Prefrontal Modulation by Repetitive Bilateral Transcranial Direct Current Stimulation (tDCS) in Crack-cocaine Addicted Inpatients.
Phase: PHASE2
Conditions: Drug Addiction, Executive Dysfunction
Sponsor: Federal University of Espirito Santo

 
Title: Prefrontal Modulation by Repetitive Bilateral Transcranial Direct Current 
Stimulation (tDCS) in Crack-Cocaine Inpatients  
 
Brief Title: Bilateral Prefrontal Modulation in Crack-Cocaine Addiction 
(tDCS_CRACK)  
 
Institution: Federal University of Espírito Santo  
 
Principal Investigator: Ester Miyuki Nakamura-Palacios, MD, PhD  
 
Identifiers: NCT02091167    
Unique Protocol ID: tDCS CRACK CEP_UFES 384281    
Secondary IDs: CNPq_ 475232/2013-5 
 
Date: October 23, 2018 
 

Transcranial direct current stimulation (tDCS) is a non-invasive brain 
stimulation tool which has proven to be efficient in modulating brain activity 
(George and Aston-Jones, 2010). Previous studies already demonstrated 
favorable effects of tDCS compared to sham stimulation in substance use 
disorders and craving. Accordingly, we have demonstrated that in crack-cocaine 
dependent subjects, five sessions of right anode/left cathode bilateral 
stimulation of the dlPFC was able to significantly reduce craving both during 
and after treatment in the real tDCS group as compared to a sham-tDCS group 
(Batista et al., 2015). Thus, we hypothesized that extension of repetitive 
bilateral dlPFC tDCS to ten sessions would have a more pronounced effect on 
craving in crack-cocaine substance use disorder, considering that a successful 
management of craving during treatment is highly desirable to prevent dropouts 
and relapses. 
 
Material and Methods 
We report this clinical trial according to CONSORT guidelines. This trial 
was registered under Clinical Trials.gov number NCT02091167. 
 
Participants  
All subjects were informed about the purposes of the experiment by the 
principal investigator and signed a written consent before entering the study. 

Thirty-five patients, 29 men and 6 women, who met DSM V criteria for 
cocaine (crack) use disorder were recruited between June of 2015 and April of 
2018 from three specialized clinics for drug use disorder treatment (one public 
and two private hospitals) from Espírito Santo State, Brazil. They all received 
standard treatment given by the clinics, consisting of psychosocial approaches 
– conducted by a professional team of psychologists, nurses, social workers 
and physicians – sometimes combined with adjunctive pharmacotherapy 
including benzodiazepines, B-complex vitamins, disulfiram and, if necessary, 
antidepressants, anxiolytics, antipsychotics, antihypertensive and gastric 
medication. It must be mentioned that in the public hospital, from where half of 
the patients was recruited, they were not allowed to have any medication, 
except non-opioid pain relievers when absolutely necessary, after they had 
been admitted to the hospital. Therefore, half of the patients were free of 
medication during the sham- or DC-stimulation. From the other half patients 
coming from the two private clinics, few of them were medicated 
(antipsychotics, antidepressants or mood stabilizers) during brain stimulation 
procedures. 
There were two dropouts in the sham-tDCS group that were excluded 
after randomization. One patient escaped from the treatment facility and the 
other had to be discontinued because of precocious discharge from the clinic for 
misconduct.  
The inclusion criteria for this study were: (1) male and female patients 
over the age of 18 years; (2) met criteria for crack-cocaine use disorder 
according to the ICD-10 Classification of Mental and Behavioral Disorders and 
the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, as 

