be a treatment strategy, as they are related and on the same neuronal network.4,51,52

The DLPFC and MPFC are considered key components of the executive network and default mode network, respectively.51,52 With regard to the neurobiology of dependence, the two areas are involved and interdependent. The delicate nature of the functions of inhibitory control and an imbalance of the reward system are at the basis of the neurobiological dependence models proposed.5

Concerning the choice of hemisphere intervention, the results of reducing cocaine craving and/or use were observed in trials stimulating the DLPFC with rTMS on the right,7 on the left,8,24 bilaterally with preference on the left25,26 and with an inhibitory TBSc pattern in the MPFC area with the coil focus on the left frontal pole.4 Only one trial achieved better results with rTMS on the right,7 a pioneer preliminary trial in this line of research with only one crossover session, comparing rTMS on both hemispheres.

Two trials8,26 used a similar number of pulses, frequency and intensity parameters, and identical target areas, and obtained similar results in reducing craving. It is possible that there are differences between the 2 techniques (superficial figure-8 and deep H-1), regarding duration of the effect but their results are similar in terms of the immediate effect.

The side effects reported in all trials were mild. The adverse effects are similar to those of trials in which the participants remain in abstinence or not before rTMS applications. Three possible factors may contribute to reliable results when no detoxification is required: reduction in the use of medications, bias elimination and improved adhesion to treatment. The 2009 Consensus53 recommends care in the use of rTMS on individuals who use substances that reduce the convulsive threshold, but does not refer to any cases of serious adverse effects from the use of rTMS with cocaine users.

The small number of samples is still a limitation of the trials using rTMS on cocaine-dependents. The absence of randomization, a sham control group and blinding in some trials have made it difficult to use the data in meta-analyses and future recommendations about the clinical use of rTMS for treating cocaine dependence. Three trials used similar frequency and intensity parameters, which may be indicative of a consensus in parameter choices.8,24,26


The trials found positive results in outcomes such as reducing cocaine craving and use. One trial did not observe a difference between the groups regarding the effect of rTMS treatment.25 We highlight the potential of rTMS for treating cocaine compulsion. The majority of the trials of rTMS applications were preferably targeted on the left hemisphere. The dorsolateral prefrontal area was a target in most of the trials, but application on the medial area was also promising for further research with cocaine-dependents. The pulse parameters applied differed between trials and seemed to bear a relationship with the effect duration. One trial showed that rTMS can be safe for active cocaine users.24 All 3 rTMS techniques employed seemed to have brought immediate benefits. Only the trials using deep rTMS made follow-ups up to 6 months afterwards and observed a prolonged effect.


The authors acknowledge Vanessa Karam de Lima Ferreira: Alcohol and Drugs Program, Institute of Psychiatry of the Federal University of Rio de Janeiro, Rio de Janeiro, Brazil and Leonardo Caldi: Design Department of University Veiga de Almeida, Rio de Janeiro, Brazil.


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repetitive transcranial magnetic stimulation; rTMS; cocaine-related disorders; dependence; drugs

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