
==== Front
Transl Psychiatry
Transl Psychiatry
Translational Psychiatry
2158-3188
Nature Publishing Group UK London

39237552
3060
10.1038/s41398-024-03060-1
Systematic Review
A systematic review of deep brain stimulation for substance use disorders
http://orcid.org/0009-0000-6040-2683
Zammit Dimech David david.zammitdimech@gmail.com

1
Zammit Dimech Audrey-Ann 1
Hughes Mark 2
http://orcid.org/0000-0002-6013-4946
Zrinzo Ludvic 3
1 https://ror.org/01nrxwf90 grid.4305.2 0000 0004 1936 7988 University of Edinburgh, Clinical & Surgical Sciences, Edinburgh, UK
2 https://ror.org/01nrxwf90 grid.4305.2 0000 0004 1936 7988 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
3 https://ror.org/02jx3x895 grid.83440.3b 0000 0001 2190 1201 UCL Institute of Neurology, Functional Neurosurgery Unit, Department of Clinical & Motor Neurosciences, University College London, London, UK
6 9 2024
6 9 2024
2024
14 36130 3 2024
19 8 2024
22 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Pharmaco-psychiatric techniques remain the mainstay, first line treatments in substance use disorders (SUD), assisting in detoxification but largely ineffective at reducing dependence. The path to rehabilitation and freedom from addiction often proves uncertain and laborious for both patients and their significant others. Relapse rates for multiple substances of abuse are considerable and the number of SUD patients is on the increase worldwide.

Objective

To assess efficacy of deep brain stimulation (DBS) as a therapeutic solution for SUDs.

Methods

A systematic electronic database search of PubMed and EMBASE retrieved DBS addiction-focused studies on humans, of which a total of 26 (n = 71) from 2007 to 2023 were deemed eligible, including the first randomized controlled trial (RCT) in this field. This review was prospectively registered with PROSPERO: CRD42023411631.

Results

In addressing SUDs, DBS targeting primarily the nucleus accumbens (NAcc), with or without the anterior limb of the internal capsule, presented encouraging levels of efficacy in reducing cravings and consumption, followed by remission in some subjects, but still reporting relapses in 73.2% of patients.

Conclusions

For treatment-refractory addictions DBS use seems limited to reducing cravings with a satisfactory degree of success, yet not clinically consistent in inducing abstinence, suggesting involvement of factors unaffected by DBS intervention. Furthermore, costs and the scale of the problem are such that DBS is unlikely to have a significant societal impact. Nevertheless, DBS may provide insight into the biology of addiction and is worthy of further research using increased methodological rigor, standardized outcome measures, and pre-established surgical protocols.

Subject terms

Human behaviour
Scientific community
issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Substance addiction is a chronic relapsing disorder, with compulsive behaviors for seeking and consuming substances that cause dependence, persisting regardless of negative consequences [1]. It encompasses an element of impulsivity, and is defined as “a failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or others” [2]. Addiction is a functional brain pathology demonstrating behavioral anomalies when interacting with the substance of abuse, characterized by progressively less controllable compulsions, resulting in deleterious physiological and psychosocial consequences. Frequent, careless and irresponsible use of the substance causes refocusing of priorities that privilege the addiction over duties and other activities [3].

The social burden of addiction

On a global scale, substance use disorders (SUDs) are a leading contributor to morbidity and mortality, generating severe health concerns and significant hardship for those afflicted by the addiction and their significant others [4]. A 2020 US national survey found that 38.7 million individuals suffered from a SUD [5]. Substances commonly subject to abuse and the creation of dependence include alcohol, opioids, cocaine, nicotine, amphetamines, methamphetamines, cannabis, hallucinogens, sedatives and tranquilizers [2]. In the West, 25% of deaths are connected to use of psychotropic substances. Worldwide, 284 million individuals aged between 15 and 64 abused drugs in 2020 [6, 7]. 21st century US victims of drug overdose are over 1 million. In 2021, 88% of them were ascribed to synthetic opioids, namely fentanyl [8]. In the EU, heroin is the major cause of drug-induced fatalities [9, 10] but a shift towards fentanyl, the main cause of the US opioid epidemic, is noted [11, 12].

Alcohol and nicotine are the substances of abuse responsible for the highest number of deaths worldwide. The heaviest consumption of alcohol occurs in Europe, with 10.1% of all deaths and 10.8% of all DALY attributable to alcohol [13, 14]. The financial burden on 48 countries, including the G20, EU and OECD countries, was projected at a loss of $1.6 trillion yearly from 2020 to 2050 [15]. In the past century nicotine claimed the lives of about 100 million individuals [16]. There are 1.13 billion smokers worldwide with half expected to die due to nicotine addiction, as each lifetime smoker loses at least 10 years of life [17]. 3000 daily deaths occur in China, both the biggest manufacturer and the largest consumer of tobacco [18]. Nicotine use is responsible for enough years lived with disability to account for over 25% of productive years lost in individuals aged between 45 and 79. The lost productivity and accompanying health care costs derived from morbidity and mortality amounts to $2 trillion every year [17].

The burden of substance addiction on society is substantial. Despite efforts at establishing treatment practices that adequately address SUDs, reported efficacy has been disappointing. Relapse rates fall within the same lamentable range, between 50% and 70% [19]. This has prompted the need for the exploration of new therapeutic venues. The clinical application of neuromodulation has yielded satisfactory results for psychiatric and movement disorders, and may hold promise for the treatment of addiction [20].

Neurosurgical interventions to treat addiction

Before 1960, pioneering experiments to treat addiction disorders were largely imprecise, with intentional brain lesions targeting ambiguous or widespread areas that resulted in unwanted, irreversible difficulties with cognition, speech and other functions [21]. Leucotomies, and later hypothalamotomies, were performed in Germany, Sweden and Russia [22]. In 1978, stereotactic cingulotomies in Indian patients with an alcohol addiction reported a 68% abstinence rate [23]. Before being banned, cingulotomies in Russia between 1999 and 2002, reported a 30% sudden remission in heroin users [24, 25]. Similarly, in China from 2000 to November 2004, when the practice was outlawed, bilateral NAcc ablation had resulted in a reduction in relapse rates of 57.5% in opioid addicts 15 months after surgery, [26] while another Chinese study reported a 5-year abstinence of 47.4% in 60 patients [27, 28]. Neural ablation procedures were followed by enhanced DBS techniques that target specific areas, with the NAcc garnering major interest. Located in the basal forebrain and positioned between the caudate and the putamen, the NAcc is a substructure, and the main component, of the ventral striatum within the basal ganglia [29].