determined by clinical evaluation; (3) in stable clinical condition with no need for 
emergency care; (4) able to read, write, and speak Portuguese; and (5) no 
severe withdrawal signs or symptoms at baseline.  
Furthermore, exclusion criteria included: (1) a condition of intoxication or 
withdrawal due to a substance other than crack-cocaine, (2) unstable mental or 
medical disorder or substance abuse or addiction other than crack-cocaine use 
disorder, except nicotine and/or caffeine; (3) diagnosis of epilepsy, convulsions, 
or delirium tremens during abstinence from crack-cocaine; (4) a previous history 
of drug hypersensitivity or adverse reactions to diazepam or other 
benzodiazepines and haloperidol; (5) any contraindication for electrical brain 
stimulation procedures such as electronic implants or metal implants. 
The study was approved by the Brazilian Institutional Review Board of 
the Federal University of Espírito Santo (CAAE 19403713.6.0000.5060), Brazil, 
and all patients signed a written informed consent form. The study was 
conducted in strict adherence to the Declaration of Helsinki and is in 
accordance with the ethical standards of the Committee on Human 
Experimentation of the Federal University of Espírito Santo, ES, Brazil.  
 
DC stimulation  
A randomized double-blind clinical trial tDCS protocol was used in the 
study. Stimulation was done using a DC stimulator (DC-Stimulator Plus, 
NeuroConn, Ilmenau, Germany) with two carbonated silicone electrodes (35 
cm²) with a thick layer of high-conductive EEG gel beneath them according to 
our previous study (Nakamura-Palacios et al.,2012). Electrodes were placed 

based on the international 10-20 electrode placement system. For tDCS, the 
cathode was placed over the left dlPFC (F3) while the anode was placed over 
the right dlPFC (F4). Each session of tDCS lasted for 20 minutes with fade-in 
and fade-out periods of 30 seconds each. Intensity was set to 2 mA.  For sham 
tDCS, the electrodes were placed at the same positions.  
During active tDCS treatment, subjects typically reported tingling 
sensations under the electrodes area, which rapidly faded (Batista et al., 2015). 
Our sham intervention was therefore designed to provide an initial period of 
tingling - the stimulator was automatically switched off after 30 seconds of either 
anodal or cathodal stimulation - so that similar sensations are perceived during 
active and sham tDCS protocols, thus serving as an ideal control condition 
(Nitsche et al., 2003;Gandiga et al., 2006;Batista et al., 2015). Data and 
instructions in the device display are identical in active and sham settings.  
For the sham stimulation procedure, the stimulator automatically 
switched off after 30 seconds of either anodal or cathodal stimulation yielding 
sensations typically elicited by tDCS. 
  
Craving assessment 
Craving was scored through a brief scale composed of five items (1, 2, 4, 
5, and 13) of the Obsessive-Compulsive Cocaine Use Scale, also known as the 
Obsessive-Compulsive Cocaine Scale (OCCS), which are based on the 
Obsessive-Compulsive Drinking Scale (Anton et al., 1995;Anton et al., 
1996;Anton, 2000), as proposed by Hormes et al. (Hormes et al., 2012) and 

Vorspan et al. (Vorspan et al., 2012).  These five-item scales assess craving in 
a narrow sense according to De Wildt et al. (de Wildt et al., 2005).  
Through this brief scale it is possible to quantify thoughts and feelings 
(obsessions), and behavioral intentions (de Wildt et al., 2005), answered on a 
scale ranging from 0 to 4, resulting in a total score between 0 and 20. Patients 
are questioned on how much of the time (total per day), when the drug is not 
used, is occupied by thoughts, ideas, desires, or impulses related to crack-
cocaine and its effects; how frequently these thoughts, ideas, desires, or 
impulses related to crack-cocaine and its effects occur; how much distress or 
disturbance these ideas, thoughts, impulses or desire related to crack-cocaine 
use cause when the person is under withdrawal; how much effort they have to 
make to resist these thoughts, ideas, desires, or impulses, or how much energy 
they have to spend to think of something else when they enter the mind under 
withdrawal; and finally ask about their drive to use crack-cocaine. 
The OCCS was applied in the week before the beginning of the real or 
sham-tDCS treatment, during the treatment (second, third and fourth weeks) 
and in the week after the end of the brain stimulation application, resulting in 
five time-points measurements. 
 
Relapses in 30- and 60-days follow-up 
After their discharge from the hospital, patients from sham- and real 
tDCS groups were followed-up for at least 60 days regarding crack-cocaine use 
relapses. A use relapse was defined as the first episode of return to the 

previous uncontrolled pattern of crack-cocaine use (rocks per day) (Klauss et 
al., 2014). Information about relapse were gathered directly when patients 
regularly returned to the hospital for clinical follow-up after their discharge 
and/or by self-report or reports of family members by telephone calls. 
 
