2024; 22(3): 512-519  https://doi.org/10.9758/cpn.24.1163
Effect of Intensified Transcranial Direct-current Stimulation Targeting Bilateral Dorsolateral Prefrontal Cortex on Craving Reduction in Patients with Opioid (Heroin) Use Disorder
Hadis Amini Tameh1, Saeed Imani1, Jaber Alizadehgoradel2, Alireza Noroozi3
1Department of Counseling, Faculty of Educational Sciences and Psychology, Shahid Beheshti University, Tehran, Iran
2Department of Psychology, Faculty of Humanities, University of Zanjan, Zanjan, Iran
3Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
Correspondence to: Saeed Imani
Department of Counseling, Faculty of Educational Sciences and Psychology, Shahid Beheshti University, Tehran 19839-69411, Iran
E-mail: S_imani@sbu.ac.ir
ORCID: https://orcid.org/0000-0002-6990-5858

Jaber Alizadehgoradel
Department of Psychology, Faculty of Humanities, University of Zanjan, Zanjan 45371-38791, Iran
E-mail: j.alizadeh@znu.ac.ir
ORCID: https://orcid.org/0000-0003-4803-0607

*This manuscript was derived from Hadis Amini Tameh’s thesis in Rehabilitation Counseling approved on August 29, 2023, at the Faculty of Psychology and Educational Sciences of Shahid Beheshti University.
Received: January 2, 2024; Revised: February 24, 2024; Accepted: March 4, 2024; Published online: March 26, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective: This study aimed to analyze the effect of the intensified transcranial direct-current stimulation (tDCS) targeting bilateral dorsolateral prefrontal cortex (DLPFC) on craving reduction in patients with opioid use disorder.
Methods: This quasi-experimental study was conducted on 30 individuals who participated voluntarily at Baharan Camp of Shahid Mahalati. The participants had already completed the detoxification phase and stayed at the camp to resolve their craving and gain occupational skills to reintegrate into the community. The participants were selected using convenience and purposive sampling methods and were then assigned to an experimental group (n = 15) and a control group (n = 15). The experimental group received ten 20-minute tDCS sessions twice a day for 5 consecutive days. There was a 20-minute break between the two stimulations. The DLPFC was stimulated with a current intensity of 2 mA (anode: F3 and cathode: F4). The control group received a sham stimulation. Both groups completed Franken’s Desires for Drug Questionnaire at baseline and after the stimulation sessions. Additionally, they completed the questionnaires once again three months after the end of the treatment to assess treatment retention.
Results: At the posttest stage, the intensified tDCS had significant effects on momentary opioid craving reduction in all measured factors, e.g., desire and intention, negative reinforcement, and control (p < 0.001). However, the results concerning treatment retention at the 3-month follow-up stage were insignificant for all factors (p < 0.001).
Conclusion: Apparently, tDCS can be used as a tool to reduce craving. However, its application as an independent and sustainable treatment remains debatable.
Keywords: Opioid-related disorders; Transcranial direct-current stimulation; Craving
INTRODUCTION

Substance abuse is a relapsing brain disorder with substantial costs for affected individuals and the whole society [1]. Recognized as a detrimental factor for individuals, families, and society, substance addiction stands as one of the most harmful diseases and social issues. Studies have demonstrated that opioids have significant effects on the dopaminergic and noradrenergic systems. Heroin is abused more widely than other opioids, and its addictive properties are stronger. Accordingly, it passes more quickly through the blood-brain barrier [2].

Frequent relapses following withdrawal are considered to be a highly detrimental contributor to relapse [3]. Craving is recognized as a critical component in the persistence of dependence and relapse [4]. It is defined as “intensely wanting,” “profound desire,” and “to want something with such a strong sense of urgency that it is difficult to keep thoughts focused on anything other than the object of the craving” [5,6]. The temptation or desire to use is a key cognitive infrastructure in the science of addiction and the primary factor in relapse to the use of drugs [7,8]. Studies have identified the limbic circuit and the prefrontal circuit as the underlying neurobiological factors of addiction. The limbic circuit, i.e., a component of the reward circuit, is closely associated with motivation and emotion in individuals. Moreover, the prefrontal circuit is responsible for inhibiting behaviors such as seeking drugs and thinking about drugs [9].