A role for deep brain stimulation

Deep brain stimulation (DBS) is an invasive neurosurgical intervention via which there is stereotactic implantation of either unilateral or bilateral electrodes targeting defined brain nuclei involved in specific neural activity [30]. They will regulate abnormal impulses or elicit neurotransmitter release depending on the area stimulated [31], triggering neuroanatomical remodeling on a cellular level [32] and thus generating an effect in terms of neuroplasticity [33, 34]. The implanted electrodes are connected via tunneled wires passing subcutaneously to a neurostimulator located in the subclavicular region underneath the pectoral muscles [35, 36]. The pulse generator will deliver electrical stimulation and thereby provide direct communication with neurons and cortico-striatal circuits [37, 38]. The pulse generator can be programmed depending on the planned treatment, the specific area being targeted, feedback from the patient and the desired therapeutic response [39].

The Food and Drug Administration (FDA) has, to date, approved DBS for the treatment of essential tremor and severe tremor in Parkinson’s Disease in 1997, and of motor symptoms in advanced Parkinson’s Disease in 2002, dystonia in 2003, obsessive-compulsive disorder (OCD) in 2009 and epilepsy in 2018 [20]. Although not FDA-approved, DBS is also used in treating Tourette syndrome, chronic pain, major depressive disorder, anorexia nervosa, obesity, migraine and cluster headaches [40, 41]. The possibility of targeting the nucleus basalis of Meynert to treat Azlheimer’s Disease is also being explored [42]. Use of DBS to treat SUDs is a relatively novel approach deserving of assessment, given results with pharmaco-psychiatric therapy.

Methods

Search strategy

The systematic review was prospectively registered with PROSPERO (ID: CRD42023411631) and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [43]. The databases consulted were PubMed and Embase, up until August 2023. Advanced search strategies were employed in mining for data and included Medical Subject Headings (MeSH) terms in PubMed: “Deep Brain Stimulation”, “Behavior, Addictive”, “Substance-Related Disorders”, “Opioid-Related Disorders”, “Cocaine-Related Disorders”, “Amphetamine-Related Disorders”, “Tobacco Use Disorder”, “Morphine Dependence”, “Heroin Dependence”, “Opium Dependence”, “Alcoholism” and “Narcotic-Related Disorders”, and a comprehensive list of terms in Embase which encompassed ‘deep brain stimulation/’, ‘addiction medicine/’, ‘substance-related disorders/’, ‘alcohol-related disorders/’, ‘amphetamine-related disorders/’, ‘cocaine-related disorders/’, ‘drug overdose/’, ‘inhalant abuse/’, ‘substance abuse, intravenous/’, ‘substance abuse, oral/’, ‘substance withdrawal syndrome/’, ‘tobacco use disorder/’ and ‘opioid-related disorders/’.

Selection criteria and process

Records retrieved were assessed in accordance with predefined inclusion and exclusion criteria. All DBS trials conducted on human beings for addiction disorders were included. The substance of concern could be any that may lead to dependence. DBS studies which were focused on other neuropsychiatric disorders, including eating disorders and mood disorders, or those focused on neurodegenerative disorders, were excluded. Studies not concerning DBS as an intervention for an addiction disorder were excluded. Only publications reported in English were considered. Animal studies were excluded. Database search results were exported to a spreadsheet, removing duplicates. Detection tools were utilized to exclude studies in Excel. Two researchers independently screened publication titles and later abstracts and full texts of the filtered studies.

Data collection

When available in the publications selected, the following data items were noted: first author, year of publication, study location, study design, sample size, patient age and sex, substance being treated for, DBS target area, DBS technical parameters including frequency, pulse width and amplitude, laterality, comorbid psychiatric pathologies, outcomes including treatment response, quality of life (QoL) parameters and adverse events, and length of follow-up period. Data was collected by two reviewers, working in conjunction.

Quality assessment

For the single RCT identified, the Cochrane risk-of-bias (RoB2) tool was used, identifying a low risk of bias on all five domains evaluated [44]. The evaluation for quality and risk of bias for the non-randomized studies retrieved was performed using the Methodological Index for Non-Randomized Studies (MINORS) [45]. Two researchers independently reviewed the publications, assessing their quality and categorizing them. All eligible studies identified were deemed adequate. They were read in their entirety before being included in the review.

Outcome evaluation

Abstinence and relapse episodes are a readily accessible, but incomplete, measure of success of DBS interventions within the context of overcoming SUDs. Benefits intimately associated with the patients’ recovery from dependence, including improved neuropsychiatric states, reduced cravings and consumption, were also reported in concomitance with non-abstinent states. Abstinence was therefore not considered the primary outcome measurement. Instead, for the purpose of providing a more comprehensive outlook, results analysis encompassed the aforementioned benefits, and data is reported for abstinence, a full relapse, and for a partial relapse in which the patient would not have attained abstinence yet still reported improvements when compared to pre-operative conditions.

Results

Study selection and characteristics

The records deemed eligible were 25, spanning from 2007 to 2023. An additional case was included following citation searching. There was one double-blind RCT [23] and 25 non-RCTs. The PRISMA flowchart is visible in Fig. 1. All publications retrieved were small scale studies, reporting results for one or a small group of patients. The total number of individual patients treated was 71, with some reported in multiple studies. Patient overlap, alongside other relevant data, is indicated in Table 1 [46–71]. Twelve patients were female. Ages ranged from 22 to 69.Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart according to 2020 guidelines, showing the phases of study [43].

Table 1 Summary of characteristics of DBS addiction studies in humans, presented in a chronological order.

