Addiction is a brain disease manifested by compulsive substance use despite harmful consequences. Drug addiction is one of the most serious and global public health problems. According to a recent survey, smoking, alcohol abuse and illegal drug use cause 11.8 million deaths each year, which is more than all cancer deaths (1). At present, several treatment methods for psychoactive substance use disorders have been developed, but the effects are unsatisfactory. In particular, achieving long-term abstinence with medical treatment has been difficult to achieve and pharmacological treatments have been ineffective in reducing drug use or criminal activity (2). It was shown that about 85% of addicts relapse within 1 year after abstinence, and people who did not receive any treatment have a greater risk of mortality (3, 4). Therefore, seeking a safe, effective and convenient treatment for refractory drug addiction is urgently needed.

With the development of neurosurgery, Deep Brain Stimulation (DBS) technology has gradually gained popularity in treating addiction. DBS uses 3D imaging technology to accurately target specific areas of the brain, such as the subthalamic nucleus (STN) and the nucleus accumbens (NAc), using intracranially implanted electrodes connected to pectorally implanted batteries and pulse generators (IPG). During stimulation, DBS electrodes influence neural activity through high-intensity pulses to achieve the desired therapeutic effect. DBS technology was originally used for the treatment of movement disorders starting in the 1980's, and has achieved satisfactory results in the treatment of progressive dyskinesias (5). By 2019, more than 160,000 patients worldwide have undergone DBS for a variety of neurological and non-neurological conditions, and DBS shows positive therapeutic effects (6). For example, the motor symptoms and levodopa-induced involuntary movements of Parkinson's disease patients have been significantly improved by DBS in the subthalamic nucleus (STN) (7).

Compared with traditional brain neurosurgery, DBS has the characteristics of reversibility and controllability, and is regarded as a safe alternative treatment compared to pharmacological treatment for neurological and psychiatric conditions. So far, the Food and Drug Administration (FDA) has approved DBS technology for Parkinson's disease (PD), obsessive-compulsive disorder (OCD), essential tremor (ET) and primary dystonia (8). In addition, tremendous efforts have been devoted to explore the therapeutic effects of DBS for neuropsychiatric diseases. Major progress has been made in the development of DBS as a treatment for refractory substance use disorders. In a study of alcohol addiction treatment with DBS, 2 out of 5 patients remained abstinent for many years, and 3 patients showed a significant reduction in alcohol consumption during the 8 years follow-up (9). Preclinical studies also show reduced relapse to cocaine and heroin seeking after NAc DBS (10–12). Therefore, DBS may become one of the most promising treatments for substance use disorders. However, the current research on the effects of DBS on drug addiction has only been conducted in limited clinical studies (13), and more trials are needed to further verify its effectiveness (14). In this review, we discuss the mechanism of DBS for addiction treatment and summarize the limited research on the application of DBS for the treatment of addiction to psychoactive substances such as nicotine, alcohol, cocaine, opioids and methamphetamine/amphetamine. The goal of the current review is to summarize the existing literature on the effects of DBS treatment for drug addiction to help advance our understanding of the neural mechanisms responsible for addiction and provide inspiration for continued clinical trials.

The etiology and pathogenesis of drug addiction are related to altered functioning of multiple brain systems. These include altered glutamate, opioid, cannabinoid, gamma-aminobutyric acid, norepinephrine and serotonergic systems. In addition, the mesolimbic dopaminergic reward system plays a central role in the pathogenesis of addiction and hypofunction of this system is a key characteristic of drug addiction. It is widely accepted that the initial reinforcing effects of drugs of abuse are mediated by large and rapid increases in the level of dopamine (DA) in the NAc. However, prolonged use of these drugs leads to hypofunction of the dopamine system (15). It has been hypothesized that DBS may alleviate addiction symptoms through normalizing dopamine levels and restore the functioning of the reward system (2).

Common addictive substances include nicotine, alcohol, cocaine, methamphetamine, marijuana, opioids, tranquilizers and sedatives (16), and the neurobiological mechanisms that produce addiction to these substances have been extensively investigated. So far, all known drugs of abuse increase dopamine in the NAc either by (1) the activation of dopamine neurons, or by (2) enhancing dopamine neurotransmission through facilitated release from terminals or blocking reuptake. For instance, studies have reported that the reinforcing properties of alcohol are closely related to the release and transmission of dopamine in the NAc. In particular, it was found that alcohol acutely increases the concentration of extracellular dopamine by 25% to 50% (17). Opioids are another commonly abused class of drugs that includes natural products obtained from opium poppy, and synthetic drugs with similar pharmacological properties (18, 19). Studies have found that the rewarding properties of opioids are mediated by enhancing the activity of dopamine neurons in the ventral tegmental area (VTA) and increasing the release of dopamine in the NAc (20). Physical dependence is common in opioid addicts and characterized by insomnia, cramps, diarrhea, nausea, vomiting and body pain, as well as irritability and anxiety when opioid use is suddenly stopped (21). The negative reinforcement effect of avoiding these withdrawal symptoms is part of the reason for continued use of opioids (22).