Approximately two centuries ago, preliminary studies conducted on animal subjects demonstrated the applicability of electrical currents in influencing the activity of the cerebral cortex. These studies revealed that excitability could vary based on the circumstances surrounding the flow of electrical current. Studies have demonstrated that when both sides of the skull are stimulated (anode-cathode), nearly 50% of the electric current passes through the brain. Hence, the effects of this electric current were introduced and exploited by placing electrodes on the skull through electrical brain stimulation with transcranial direct-current stimulation (tDCS) [10]. This technique involves the use of anode (positive pole) and cathode (negative pole) electrodes, which are placed on the scalp to apply a mild electric current to the brain. The anode leads to the depolarization of the resting membrane potential, which increases excitability and automatic cell firing. The cathode leads to the hyperpolarization of the resting membrane potential, thereby reducing excitability and automatic cell firing [11].

The tDCS technique has been used for approximately three decades. In comparison with other psychological and medicinal approaches or brain stimulation methods, e.g., transcranial magnetic stimulation and deep brain stimulation, tDCS is characterized by its efficacy, lack of significant side effects, painlessness, non-invasiveness, implementation on an outpatient basis, simplicity, relatively low cost, and non-interference with other treatment modalities [12-14]. In most studies, the dorsolateral prefrontal cortex (DLPFC) is targeted for stimulation due to its accessibility and connection to drug craving and the limbic system. The limbic system plays a key role in controlling temptation and substance intoxication [15-17]. Neurological studies have found that a decrease in the activity of the DLPFC is associated with an increased risk of relapse and resumption of substance use [18]. Therefore, the activation of this cortex for the treatment of drug addiction is considered one of the most recent approaches to addiction treatment [19].

According to a review of the results from various studies, tDCS is associated with reductions in craving and other symptoms of drug intoxication [20-22]. Furthermore, few studies have used this technique to treat addiction [23]. Review studies on various treatment protocols indicate that 2-mA stimulation is superior to 1-mA stimulation. Moreover, multi-session interventions outperform single-session ones, and the intensified stimulation is stronger than the single stimulation [24-27]. According to the literature review, there appears to be a dearth of research on the use of tDCS technique, inadequate studies on addiction, and a lack of investigation into the long-term effects of this technique on craving reduction. Given the significant rate of opioid consumption in Iran and the greater addictiveness of heroin in comparison with other opioids, this study aims to analyze the enduring effect of brain tDCS targeting bilateral DLPFC on craving in patients with opioid use disorder (heroin).

METHODS

Participants

This quasi-experimental research adopted a pretest-posttest sham group design. The statistical population included individuals with substance use disorder who had voluntarily referred to the Baharan Camp of Shahid Mahalati. Convenient purposive sampling was employed to select 30 individuals. Since the statistical population involved a limited number of people, it was not possible to conduct an intervention on a larger sample size. Therefore, the 30 participants were equally assigned to an experimental group (n = 15) and a control group (n = 15). Three months after the intervention ended, the participants were followed up to assess the stability of tDCS effect.

The inclusion criteria were as follows: being diagnosed with a substance use disorder per the Diagnostic and Statistical Manual of Mental Disorders, fifth Edition (DSM-5) and being male. The exclusion criteria were as follows: 1) the use of psychiatric medications as they would affect tDCS treatment (medicines prescribed by the psychiatrist to improve psychiatric disorders such as depression and anxiety), 2) the diagnosis of bipolar or psychotic mood disorder based on DSM-5 criteria, 3) the presence of intracranial implants (e.g., shunts, stimulators, and electrodes) and any other non-removable metal objects near the head (e.g., the mouth); and 4) a history of convulsions and epilepsy.

The study was approved by the Institutional Review Board of Faculty of Psychology and Educational Sciences of Shahid Beheshti University (IRB no. IR.SBU.REC.1402.004). All participants initially provided their informed consent.

Measures

Desires for Drug Questionnaire: this scale designed by Franken et al. [7]. It centers on consumption craving as a motivational state and assesses heroin craving at the present moment. The questionnaire consists of 14 items organized into three factors. “Desire and Intention,” including items 1, 2, 12, and 14, represents the first factor. Con-cerning the second factor, i.e., “Negative Reinforcement,” items 5, 9, 11, 4, and 7 are included. This factor pertains to the belief that drug use can solve life challenges and establish pleasure. Finally, “Control” comprises items 3, 8, 6, 10, and 13. Notably, there is a high correlation between these three components. Franken et al. [7] used Cronbach’s alpha method to report the total reliability of this questionnaire as 0.85 and those of its subscales as 0.77, 0.80, and 0.75, respectively. The internal consistencies of the subscales conducted by Hassani-Abharian et al. [28] on individuals who abused various types of opioids, including crack and heroin, were found to be 0.89, 0.79, and 0.4, respectively. For methamphetamine abusers, the internal consistency coefficients of the subscales were 0.78, 0.65, and 0.81, respectively. The internal consistency was also assessed using Cronbach’s alpha method. The results indicated that the internal consistency for the total scale was 0.96 for opium users, 0.95 for crack users, 0.90 for methamphetamine users, 0.94 for heroin smokers, 0.94 for heroin inhalers, and 0.98 for injecting heroin users.