Authors	Study	Patients	Age	Sex	Addiction	Target	Parameters +	Laterality	Follow-up	
Kuhn et al. [53]	Case report	1	54	M	Alcohol	NAcc	130 Hz; 90 μs; 3–4.5 V	Bilateral	1 year	
Xu et al. [54]	Case report	1	24	M	Heroin	NAcc	145 Hz; 90 μs; 2.5 V	Bilateral	2 years	
Muller et al. [55]	Case series	3	36-40	M	Alcohol	NAcc	130 Hz; 90 μs; 3.5–4.5 V	Bilateral	1 year	
Kuhn et al. [49]	Case series	10	28-58	F: 3 M: 7	Nicotine	NAcc	130–145 Hz; 90, 180 μs; 3–6.5 V	Unilateral: 5 Bilateral: 5	30 months	
Mantione et al. [50]	Case report	1	47	F	Nicotine	NAcc	185 Hz; 90 μs; 3.5 V	Bilateral	2 years	
Zhou et al. [56]	Case report	1	24	M	Heroin	NAcc	145 Hz; - μs; 0.8–2.5 V	Bilateral	6 years	
Kuhn et al. [57]	Case report	1	69	M	Alcohol	NAcc	130 Hz; 120 μs; 5.5 V	Bilateral	1 year	
Valencia-Alfonso et al. [58]	Case report	1	47	M	Heroin	NAcc	180 Hz; 90 μs; 3.5 V	Bilateral	10 months	
Heldman et al. [59]	Case report	1a	38	M	Alcohol	NAcc	130 Hz; 90 μs; 3.5 V	Bilateral	2 years	
Voges et al. [60]	Case series	5b	36-65	M	Alcohol	NAcc	130 Hz; 90 μs; 3.5–4.5 V	Bilateral	x̄ 3.1 years (max: 4 yrs)	
Kuhn et al. [61]	Case report	2	31, 33	F, M	Heroin	NAcc	130–140 Hz; 90–120 μs; 4.5–5 V	Bilateral	2 years	
Gonçalves-Ferreira et al. [47]	N-of-1 trial	1	36	M	Cocaine	NAcc, BNST, ALIC	Right: 150 Hz; 150 μs; 3–4 V Left: 150 Hz; 150 μs; 2.5–3 V	Bilateral	30 months	
Muller et al. [62]	Case series	5c	35-55	M	Alcohol	NAcc	130 Hz; 90 μs; 3.5–4.5 V	Bilateral	8 years	
Ge et al. [63]	Open-label pilot	7	26-50	F: 1 M: 6	Heroin	NAcc, ALIC	145–185 Hz; 150–240 μs; 2–3.3 V	Bilateral	2 years (max: 40 months)	
Zhang et al. [64]	Case report	1	39	M	Heroin	VC, VS	130 Hz; 90 μs; 2.5–5.5 V	Bilateral	105 days	
Zhang et al. [51]	Case report	1	33	M	Methamphetamines	NAcc, VC	130 Hz; 210 μs; 3 V	Bilateral	1 year	
Chen et al. [65]	Open-label pilot	8d	22-50	F: 1 M: 7	Heroin	NAcc, ALIC	130–185 Hz; 150–240 μs; 1.5–7 V	Bilateral	2 years	
Ge et al. [52]	Case report	2	38, 49	M	Methamphetamines	NAcc, ALIC	150, 165 Hz; 210, 240 μs; 2.5,3.3 V	Bilateral	30 months	
Zhang et al. [66]	Case report	1	42	M	Heroin	NAcc	-	Bilateral	1 year	
Zhu et al. [67]	Case report	1	28	M	Buccinazine, Morphine, Hypnotics	NAcc, AC	145–160 Hz; 90 μs; 2.7–2.8 V	Bilateral	1 year	
Leong et al. [68]	Open-label pilot	8	32-63	F: 4 M: 4	Alcohol	ACC	-	Bilateral	48 weeks	
Mahoney et al. [69]	Case report	1	30	M	Opioids, Benzodiazepines	NAcc, VC	145 Hz; 90 μs; 6 V	Bilateral	12 weeks + 1 year	
Davidson et al. [70]	Open-label pilot	6	30-66	F: 2 M: 4	Alcohol	NAcc	130 Hz; 90 μs; 3.5–4.5 V	Bilateral	1 year	
Bach et al. [46]	RCT	12	DBS: x̄ 44.2, Control: x̄ 47.7	M	Alcohol	NAcc, ALIC	130 Hz; 90 μs; 3.5–4.5 V	Bilateral	Blind: 6mo N/Blind: 12 m	
Rezai et al. [71]	Open-label pilot	4e	22-44	M	Opioids	NAcc,VC	125–145 Hz; 90–300 μ; 3.0–4.5 V	Bilateral	12 weeks + 1 year	
Vorspan et al. [48]	Case report	1	40 s	M	Cocaine	StN	130 Hz; 60 μs; 1.25–3 V	Bilateral	2 years	
StN subthalamic nucleus, NAcc nucleus accumbens, BNST bed nucleus of the stria terminalis, ALIC anterior limb of internal capsule, ACC anterior cingulate cortex, VC ventral capsule, VS ventral striatum, AC anterior capsulotomy, Hz hertz, μsec microsecond, V Volts, RCT randomized controlled trial, x̄ Mean, yrs years.

+Parameters include frequency, pulse width and amplitude presented in that order.

apatient reported earlier in Muller et al. [55].

b3 of 5 patients reported earlier in Muller et al. [55].

c3 of 5 patients reported earlier in Muller et al. [55]; 2 of 5 patients reported earlier in Voges et al. [60]

d5 of 8 patients reported earlier in Ge et al. [63].

e1 of 4 patients reported earlier in Mahoney et al. [69].

Patients voluntarily subjecting themselves for surgery had several years of substance abuse behind them, with a history of unsuccessful pharmacotherapeutic interventions. Eleven publications addressed addiction for opioids while nine focused on alcohol use disorders. Two studies focused on cocaine addiction [47, 48], two on nicotine [49, 50], and two involved abuse of methamphetamines [51, 52].

Risk of bias

RCT assessment using RoB2 demonstrated a low risk of bias with a detailed randomization process, a strict protocol for interventions, a six-month blinding period, complete data for primary outcomes of all participants and for secondary outcomes for most participants, validated measures and blinded assessments. Despite the challenging recruitment that resulted in a small sample size, the methodology was robust and reporting transparent. The observational studies were assessed via MINORS, resulting in adequate scores. A few MINORS categories were not applicable to most studies given the study design of most publications but overall, they scored well on stating objectives, endpoints and their assessment, as well as follow-up.

Target area and stimulation parameters

The target area in the brain varied slightly, focusing mostly on targets around the ventral capsule, including the NAcc and the bed nucleus of the stria terminalis (BNST). In most cases, researchers described intervention on the NAcc, with exceptions including the BNST [47], anterior cingulate cortex [68], and subthalamic nucleus [48]. In all cases except one [26], lead implantation was performed bilaterally. The electrical stimulation parameters applied to patients varied in frequency, pulse width and amplitude. In some studies, the starting parameters were modified in attempts to adjust to the individual patients’ perceived therapeutic needs, such as insomnia [65]. In one instance anxiety and hypomania at 4.5 Volts were controlled at 3.7 Volts, with a further reduction to 3.3 Volts addressing insomnia and teeth grinding [52]. Kuhn et al. [49] had reported increased efficacy of DBS in tobacco use disorder patients on application of higher voltage [49]. In subsequent studies by Kuhn et al. [57, 61], however, the maximum voltage was lowered for alcohol and heroin dependence [57, 61]. The highest amplitude setting was noted in Chen et al. [65], 7 Volts, but this did not prevent the two patients receiving high voltage stimulation from eventually relapsing [65]. Pulse stimulation frequency across studies ranged from 130 to 185 Hertz. Pulse width ranged between 90 and 240 μsec. Data described in this section is present in Table 1.