Addiction caused by these psychoactive substances is considered to be a relapse disorder with repeated stages. It is a cycle composed of three stages of “drug use,” “withdrawal” and “craving and relapse”(15), and animal and human imaging studies have revealed the neural circuits that mediate the three phases of the addiction cycle. The VTA and striatum play a key role in the drug use phase, and the extended amygdala plays a key role in the withdrawal phase. The orbital frontal cortex-dorsal striatum, pre-frontal cortex, basolateral amygdala, hippocampus and insula play a key role in the craving phase (22). Therefore, DBS may affect the release of neurotransmitters and neuronal firing by affecting the key nuclei in these circuits, thereby reducing craving and relapse.

At present, the specific mechanism that underlie the therapeutic effects of DBS for the treatment of psychiatric disease has not been fully understood, but great progress has been made in the treatment for obsessive-compulsive disorder (23, 24), major depressive disorder (25), Tourette's syndrome (26) and other neurological disorders such as Parkinson's disease (27). DBS is thought to produce therapeutic effects through the following mechanisms.

Since 2003, several clinical trials of DBS treatment in addiction to psychoactive substances such as tobacco, alcohol, cocaine, opioids and methamphetamine/amphetamine have been completed. The stimulation parameters, outcome, duration of follow-up and reported side effects have been summarized in Table 1. All of the reported NAc DBS trials showed positive treatment effects on addiction. So far, all clinical trials have been small scale, and much of the clinical data comes from case reports.

Drug addiction is a chronic mental disorder characterized by compulsive drug-seeking and use behavior. Substance use disorders are a major socioeconomic burden to society. In recent decades, DBS has emerged as an effective way to treat addiction to psychoactive substances, providing a novel option for patients with high relapse risks after traditional treatments have failed.

Although the NAc is the most widely used site for the stereotactic implantation of DBS electrodes for the treatment of addiction (61, 62), therapeutic effects have also been reported in other brain regions. Preclinical data demonstrated that DBS of the infralimbic cortex, the brain region sending major glutamatergic projections to the NAc attenuated cocaine-primed reinstatement of drug seeking in rats (63). In another preclinical study, Fakhrieh-Asl and colleagues (64) reported that DBS of the OFC prevented morphine conditioned place preference (CPP), facilitated extinction of morphine CPP, and blocked drug priming-induced reinstatement of morphine seeking in rats. In addition, Ibrahim and colleagues (65) proposed the insula, a region of the cerebral cortex involved in critical aspects underlying substance use disorders, such as decision making, anxiety, cognition, mood, as a promising DBS target of addiction. Moreover, although the SNr is not commonly thought of as a component of the neural circuits that regulate drug seeking, several studies suggesting that SNr may serve as a potential therapeutic target for drug addiction. The potential role of SNr in addiction has also been documented in recent studies. It was found that activation of SNr-GABA neurons prevented cocaine CPP (66). However, Galaj and collegues found that optogenetic activation of SNr-GABA neurons increased heroin self-administration (67). Interestingly, DBS of the substantia nigra pars reticulata (SNr) promoted extinction and prevented reinstatement of methamphetamine-induced CPP, suggesting SNr might be a potential therapeutic target for the treatment of methamphetamine addiction (68). It should be mentioned that the frequency might be important for SNr DBS because high frequency DBS produced therapeutic effects on the extinction and reinstatement of methamphetamine seeking, while slow frequency stimulation impaired extinction (68). Future studies, in particular clinical trials, are needed to explore the effectiveness of these brain regions as a target for addiction treatment.

It should be mentioned that DBS is an invasive surgical intervention with potential risks, including hemorrhage and infection (69, 70). Alternative non-invasive neuromodulation methods, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), have also shown promise as treatments for drug addiction (71–73). In particular, rTMS has been shown to reduce heroin and methamphetamine craving (74, 75). Interestingly, repeated NAc ultrasound stimulation also suppressed morphine CPP, suggesting NAc ultrasound stimulation might also be applied as a potential non-invasive therapeutic option in treating addiction (76). However, the effectiveness of these non-invasive methods in drug addiction treatment needs to be verified with larger clinic trials.

In conclusion, the application of DBS treatment for drug addiction is challenging but promising. However, it should be mentioned that most results are obtained from case reports. Further double-blinded studies and clinical trials, potential synergy with other non-invasive interventions, and larger patient populations are needed for validating DBS as a standard treatment option for refractory substance use disorders.

RC, JZ, and ST wrote the paper. JP, HL, YC, and SZ collected the literature. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the National Science Foundation of China (NSFC 81301144) and Research Learning and Innovative Experiment Project for University Students of University of South China (210XCX486, 210XCX510, and 200XCX322).

The 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.

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