Procedures  
Those patients who were eligible according to inclusion and exclusion 
criteria described above and agreed to participate in this study signed an 
informed consent sheet. All data were 
originally acquired from participants entering this single research center clinical 
trial to investigate the efficacy of tDCS treatment.  
After global physical and clinical examination subjects were randomly 
assigned to one of the two groups (sham- and real tDCS) in a 1:1 ratio using a 
computer-generated block randomization sequence that was kept with the 
unblinded study coordinator (not involved in the recruitment). The co-
investigator conducting treatments was only given a list of 5-number blinding 
codes to be loaded to the DC-stimulator before each session of brain 
stimulation. The device is previously settled with specific settings for the study.  
After patients had been admitted to the hospitals, they were maintained 
under regular treatment for 30 days in average or until they had reached a 
global clinical stabilization, to have them started in the sham- or real tDCS 
treatments. The brain stimulation application was then performed in one 20-min 
session a day, every other day, including weekends, up to a total of 10 

sessions, always in the afternoon period, in the following five weeks and they 
were followed-up after the end of the stimulation treatment for up 60 days after 
their discharge from the hospitals. 
Craving was measured once a week over five weeks (once before the 
beginning of the stimulation sessions, three times over the stimulation sessions 
and once more after the end of stimulation sessions) with a total of five time-
points measurements. Relapses were collected after discharge from the 
hospital up to 60 days after intervention.  
Participants and experimenters were blinded for brain stimulation 
assignments from the beginning of the study protocol up to the end of the 60-
days follow-up after the end of sham- or real tDCS treatment, resulting in a 
double-blind experimental design. 
 
Statistical Analysis  
 We powered the study for a medium effect size based on the results of 
our previous study (Batista et al., 2015) in which the effect size (partial ղ2) for 
the main within-subject factor in the respective two-way ANOVA with repeated 
measures was 0.10384 when comparing craving scores once before, twice 
during and once after 5-sessions of tDCS (four time-points). The tDCS 
electrode montage was identical in the studies, and patient populations of 
crack-cocaine users were similar. We used the correction for SPSS input into 
the G*Power 3.1.9.2.  With this effect size, for the two-way mixed model 
ANOVA of the present study with the within factor craving measurements, the 

between-subject factor tDCS condition, the dependent variable craving score, 
and craving measurements x condition interaction as the primary outcome 
parameter, with a power of 80%, and a two-sided probability of a type I error of 
5%, the resulting minimum sample size was 30 participants. To account for 
waiving or dropouts, which were expected to be very common in this condition, 
we increased the estimated sample size to approximately 10%, resulting in 33 
subjects in total (approximately 16 to 17 subjects in each group). 
Most of data (age, patterns of crack-cocaine use, 5-items OCCS) were 
normally distributed according to the D'Agostino & Pearson normality test, thus 
they were analyzed by parametric tests. Between-group (sham- and real tDCS) 
comparisons were conducted by unpaired Student´s t-tests. For all other non-
parametric data (gender, schooling, employment, marital state and tobacco 
use), Chi-square or Fisher tests were used to compare sham and real tDCS 
groups.  
Besides the two-way ANOVA with repeated measures followed by 
Bonferroni-corrected t-tests, linear regression analyses were done over craving 
scores obtained along the 4-week treatment (five time-points measurements) 
for both groups. Additional comparisons between initial and final OCDS scores 
were done by paired t-tests for each group, and differences between final and 
initial scores were compared between sham-tDCS and real tDCS groups with 
unpaired t-test. Effect sizes were calculated using Cohen’s d and corrected by 
Hedges’s gs for unpaired and Hedges’ gav for paired t-tests (Lakens, 2013).   
A two-tailed p-value of 0.05 or less was considered to indicate statistical 
significance. SPSS Statistics Base 24.0 (SPSS Inc, USA) and GraphPad Prism 

7.0 (GraphPad Software Inc, USA) were employed for statistical analysis and 
graphic presentations.