Benefits of DBS

Although at varying degrees, studies reported therapeutic benefits for most of the patients. Even in Zhang et al. [64], where the patient passed away about 100 days from surgery due to a heroin overdose, cravings were reduced [64]. Whether this could be attributed to acquiescence bias by the patient cannot be determined, especially given the tragic conclusion of the trial. Although most patients (73.2%) did not achieve complete abstinence, many reported reductions in cravings and in episodes of heavy consumption. Whether these improvements translated into practical long-term psychosocial benefits for the patients was not reported in most publications, although some mention patients finding employment [52, 55, 60, 69, 71], marrying and having children [52] or improving family ties [71]. Others report the deaths of patients, unrelated to surgery [62, 64, 70]. A summary of patient outcomes is available in Table 2.Table 2 Summary of clinical outcomes of DBS addiction studies in humans, presented according to substance.

Authors	Patients	Follow-up	Outcomes	
Alcohol	
Kuhn et al. [53]	1	1 year	Greatly reduced cravings and alcohol use.	
Muller et al. [55]	3	1 year	Immediate reduction of cravings in all patients. 2 of 3 patients abstinent. 1 patient abstinent for most of the follow-up period but relapsed, with reduced consumption despite being in jail.	
Kuhn et al. [57]	1	1 year	By the 8th month there was a significant reduction in alcohol use. The patient was abstinent at the 1-year follow-up check point.	
Heldman et al. [59]	1	2 years	The patient remained abstinent. Reduced risk-taking behavior.	
Voges et al. [60]	5	x̄ 3.1 years (max: 4 yrs)	2 patients remained abstinent. 2 patients relapsed infrequently and reduced overall consumption. 1 patient abstinent until 16 months, with reduced cravings, then relapsed due to bilateral electrode dislocation.	
Muller et al. [62]	5	8 years	1 patient abstinent for 8 years. 1 patient abstinent for 6 years then lost to follow-up. 1 patient reduced consumption, relapsed, died due to other causes after 4 years. 1 patient relapsed after 16 months, electrode dislocation after 30 months, died due to other cause after 8 years. 1 patient reduced consumption, relapsed.	
Leong et al. [68]	8	48 weeks	All patients abstinent at least 6 months. 2 participants relapsed at the 48 week follow-up. Alcohol cravings reduced by 60.7%. Alcohol consumption reduced by 80%. Depression reduced by 63.5%. No changes in anxiety.	
Davidson et al. [70]	6	1 year	Patients experienced reduced cravings. 5 of 6 patients greatly reduced consumption. 1 of these 5 patients stated she drank due to habit but had reduced consumption by a third. Improved mood disorders, especially anxiety, except for 1 patient who remained severely depressed throughout. This was the only patient to not reduce consumption despite reduced cravings. After being abstinent for 6 months he relapsed and also required detoxification. 1 patient died 14 months post-op from a myocardial infarction.	
Bach et al. [46]	12	Blinded: 6 months Unblinded: 12 months	For first 6 months DBS vs control. For additional 12 months all DBS on. Increased abstinent days (first alcohol use mean time during first 6 months: DBS = 70.5 days, control = 29.7 days; but no significant difference) reduced cravings, reduced heavy drinking days, improved mood in DBS patients compared to controls. 1 DBS patient remained abstinent for 6 months, and 1 for 5 months. During additional 12 months with all patients on DBS there was no difference in mean time to first alcohol use.	
Opioids	
Xu et al. [54]	1	2 years	The patient remained abstinent.	
Zhou et al. [56]	1	6 years	The patient remained abstinent for the full 6 year follow-up. He regained a healthy weight and showed improvement in cognitive functions. Electrode removal after 3 years from operation.	
Valencia-Alfonso et al. [58]	1	10 months	Reduced consumption initially, then abstinence for 6 months except for a 2 week period.	
Kuhn et al. [61]	2	2 years	The patients remained abstinent, except for a single episode a few weeks after surgery. Reported reduced cravings. They consumed amphetamines for weight management or out of boredom, but in general presented improved mood disorders. Worsening was due to 1 patient requiring a battery change.	
Ge et al. [63]	7	2 years (max: 40 months)	4 patients abstinent after 40, 35, 23 and 21 months respectively. 2 patients relapsed after 7 and 10 months of abstinence. 1 patient lost to follow-up at 3 months. Improved mood and vigor in abstinent patients.	
Zhang et al. [64]	1	105 days	Early improvement. Gradual drug cravings and consequent relapses 2 months after. Death from heroin overdose.	
Chen et al. [65]	8	2 years	5 patients abstinent after 3 years. 2 patients relapsed after 7 and 10 months of abstinence. 1 patient lost to follow-up at 3 months. In abstinent patients: improved psychiatric disorders, sexual life, QoL. Gained weight. 1 got married. 2 conceived children. No positive effects, changes noted in relapsed patients.	
Zhang et al. [66]	1	1 year	Remained abstinent except for a relapse episode halfway through the follow-up period at 6 months.	
Zhu et al. [67]	1	1 year	Cravings reduced by 3 months. Patient abstinent by 1 year. Improvement in mood disorders, cognition, insomnia.	
Mahoney et al. [69]	1	12 weeks + 1 year	Patient remained abstinent. Improved cravings, executive function and mood disorders.	
Rezai et al. [71]	4	12 weeks + 1 year	2 patients abstinent for >1150 and >520 days. 1 participant had reduced cravings and anxiety but was not compliant and dropped out early. 1 patient relapsed but with reduced frequency and less adverse consequences.	
Nicotine	
Kuhn et al. [49]	10	30 months	3 patients remained abstinent. The rest relapsed.	
Mantione et al. [50]	1	2 years	The patient relapsed until the 10th month post-op, when OCD was eventually managed. The patient was then abstinent and showed improvement in weight management, OCD and mood disorders.	
Cocaine	
Goncalves-Ferreira et al. (2016)	1	30 months	Significant reduction in dependence and use of cocaine.	
Vorspan et al. [48]	1	2 years	3 double-blind crossovers did not demonstrate correlation with abstinence periods. No craving reduction.	
Methamphetamines	
Zhang et al. [51]	1	1 year	Abstinent for 1 year. Reduced cravings. Improved mood disorder.	
Ge et al. [52]	2	30 months	1 patient remained abstinent, gained weight and improved his sexual life. 1 patient relapsed but showed displaced electrode on CT and MRI, not implanted accurately in nucleus accumbens.	