Interventions

Initially, the code of ethics was acquired, and the requisite coordination was made with the Baharan Camp management. The consent forms were provided for the eligible participants, considering the possibility of minor side effects (e.g., headache or burning at the site of electrode installation). The participants were then assigned to an experimental group and a sham group. All participants completed the measurement tests at baseline, after the 10 stimulation sessions, and three months after the treatment ended. The stimulation sessions in the present study were of an intensified type, administered twice daily with a 20-minute interval. Each session had an intensity of 2 milliamps, which differs from previous studies. The participants had a 20-minute break between the two stimulations. Measurements were taken on their heads at the beginning of each session. In the experimental group, the anode electrode was positioned on the F3 point, whereas the cathode electrode was positioned on the F4 point. To mitigate bias in the results, the research followed a single-masked design, i.e., the participants were unaware of the testing process. The device model is labeled Neurostim2 manufactured by Medina Teb Gostar Company. This device features two completely separate channels that can be deployed concurrently. It is powered by a lithium battery with a capacity of 1,800 mAh. The maximum current intensity of this device is 2 mA. It transmits a constant electric current by connecting electrodes made of carbon and conductors with different polarities (i.e., anode and cathode). The physiotherapy pads used in this study measured 5 × 5 cm2. These pads are inserted into a sponge saturated with a 9% sodium chloride solution. The purpose is to enhance the conductivity of the electric current and prevent excessive heat. The intensity of the current, the size of the electrodes, and the duration of the stimulation are all controlled by the researcher and are easily adjustable. The independent t test, chi-square test, and mixed-design repeated measures analysis of variance were used for data analysis in IBM SPSS Statistics 26.0 (IBM Co.).

RESULTS

Table 1 reports descriptive statistics of demographics in each group. Both the experimental group and the control group consisted of 15 participants each. The data overview of the dependent variables before, after and follow-up is presented in Table 2.

The effect of tDCS on craving reduction was analyzed through a mixed-design repeated measures analysis of variance (ANOVA). Table 2 lists the findings. Additionally, the Bonferroni test was conducted to draw pairwise comparisons of the research groups.

A mixed model repeated measures ANOVA was conducted for the respective dependent variable (craving) with “group” (active vs sham) as the between-subject and time (pre-intervention, post-intervention, follow-up) as the within-subject factors. Mauchly’s test was used to evaluate the sphericity of the data before performing the repeated measures ANOVA. In case that the assumption of sphericity was violated, the degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity. Post-hoc analyses were calculated using Bonferroni-corrected Student’s t tests.

According to Table 3, the interaction effect (time × group) was significant on the momentary craving for substances and the factors of desire, intention, and control. Additionally, the eta-squared value exceeded 0.1, indicating a large and significant difference between the groups in the statistical population. The results also indicated that time had significant effects on drug craving and its three factors. However, the results revealed that the group had insignificant effects on drug craving and its factors. At the pretest stage, there were no significant differences between the tDCS and sham groups in momentary craving and its factors, according to the results of the Bonferroni analysis. In other words, the tDCS group experienced significant changes from the pretest stage to the posttest stage as opposed to the sham stimulation group. Although there was a difference between the experimental group and the sham group in the mean score during the follow-up phase, it did not reach statistical significance. Table 4 reports the analysis results.

DISCUSSION

This study aimed to analyze the effect of the intensified tDCS targeting bilateral DLPFC on drug craving reduction among individuals with heroin use disorder.

The results indicated a significant decrease in the craving of the experimental group members. This finding is consistent with the results reported by other studies [20,25,29,30].

