Substance use disorder (SUD) is a chronic medical condition characterized by persistent substance abuse despite adverse consequences. This condition poses a substantial global health concern, as underscored by the Global Burden of Disease (GBD) study in 2015 (1). Tobacco smoking has the highest mortality rate (110.7 deaths per 100,000 people), followed by alcohol and illicit drugs (33.0 and 6.9 deaths per 100,000 people, respectively) (2, 3). The impact of SUD is not limited to health outcomes but also poses significant economic consequences. For example, the opioid epidemic in the United States alone resulted in an economic burden of $1.02 trillion in 2017 (4).

Despite the existence of multiple approaches for treating SUD, their effectiveness has been suboptimal. Achieving long-term abstinence from substance use through medical interventions has been a difficult task, with pharmacological treatments showing limited success in reducing drug use or criminal behaviors. Studies have shown that approximately 85% of individuals who struggle with addiction experience a relapse within the first year after attempting abstinence.

During the 1960s, neurosurgical procedures such as cingulotomy, hypothalamotomy, and substantia innominate resection were attempted as treatments for SUD; however, their success rates were inconsistent (5). Nevertheless, these procedures fell out of favor due to the introduction of new pharmacological treatments and ethical concerns surrounding their use (6, 7). Advancements in DBS methodology and safety have raised interest in its use for treating neuropsychiatric disorders, including SUD, depression (8), obsessive–compulsive disorder (OCD) (9), and Tourette syndrome (10). DBS shows promise as a treatment for SUD, particularly for those with severe and persistent opioid, benzodiazepine, alcohol, cocaine, heroin and nicotine addiction. Existing evidence on DBS for SUD mostly relies on small cohort studies, making it challenging to draw clear conclusions.

Our study aims to review and meta-analyze the SUD literature to better understand the effectiveness of DBS and its influencers on SUD in its most severe form: addiction. Addiction, specifically, refers to a complex brain disorder that is a subset of substance use disorders. It is characterized by compulsive drug-seeking behavior, continued substance use despite negative consequences, and a loss of control over substance use. In other words, addiction is a chronic and relapsing condition that involves a compulsive drive to seek and use a substance, even when it becomes detrimental to an individual’s physical and mental health, relationships, and overall well-being.

This systematic review and meta-analysis followed the Cochrane Handbook for Systematic Reviews of Interventions (11) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring a rigorous and standardized approach to the study’s methodology (12).

The concept that targeted brain lesioning or natural brain injuries could lead to the elimination of addictive behavior is not a recent idea. Joutsa et al. conducted a study that explored how brain damage in specific regions can induce remission from drug addiction. The study suggests that investigating these cases can aid in the identification of new treatment targets. By analyzing data from two patient groups with smoking addiction and brain damage, researchers identified a disrupted brain circuit that was linked with addiction remission. This circuit was characterized by positive connectivity to certain regions and negative connectivity to others, and its hubs could potentially be targeted for therapeutic neuromodulation. The results indicate that brain lesions causing addiction disruption map to a specific circuit in the human brain, providing potential targets for novel treatments (32). Addiction is characterized by a persistent desire to consume a substance or engage in a behavior, known as craving, which can be difficult to quantify through self-reported measures alone. However, functional magnetic resonance imaging (fMRI) has enabled researchers to identify a neurobiological marker, referred to as the Neurobiological Craving Signature (NCS), which is associated with cue-induced cravings for drugs and food. The NCS is based on activity patterns in distinct brain regions and may hold promise as a tool for developing clinical interventions aimed at reducing cravings and preventing relapse (33).

Individuals who are chronically dependent on stimulants, as well as their nondependent siblings, have demonstrated a decrease in the size of their insula (34). The patients in these instances did not need to exert any self-control to resist the urge to smoke since they did not experience any desire to smoke. This similarity between the suppression of cravings resulting from anterior cingulate and NAc surgery may not be accidental as both the insula and the anterior cingulate are closely linked to the NAc (35). At the cellular level, addictive drugs alter the levels of dopamine outside the synapses within the “DA motive system,” with the NAc being the primary area affected (36). Continued usage of these substances causes changes at the cellular level, such as in the anterior cingulate and orbitofrontal cortices (37). These changes contribute to the desire to seek out drugs and the likelihood of relapse, which are defining features of drug addiction (37). The NAc has been separated both anatomically and functionally into two distinct parts: the core, which is situated in the ventral and medial area, and the shell, which is found in the lateral region of the NAc (38). The NAc shell area obtains inputs from the limbic system that originate from the basolateral amygdala (BLA) and ventral subiculum. It primarily transmits these inputs to the preoptic area of the hypothalamus. On the other hand, the NAc core region receives inputs from the BLA and parahippocampal cortex and sends outputs to motor circuits (39). According to the present evidence, it is believed that the shell regulates reward or drug-seeking behavior by utilizing spatial/contextual information, while the core regulates these behaviors through specific signals (40). Furthermore, in vivo microdialysis experiments on animals suggest that drug abuse has varying effects on the core and shell areas. The shell shows a significant increase in dopamine concentrations, while the core experiences only a slight increase (41). Research indicates that dopamine neurotransmission plays a vital role in reinforcing drug use (42).