Relapses post-DBS

Some patients did go on to present a largely unchanged situation or a consumption of substances other than the one being treated for. Apart from the aforementioned fatal overdose [64], Voges et al. [60] and Muller et al. [62] report on the same individual having stayed abstinent from alcohol for 16 months until a series of relapses [60, 62]. He coincidentally re-presented following a generalized seizure after being lost to follow-up, where it was radiographically confirmed that electrode dislocation had occurred. Three patients reported in both Ge et al. [63] and Chen et al. [65] also demonstrated only temporary improvement [63, 65]. One of the patients being treated for methamphetamine use in Ge et al. [52] relapsed at 6 months but CT and MRI scans had confirmed that one of the electrodes was not accurately implanted in the NAcc [52]. One of the six patients enrolled by Davidson et al. [70] consistently reported reduced alcohol cravings and was abstinent for 6 months, but severe depression persisted with multiple relapses and the need for detoxification [70]. In Kuhn et al. [61], although patients being treated for heroin addiction remained abstinent for the opioid and presented improved mood, they both reported amphetamine consumption [61]. One of the patients engaged in significant alcohol use after almost 2 years post-op. However, it was later reported that he required a battery change. Kuhn et al. [49] reported seven full relapses [49], Leong et al. [68] two within 1 year [68] and Rezai et al. [71] one [71].

Success rates

Table 3 provides data about abstinence, partial relapses and full relapses. Patients considered to have relapsed completely totaled 23.9% (n = 17), seven of whom were from one study exploring nicotine addiction [26]. 26.8% of patients (n = 19) remained abstinent throughout follow-up while 49.3% (n = 35) exhibited occasional relapses. Table 4 presents this data for five distinct subgroups categorized by substance of abuse, providing a more immediate and clear picture of results achieved. It is important to note that the follow-up period varied quite considerably between the studies, ranging from around 100 days to 8 years. This impacts on the end-state report for the patients, with longer follow-up periods expressing increased scientific value.Table 3 Numerical representation of patients and outcomes for DBS addiction studies in humans.

Authors	Follow-up	Patients	Non-overlapping patients	Abstinent	Partial relapse	Full relapse	
Kuhn et al. [53]	1 year	1	1		1		
Xu et al. [54]	2 years	1	1	1			
Muller et al. [55]	1 year	3	3	2	1		
Kuhn et al. [49]	30 months	10	10	3		7	
Mantione et al. [50]	2 years	1	1		1		
Zhou et al. [56]	6 years	1	1	1			
Kuhn et al. [57]	1 year	1	1		1		
Valencia-Alfonso et al. [58]	10 months	1	1		1		
Heldman et al. [59]	2 years	1	0				
Voges et al. [60]	x̄ 3.1 years (max: 4 yrs)	5	2		1	1	
Kuhn et al. [61]	2 years	2	2		2		
Goncalves-Ferreira et al. (2016)	30 months	1	1		1		
Muller et al. [62]	8 years	5	0				
Ge et al. [63]	2 years (max: 40 months)	7	7	4		3	
Zhang et al. [64]	105 days	1	1			1	
Zhang et al. [51]	1 year	1	1	1			
Chen et al. [65]	2 years	8	3	3			
Ge et al. [52]	30 months	2	2	1		1	
Zhang et al. [66]	1 year	1	1		1		
Zhu et al. [67]	1 year	1	1		1		
Leong et al. [68]	48 weeks	8	8		6	2	
Mahoney et al. [69]	12 wks + 1 yr	1	1	1			
Davidson et al. [70]	1 year	6	6		5	1	
Bach et al. [46]	6 + 12 months	12	12	1	11		
Rezai et al. [71]	12 wks + 1 yr	4	3	1	1	1	
Vorspan et al. [48]	2 years	1	1		1		
Patients (numbers):			71	19	35	17	
Patients (percentages):			100%	26.80%	49.30%	23.90%	

Table 4 Numerical representation of patients and outcomes for DBS addiction studies according to substance.

Authors	Follow-up	Patients	Non-overlapping patients	Abstinent	Partial relapse	Full relapse	
Alcohol	
Kuhn et al. [53]	1 year	1	1		1		
Muller et al. [55]	1 year	3	3	2	1		
Kuhn et al. [57]	1 year	1	1		1		
Heldman et al. [59]	2 years	1	0				
Voges et al. [60]	x̄ 3.1 years (max: 4 yrs)	5	2		1	1	
Muller et al. [62]	8 years	5	0				
Leong et al. [68]	48 weeks	8	8		6	2	
Davidson et al. [70]	1 year	6	6		5	1	
Bach et al. [46]	6 + 12 months	12	12	1	11		
Patients (numbers) [alcohol]:	33	3	26	4	
Patients (percentages) [alcohol]:	100%	9.10%	78.80%	12.10%	
Opioids							
Xu et al. [54]	2 years	1	1	1			
Zhou et al. [56]	6 years	1	1	1			
Valencia-Alfonso et al. [58]	10 months	1	1		1		
Kuhn et al. [61]	2 years	2	2		2		
Ge et al. [63]	2 years (max: 40 months)	7	7	4		3	
Zhang et al. [64]	105 days	1	1			1	
Chen et al. [65]	2 years	8	3	3			
Zhang et al. [66]	1 year	1	1		1		
Zhu et al. [67]	1 year	1	1		1		
Mahoney et al. [69]	12 wks + 1 yr	1	1	1			
Rezai et al. [71]	12 wks + 1 yr	4	3	1	1	1	
Patients (numbers) [opioids]:	22	11	6	5	
Patients (percentages) [opioids]:	100%	50%	27.30%	22.70%	
Nicotine	
Kuhn et al. [49]	30 months	10	10	3		7	
Mantione et al. [50]	2 years	1	1		1		
Patients (numbers) [nicotine]:	11	3	1	7	
Patients (percentages) [nicotine]:	100%	27.30%	9.10%	63.60%	
Cocaine	
Goncalves-Ferreira et al. (2016)	30 months	1	1		1		
Vorspan et al. [48]	2 years	1	1		1		
Patients (numbers) [cocaine]:	2	0	2	0	
Patients (percentages) [cocaine]:	100%	0%	100%	0%	
Methamphetamines	
Zhang et al. [51]	1 year	1	1	1			
Ge et al. [52]	30 months	2	2	1		1	
Patients (numbers) [meth]:	3	2	0	1	
Patients (percentages) [meth]:	100%	66.70%	0%	33.30%	

Neuropsychiatric benefits

Comorbid psychiatric diagnoses were reported in most publications (n = 21) [46, 47, 49–53, 55–57, 60–65, 67–71], with many indicating post-op improvement. Some patients, having been embroiled in a long-term addiction pathology, and having failed multiple attempts at remission via more conservative means, carried the burden of numerous concurrent neuropsychiatric disorders including depression, anxiety, agoraphobia, eating disorders, Tourette’s syndrome, OCD, antisocial personality disorder, panic disorder, post-traumatic stress disorder, bipolar disorder, anhedonia and sleeping disorders.