This finding can be attributed to the action mechanism of tDCS on the brain’s prefrontal cortex. Neuroimaging studies reveal numerous connections between the prefrontal cortex and the limbic region, i.e., a specialized area responsible for experiencing emotions. The prefrontal cortex is responsible for recognizing actions and their outcomes as well as predicting the outcomes of social control. When this area is stimulated, social control increases, and a person can better predict the outcomes of their behavior, reducing consumption craving [31]. The anode in bilateral DLPFC stimulation increases excitability, resulting in a positive charge on the inner surface of the cell membrane. Conversely, the cathode decreases excitability, leading to a negative charge on the cell membrane’s inner surface. The direction of change depends on the polarity of the active electrode. Moreover, tDCS is a noninvasive technique for improving brain function by making certain changes. This technique has been widely used for treating diverse psychiatric disorders and in neuroscience research [32].

The stability of this technique is negligible and statistically insignificant, as evidenced by the 3-month follow-up of the experimental and control groups. Other studies have also indicated that the stability of tDCS remains a subject of debate [33,34].

This study analyzed the stability of tDCS effect on craving reduction by using only the Desires for Drug Questionnaire [7]. The inability to capture brain maps prevented the examination of brain changes in the partici-pants. However, it is reasonable to warrant further research on the long-term effects of this technique using more extensive sample sizes and longer durations of time. This seems necessary considering the benefits of this therapeutic approach—e.g., its cost-effectiveness, simplicity, and limited negative consequences—along with its demonstrated efficacy in both short-term and long-term across multiple studies and addiction types [33].

Studies have primarily focused on the immediate effects of tDCS on craving. To establish this approach as a viable long-term treatment, further studies must be incorporated with larger sample sizes and extended treatment durations (i.e., the number of required sessions). Given the intricate neurobiological nature of addiction, an additional inquiry arises regarding the potential use of neuromodulation techniques. Can these techniques serve as standalone or complementary interventions that enhance the efficiency of other approaches, e.g., drug therapy and psychotherapy? One potential avenue for advancing the application of neuromodulation techniques is through the use of neurocognitive profiles. These profiles can provide valuable insights into which particular types of techniques may be advantageous for an individual [34].

This study aimed to analyze the impact of the intensified stimulation protocol, which was implemented twice daily with a 20-minute interval between sessions. The stimulation intensity was set at 2 mA for 20 minutes. The rationale for selecting this protocol is based on previous research demonstrating that the cerebral cortex retains the effects of intensified stimulation for a longer duration when the interval is 20 minutes. The finding was obtained by comparing it to non-repeated stimulation with long intervals and is similar to the characteristics observed in the last phase of long-term potentiation. Studies also indicate that 2-mA stimulation outperforms 1-mA stimulation, that multi-session interventions are superior to single sessions, and that 20 minutes of stimulation has greater effects than other durations (e.g., 15 and 30 minutes) [23,35-37]. This study demonstrated the effectiveness of this protocol at the posttest stage. However, the lack of sustainable effects in the follow-up phase should be analyzed in future research. Is it possible to use alternative protocols to achieve a stable effect? Does this matter rely on additional variables?

This study faced certain limitations. For instance, the participation of the sample members in the camp was voluntary. Checking to see if these people’s motivation to improve is effective in the treatment process was one of the unexplored issues in this study, constituting a major limitation that may have biased the results. Additionally, tDCS is a brain treatment. Therefore, brain maps are necessary to provide an accurate explanation of the cause of therapeutic changes and the reason for their lack of stability at the 3-month follow-up stage. These maps can illustrate the process of changes and neurological adjustments that occur after the intervention and over a few months. This study also faces a limitation regarding gender bias. Since all participants were male, caution is needed in generalizing and interpreting the results. This study could not use brain maps for a more detailed investigation due to the absence of a research assistant, a neuroscience specialist, and insufficient financial resources. Another limitation of the study is that it lacks a double-masked design. The researcher’s awareness of the protocol procedure may have biased the results. There is a research gap regarding the cognitive variables involved in the treatment of individuals with substance use disorder or drug addiction through electrical brain stimulation. There is ongoing debate regarding the efficacy of tDCS as a stable treatment, and the stability of this treatment was not statistically significant in the current study. Therefore, future research should examine mediating cognitive variables, e.g., participants’ motivation for improvement. One suggestion to clarify the effectiveness of tDCS is to conduct a comparative study that combines tDCS with psychotherapy, drug therapy, and independent treatment. Time and funds will be allocated to best serve the affected individuals and the community in the wake of this clarification.