Traditionally, the most popular DBS target for treating addiction is the NAc. Electrodes implanted in this region deliver electrical impulses that are thought to modulate the brain activity and reduce substance-related cravings and compulsions (43). Luigjes and co-authors conducted a review of potential DBS targets for substance use disorder and identified six brain regions that were studied in seven animal studies and two brain regions in eleven human studies. These regions included the NAc, STN, dorsal striatum, lateral habenular nucleus, mPFC, and hypothalamus. Based on their analysis, they determined that the NAc is the most promising target for DBS treatment in patients with addiction that has been unresponsive to other therapies (44). According to our meta-analysis, all patients received DBS targeting the NAc, except for Chen (19) who reported using stimulation in the anterior limb of the internal capsule (ALIC) in addition to the NAc. The NAc is a commonly targeted area for the treatment of OCD and depression as well, suggesting a shared involvement of the NAc in various psychiatric disorders involved in reward processing (45). However, the way in which NAc DBS treatment works for addiction is not yet fully understood. According to several animal studies, it appears that the decrease in addictive behavior relies on the restoration of normal activity in the NAc shell, which is the region of the NAc responsible for processing the pleasurable effects of drugs (46, 47). However, the mechanism behind the treatment of addiction through NAc DBS remains uncertain. Additionally, research has revealed that the impact of NAc shell DBS is reliant on modifying the activity in the prefrontal cortex, which is located upstream (46–49). A recent study showed that DBS of the NAc shell resulted in a minor increase in cocaine self-administration and a reduction in irritability-like behavior during cocaine withdrawal. This finding suggests that DBS may not reduce cocaine intake in individuals with long-term cocaine use but may be beneficial in managing negative emotional symptoms that arise during cocaine abstinence (50).

To our knowledge, this is the first and largest meta-analysis that investigated the impacts of DBS for the treatment of addiction, which included 16 studies and 50 subjects. The analysis estimated a mean effect size of 56.0 with a 95% confidence interval of [40.5; 71.5], indicating that DBS is effective for addiction treatment, but there is substantial heterogeneity among the studies. The study also performed subgroup analyses based on age, type of substance use, and duration of addiction, and the results showed significant differences in the mean effect size for different subgroups. The sensitivity analysis indicated that the pooled estimate was not strongly influenced by any individual study.

The results of the pooling analysis are important clinically and for research because they suggest that DBS could serve as an effective treatment for addiction, which is a chronic and relapsing brain disease that affects millions of people worldwide. The findings have significance for healthcare providers and individuals seeking treatment since they indicate that DBS could be a potential strategy for addressing addiction, particularly in cases where patients are treatment resistant. The use of DBS in the treatment of addiction was associated with a relapse rate of 8%, compared to the typical 85% relapse rate observed in early abstinence (51, 52). The meta-analysis discovered that the length of addiction plays a crucial role in determining the effectiveness of DBS in treating addiction, which is consistent with the principles of medical treatment that consider addiction duration and response to therapy. The duration of addiction can impact the probability of attaining and sustaining abstinence from drugs or alcohol. Scott et al. (53) have shown that even occasional abstinence from drugs and alcohol is linked to decreased mortality risk. Long-term treatment has a direct and indirect influence on mortality, with the duration of sustained abstinence being a significant factor (53).

The results of the pooling analysis show that DBS has a large and significant effect size on reducing drug craving and consumption, but also reveal substantial heterogeneity among the studies, indicating that there are differences in the outcomes depending on factors such as age, type of drug, and duration of addiction. These differences suggest that DBS may not work equally well for all patients with addiction, and that there may be optimal parameters for selecting candidates, choosing target regions, and adjusting stimulation settings. Therefore, more research is needed to identify the mechanisms of action, the safety and ethical issues, and the long-term effects of DBS for addiction.

There are several factors that should be taken into consideration regarding the limitations of this study. Initially, the study’s meta-analysis only includes a limited number of studies (16) and has a restricted sample size (50 patients). This could have resulted in an analysis that lacked sufficient power, particularly in subgroup analyses, reducing the overall applicability of the findings.

Additionally, there is considerable variability among the studies incorporated in the analysis, which may impede the ability to arrive at firm conclusions. Despite attempts to explore potential causes of heterogeneity using subgroup analyses, the outcomes must be viewed with caution, as the limited number of studies in each subgroup and the considerable level of variability noted may impact their reliability.

We investigated the current literature and showed that DBS has favorable effects on addiction and may reduce clinical scores by up to 56%. Moreover, DBS seems to reduce relapse to 8% compared to the 85% quoted relapse rate observed in early abstinence. Nevertheless, the considerable heterogeneity among studies highlights the need for larger, standardized randomized controlled trials that explore the effect of DBS on addiction in greater detail, including the factors that contribute to these findings through subgroup analysis. Despite this limitation, this study indicates that DBS has the potential to serve as a valuable adjunct to best medical therapy or even as a standalone treatment for addiction.

OF and NS contributed to conception and design of the study and wrote the first draft of the manuscript. NS organized the database and performed the statistical analysis. NS, OF, AL, AY, and AL wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the Department of Neurosurgery at the University of South Florida.

AL is the scientific director of Functional Neuromodulation Ltd. and a consultant to Medtronic, Abbott, Boston Scientific, Insightec, and the Focused Ultrasound Foundation. CS has fellowship grants from Michael and Amira Dan Foundation and the Turkish Neurosurgical Society.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1231760/full#supplementary-material