The various assessment tools used to gauge presence and severity of neuropsychiatric disorders included the Beck Depression Inventory (BDI) [46, 53, 61, 67, 70], State-Trait Anxiety Inventory [46, 53, 68], Minnesota Multiphasic Personality Inventory [54, 56], Symptom Checklist 90 [52, 55, 56, 59, 60, 62, 65], Yale-Brown Obsessive Compulsive Scale [47, 50, 63, 65], Hamilton Anxiety Scale [46, 50, 61, 67], Hamilton Depression Scale (HAMD) [46, 50, 52, 63, 65, 67, 70], Self-Rating Depression Scale [56], Self-Rating Anxiety Scale [59], Montgomery-Åsberg Depression Rating Scale [47, 48], Clinical Global Impressions Scale [47], Global Severity Index [60], Young Mania Rating Scale [67], Beck Anxiety Inventory [67, 70], Pittsburgh Sleep Quality Index [67], Global Assessment of Functioning Scale (GAF) [46], Chapman Anhedonia Scale [46], and the Snaith-Hamilton Pleasure Scale (SHAPS) [46].

From the eight patients in Chen et al. [65] three were diagnosed with OCD, one with depression and two presented with both [65]. Of the latter, both relapsed after 6 months and showed no improvement in neuropsychiatric symptoms or QoL. Benefits were reported for five patients, who all gained weight (except for one female), had improved sexual lives, neuropsychiatric symptoms, and QoL. In Kuhn et al. [61] there was marked improvement in mood disorder for one patient but progressive worsening in the other, accompanied by use of alcohol and amphetamines [61]. The issue improved after replacement of the impulse generator. One patient in Ge et al. [52] relapsed, with accompanying depressive symptoms, although the authors attributed it to inaccurate lead placement [52]. Bach et al. [46] reported reduced anhedonia and depression, and improved QoL for patients whose implanted neurostimulator was on early in the trial, but no improvement for those on sham stimulation [46]. After 6 months, when the DBS vs control phase was over, the SHAPS mean scores were 0.8 vs 6.2, noting a significant difference between the two groups. Mean scores for BDI were 8.6 vs 14.5, for HAMD 4.0 vs 8.0, for GAF 63.3 vs 52.8 and for the World Health Organization Quality of Life Questionnaire (WHO-QoL) 55.0 vs 48.9. For neither of these scores was there a significant difference between the two groups. Davidson et al. [70] noticed positive changes in depression and anxiety by 28% and 51% respectively, except for one patient who remained severely depressed and did not benefit from DBS, requiring hospitalization for detoxification [70]. Leong et al. [68] reported a decrease in depressive symptoms by 63.5% but no effect on anxiety [68]. Most studies reported improvements in their patients’ accompanying disorders when abstinence or reduced consumption were achieved.

With regards to QoL, most publications did not report any or enough detail (n = 22) [47–60, 62–64, 66, 68–71], at times providing brief subjective mentions of the patients’ status. Four studies made use of QoL assessment tools, including the Modular System for Quality of Life [61], Medical Outcomes Study 36-Item Short-Form Health Survey [65, 67], Work and Social Assessment Scale [67], or the WHO-QoL [46].

Discussion

To our knowledge, this is the most comprehensive systematic review of the application of DBS for SUDs. Many SUD patients have received assistance via contemporary pharmaco-psychiatric interventions but success rates for reduction in substance craving, seeking and consumption have not been satisfactory. Socioeconomic costs are significant and increase exponentially over time as interrelated complications present a cumulatively detrimental effect. As individual lives are devastated, becoming refractory to treatment, the whole community pays the price for inaction in health care expenses, criminality and justice system costs including law enforcement, motor vehicle accidents and lost productivity [6, 12, 13, 15, 17]. A new approach is urgently required, to reduce relapse rates and improve the QoL of severely addicted individuals.

DBS as a therapeutic alternative

Most publications reported reduction in cravings, which is a fundamental initial step in countering substance dependence. Only 26.8% of the patients achieved abstinence but 49.3% demonstrated significant reduction in consumption, with some from this subset also showing sustained periods of abstinence. It should be noted that outcomes were reported within the context of the time frame set for the respective studies, ranging from 10 months to 8 years. Ideally, patients are followed-up for periods of time that extend to at least 5 years to determine whether abstinence has been achieved, and even then, the risk of relapse cannot be considered completely averted [72, 73]. Only two studies included in this review followed patients beyond 5 years [56, 62]. The patient in Zhou et al. [56] was followed for 6 years and was abstinent all throughout. From the five patients in Muller et al. [62] only one patient was abstinent after 8 years.

Some patients did not extinguish addictions and did not show a reduction in consumption despite admitting to reduced cravings [49, 52, 60, 62–65, 68, 70, 71]. In some instances, these cases were explained by the researchers as originating from displaced leads [52, 60, 62] and in others it was remarked how the patients had not overcome comorbid neuropsychiatric pathologies that compromised recovery [64, 70], or were unmotivated to overcome their dependence [49, 71]. Regardless, these ultimately represent a failure of the intended therapy to provide the expected benefit. The RCT [46] is expected to deliver the highest level of evidence on the efficacy of DBS in treating SUDs. However, it only recruited 12 patients despite having been planned for 30. This is attributable to the application of strict recruitment criteria, with possible influence of socioeconomic factors that excluded many patients refractory to conservative therapy. Ultimately, this diminishes the analytical capacity of the study and reduces generalizability to the larger population. There was no statistically significant difference in selected outcome between the experimental and control groups.

When considering DBS as a therapeutic alternative in the treatment of SUDs it should also be remembered that DBS is a costly and invasive surgical intervention and as such it carries risks, including infection, device failure and side effects such as insomnia, hypomania and impulsivity. Serious complications include the possibility of intracerebral hemorrhage or stroke, although these are rare [74]. Moreover, implantable pulse generators require replacement, with non-rechargeable models lasting for longer [75]. Long-lasting success of the therapeutic process also necessitates joint specialist collaboration within dedicated centers. Consequently, when considering the increasing number of patients not responding to pharmaco-psychiatric treatment for SUD, the possibility of securing all the resources required to make a significant impact on this sociocultural phenomenon seems unlikely or, at best, conducive to only marginal benefits to a small percentage of patients.