ACKNOWLEDGEMENTS

I am appreciative to all individuals who participated and collaborated in this research.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Saeed Imani, Jaber Alizadehgoradel. Methodology: Saeed Imani, Jaber Alizadehgoradel. Investigation: Hadis Amini Tameh, Alireza Noroozi. Data acquisition: Hadis Amini Tameh, Alireza Noroozi. Formal analysis: Saeed Imani, Jaber Alizadehgoradel, Hadis Amini Tameh, Alireza Noroozi. Statistical analysis: Hadis Amini Tameh, Alireza Noroozi. Visualization: Saeed Imani, Jaber Alizadehgoradel. Supervision: Saeed Imani, Jaber Alizadehgoradel. Writing—original draft: Saeed Imani, Jaber Alizadehgoradel. Writing—review & editing: Saeed Imani, Jaber Alizadehgoradel. All authors read and approved the final version of the manuscript.

Tables

Demographic data

Variable Intensified direct current stimulation (tDCS) Sham stimulation p value
Sample size 15 15 0.999
Age (yr) 29.46 ± 7.12 29.53 ± 6.18 0.978
Age of onset (yr) 24.46 ± 3.99 25.00 ± 4.12 0.722
Marital status 0.624
Single 12 13
married 3 2
Length of substance use 4.80 ± 2.85 4.93 ± 2.93 0.901
Substance abuse by family members 0.713
Yes 8 9
No 7 6
Education 0.919
Under diploma 5 4
Diploma 8 9
University education 2 2

Values are presented as mean ± standard deviation or number only.

tDCS, transcranial direct-current stimulation.

Means and standard deviations of craving before and after the intensified tDCS interventions

Measure Outcome variable Time Intensified direct current stimulation (tDCS) Sham stimulation
Craving Desire and intention Pre-intervention 14.53 ± 2.85 15.06 ± 2.98
Post-intervention 11.86 ± 2.64 14.73 ± 2.46
Follow-up 13.26 ± 3.08 15.20 ± 2.98
Negative reinforcement Pre-intervention 15.26 ± 4.25 16.06 ± 3.91
Post-intervention 12.60 ± 2.38 15.33 ± 3.37
Follow-up 13.93 ± 3.19 16.20 ± 3.60
Lack of control Pre-intervention 15.86 ± 3.87 15.93 ± 4.07
Post-intervention 12.26 ± 1.28 14.86 ± 3.33
Follow-up 13.80 ± 3.85 16.00 ± 3.58
Total score Pre-intervention 45.66 ± 10.41 47.06 ±10.43
Post-intervention 36.73 ± 6.56 44.93 ± 8.07
Follow-up 41.00 ± 8.70 47.40 ± 8.63

Values are presented as mean ± standard deviation.

tDCS, transcranial direct-current stimulation.

The results of mixed-design repeated measures analysis of variance on scores of momentary craving and its factors in study groups

Variable Reference Degrees of freedom Mean of squares F Significance level Eta squared (effect coefficient)
Desire and intention Time 56.2 17.211 8.389 0.001 0.231
Group 28.1 71.111 3.532 0.071 0.112
Time × group 56.2 10.344 5.042 0.010 0.153
Negative reinforcement Time 56.2 22.300 8.912 < 0.001 0.241
Group 28.1 84.100 2.640 0.115 0.086
Time × group 56.2 7.633 3.050 0.055 0.098
Control Time 56.2 41.111 22.146 < 0.001 0.442
Group 28.1 59.211 1.668 0.207 0.056
Time × group 56.2 13.911 7.494 0.001 0.211
Total score Time 56.2 233.233 22.314 < 0.001 0.443
Group 28.1 640.000 2.947 0.097 0.095
Time × group 56.2 93.100 8.907 < 0.001 0.241

The results of the Bonferroni-corrected pairwise comparison test for the drug craving variable and its factors in three stages per group

Variable Stage tDCS Sham


Mean difference p value Mean difference p value
Desire and intention Pretest Posttest 2.667 < 0.001 0.333 0.982
Follow-up 1.267 0.108 −0.133 0.997
Posttest Follow-up −1.400 0.039 −0.467 0.971
Negative reinforcement Pretest Posttest 2.667 0.001 0.733 0.753
Follow-up 1.333 0.107 −0.133 0.997
Posttest Follow-up −1.333 0.036 −0.867 0.273
Control Pretest Posttest 3.600 < 0.001 1.067 0.069
Follow-up 2.067 0.002 −0.067 0.999
Posttest Follow-up −1.533 0.017 −1.133 0.104
Total score Pretest Posttest 8.933 < 0.001 2.133 0.307
Follow-up 4.667 0.002 −0.333 0.982
Posttest Follow-up −4.267 0.001 −2.467 0.078

tDCS, transcranial direct-current stimulation.

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