DBS targets in treating SUDs

Most studies focused on targets around the ventral capsule, including the BNST and especially the NAcc. This has been deemed the safest and most effective approach, as suggested by numerous preclinical studies [29]. Located in the basal forebrain and positioned between the caudate and the putamen, the NAcc is a substructure, and the main component, of the ventral striatum within the basal ganglia [29]. The dual characteristics of the NAcc suggest that the core is involved in the initiation of cue-primed substance attainment and the shell is concerned with reinforcement of that behavior [76, 77]. The NAcc plays a prominent role in the mesocorticolimbic reward circuitry due to its neuronal connections and the function it exerts in the formation of addiction, making its direct stimulation via DBS effective in reducing the craving for substances of abuse and preventing relapse [78, 79].

It is very likely that multiple mechanisms account for the effects of DBS, including neural oscillation, electrical stimulation of nerves and neurochemical effects on a local and a wider neural network, neuroplasticity, neurogenesis, and neuroprotection modulation [80]. Newer, improved protocols of DBS delivery are being refined, intended to enhance its therapeutic effects for multiple clinical applications, including the treatment of SUDs [81]. Different forms of stimulation, such as adaptive, burst, and coordinated reset, and a deeper understanding of neuronal circuit architecture can help create more tailored therapy, better adjusted at inducing changes in the targeted circuity and in reaching the intended therapeutic outcome [82].

A vulnerable population

Most patients present co-occurring neuropsychiatric conditions which, to a certain extent, hinder their recovery from SUDs. OCD, depression and anxiety are among the most encountered psychiatric pathologies. For some patients, reduced cravings helped address their accompanying neuropsychiatric issues. The ensuing synergistic effect boosted recovery, resulting in improved health, weight, sexual life, mood and social life [50, 67]. In other instances, despite reporting reduced cravings, patients struggled with comorbid disorders, impeding rehabilitation. Some consumed other substances of abuse because of “boredom” or “habit”, demonstrating a tendency for poly-substance abuse [49, 61, 64, 70]. While this might hint at potential neural circuitry compromise originating from prolonged exposure to the substance of interest, it also opens a window onto the relevance of cues derived from the social context of the individual. A patient with SUD will more readily relapse in the presence of others engaging in consumption or within environments where in the past the individual would have consumed the substance. Impactful life events can be potent psychosocial stressors that also facilitate relapse. The way a patient conceives their relationship with the substance of abuse and whether there is intrinsic acceptance that an addictive pattern of behavior exists, is also key to successful treatment.

Patients should be placed in context, considering the multidimensionality of their reality. Environmental cues, comorbid pathologies, their thought processes and their socioeconomic situation should be considered. With a vulnerable patient population such as the one amenable for DBS intervention the risk of the individual being alienated from social support structures and potential financial ruin runs higher as the patient gets entangled in physiological reward circuitry processes over which control only grows more ephemeral. Therapeutic targets should include prompt reinsertion into a social group, re-learning an approach to creating and strengthening social relationships, and the acquisition of skills to assist with reintroduction into a workplace environment [83].

Study limitations

The main limitation of the study is the small sample size of the patient population across the publications retrieved, with most being case studies reporting on one single patient. Recent trials engaged more participants but even the first RCT [46] presents limited statistical power, with just 12 subjects involved. Publication bias needs to be considered as small sample sizes, and the absence of randomization and a control group make research more vulnerable for this [84, 85]. Studies not available in English were not considered for review. Inclusion criteria could not be severely restrictive to capture as much of the limited data available on the subject as possible. Outcomes for the primary intent of the research varied across the studies, making comparisons imprecise. Measurements were often based on self-reports and the methodologies employed often differed between studies. Blinding and randomization were only utilized in three studies. Parallel variables that could influence the outcome of research into alleviating dependence, such as concomitant neuropsychological pathologies and relevant social and emotional cues, were not always reported and measured.

Conclusion

Clinical studies suggest that DBS as a therapeutic option for treatment-refractory SUDs has not yielded high enough remission rates that would currently justify substituting more readily available, cheaper, and less invasive pharmaco-psychiatric approaches. Studies have reported satisfactory efficacy levels in reducing cravings and heavy consumption. This is an improvement on current treatment modalities, which assist with detoxification but have often proven limited in preventing relapse. However, achieving and maintaining abstinence via DBS has also proven difficult, indicating learned behavior and the engagement of areas of the brain that are untapped or insufficiently modified with present day DBS techniques. Use of DBS as mainstream therapy for SUDs faces several challenges given the considerable resources required, and this contrasts with the level at which SUD patients are increasing in number worldwide. More research is necessary, with heightened methodological rigor and standardization of parameters, including patient selection, objective outcome assessments, longer follow-up periods and a pre-established surgical protocol. The development of enhanced techniques and more specific procedure methodologies would be expected to improve therapeutic delivery of DBS for SUDs, overcoming the current limitations. SUDs are difficult to address for physicians, the patients, and their significant others. They hold hostage invaluable human potential which would otherwise be employed productively for the benefit of society. Use of DBS in this domain holds promise, perhaps at present primarily as a vehicle for gaining better understanding of addiction dynamics in the brain, investigating the neural circuits and the biological mechanisms concerned, with the prospect of applying new protocols that will augment the efficacy of DBS in treating SUDs. This study is intended to encourage further research into the potential of DBS to address addiction disorders and inform future therapy.

Author contributions

DZD: study concept and design, literature search and data acquisition, analysis and interpretation of data, manuscript drafting. AAZD: study concept and design, literature search and data acquisition, analysis and interpretation of data, manuscript drafting. MH: supervision, manuscript revision. LZ: analysis and interpretation of data, supervision, manuscript revision.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Competing interests

The authors declare no competing interest.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Zou Z Wang H d’Oleire Uquillas F Wang X Ding J Chen H Definition of substance and non-substance addiction Adv Exp Med Biol 2017 1010 21 41 10.1007/978-981-10-5562-1_2 29098666
Zou Z, Wang H, d’Oleire Uquillas F, Wang X, Ding J, Chen H. Definition of substance and non-substance addiction. Adv Exp Med Biol. 2017;1010:21–41.29098666 10.1007/978-981-10-5562-1_2
2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013
3. Angres DH Bettinardi-Angres K The disease of addiction: origins, treatment, and recovery Dis Mon 2008 54 696 721 10.1016/j.disamonth.2008.07.002 18790142
Angres DH, Bettinardi-Angres K. The disease of addiction: origins, treatment, and recovery. Dis Mon. 2008;54:696–721.18790142 10.1016/j.disamonth.2008.07.002
4. Substance Abuse and Mental Health Services Administration (US), Office of the Surgeon General (US). Facing addiction in America: the surgeon general’s report on alcohol, drugs, and health. Washington (DC): US Department of Health and Human Services; 2018. https://www.ncbi.nlm.nih.gov/books/NBK424857/ November 2016.
5. Substance Abuse and Mental Health Services Administration. Results from the 2020 national survey on drug use and health: detailed tables. Rockville. https://www.samhsa.gov/data/ Accessed 30 July 2024.
6. Global Burden of Disease Collaborative Network. Global burden of disease study 2019 (GBD 2019) reference life table. 2021. https://ghdx.healthdata.org/gbd-2019 Accessed February 27, 2023.
7. UNODC, World Drug Report 2022. United Nations Publication, 2022.
8. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2021. http://wonder.cdc.gov. Accessed February 15, 2023.
9. European Monitoring Centre for Drugs and Drug Addiction. European drug report 2015: trends and developments. https://www.euda.europa.eu/publications/edr/trends-developments/2015_en. Accessed 4 June 2015
10. European Monitoring Centre for Drugs and Drug Addiction. European drug report 2022: trends and developments. https://www.euda.europa.eu/publications/edr/trends-developments/2022_en. Accessed 14 June 2022.
11. OECD. Addressing problematic opioid use in OECD countries, OECD health policy studies, OECD publishing, Paris 2019. 10.1787/a18286f0-en.
12. Pan American Health Organization. The burden of drug use disorders in the region of the Americas, 2000-19. https://www.paho.org/en/enlace/burden-drug-use-disorders 2021
13. Global status report on alcohol and health 2018. Geneva: World Health Organization. https://www.who.int/about/policies/publishing/copyright. 2018.
14. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2018;392:1015–35.
15. OECD. Preventing harmful alcohol use, OECD health policy studies, OECD publishing, Paris 2021. 10.1787/6e4b4ffb-en.
16. Jha P Avoidable global cancer deaths and total deaths from smoking Nat Rev Cancer 2009 9 655 10.1038/nrc2703 19693096
Jha P. Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer. 2009;9:655.19693096 10.1038/nrc2703
17. Vital Strategies. The tobacco Atlas. Accessed February 16, 2023. https://tobaccoatlas.org/ Accessed 16 February 2023.
18. World Health Organization. Tobacco in China. https://www.who.int/china/health-topics/tobacco. Accessed 20 February 2023.
19. Kadam M Sinha A Nimkar S Matcheswalla Y De Sousa A A comparative study of factors associated with relapse in alcohol dependence and opioid dependence Indian J Psychol Med 2017 39 627 33 10.4103/IJPSYM.IJPSYM_356_17 29200559
Kadam M, Sinha A, Nimkar S, Matcheswalla Y, De Sousa A. A comparative study of factors associated with relapse in alcohol dependence and opioid dependence. Indian J Psychol Med. 2017;39:627–33.29200559 10.4103/IJPSYM.IJPSYM_356_17
20. Mahoney JJ Hanlon CA Marshalek PJ Rezai AR Krinke L Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment J Neurol Sci 2020 418 117149 10.1016/j.jns.2020.117149 33002757
Mahoney JJ, Hanlon CA, Marshalek PJ, Rezai AR, Krinke L. Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment. J Neurol Sci. 2020;418:117149. ents/2014_en citation33002757 10.1016/j.jns.2020.117149
21. Gardner J A history of deep brain stimulation: technological innovation and the role of clinical assessment tools Soc Stud Sci 2013 43 707 28 10.1177/0306312713483678
Gardner J. A history of deep brain stimulation: technological innovation and the role of clinical assessment tools. Soc Stud Sci. 2013;43:707–28.10.1177/0306312713483678
22. Dieckmann G Schneider H Influence of stereotactic hypothalamotomy on alcohol and drug addiction Appl Neurophysiol 1978 41 93 98 365104
Dieckmann G, Schneider H. Influence of stereotactic hypothalamotomy on alcohol and drug addiction. Appl Neurophysiol. 1978;41:93–98.365104
23. Kanaka TS Balasubramaniam V Stereotactic cingulumotomy for drug addiction Appl Neurophysiol 1978 41 86 92 365103
Kanaka TS, Balasubramaniam V. Stereotactic cingulumotomy for drug addiction. Appl Neurophysiol. 1978;41:86–92.365103
24. Orellana C Controversy over brain surgery for heroin addiction in Russia Lancet Neurol 2002 1 333 10.1016/S1474-4422(02)00175-8 12849380
Orellana C. Controversy over brain surgery for heroin addiction in Russia. Lancet Neurol. 2002;1:333.12849380 10.1016/S1474-4422(02)00175-8
25. Li N Wang J Wang X Chang C Ge S Gao L Nucleus accumbens surgery for addiction World Neurosurg 2013 80 S28.e9 19 10.1016/j.wneu.2012.10.007 23046915
Li N, Wang J, Wang X, Chang C, Ge S, Gao L, et al. Nucleus accumbens surgery for addiction. World Neurosurg. 2013;80:S28.e9–19.23046915 10.1016/j.wneu.2012.10.007
26. Gao G Wang X He S Li W Wang Q Liang Q Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery Stereotact Funct Neurosurg 2003 81 96 104 10.1159/000075111 14742971
Gao G, Wang X, He S, Li W, Wang Q, Liang Q, et al. Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery. Stereotact Funct Neurosurg. 2003;81:96–104.14742971 10.1159/000075111
27. Yen CP Kuan CY Sheehan J Kung SS Wang CC Liu CK Impact of bilateral anterior cingulotomy on neurocognitive function in patients with intractable pain J Clin Neurosci 2009 16 214 9 10.1016/j.jocn.2008.04.008 19101146
Yen CP, Kuan CY, Sheehan J, Kung SS, Wang CC, Liu CK, et al. Impact of bilateral anterior cingulotomy on neurocognitive function in patients with intractable pain. J Clin Neurosci. 2009;16:214–9.19101146 10.1016/j.jocn.2008.04.008
28. Ge S Chang C Adler JR Zhao H Chang X Li G Long-term changes in the personality and psychopathological profile of opiate addicts after nucleus accumbens ablative surgery are associated with treatment outcome Stereotact Funct Neurosurg 2013 91 30 44 10.1159/000343199 23154203
Ge S, Chang C, Adler JR, Zhao H, Chang X, Li G, et al. Long-term changes in the personality and psychopathological profile of opiate addicts after nucleus accumbens ablative surgery are associated with treatment outcome. Stereotact Funct Neurosurg. 2013;91:30–44.23154203 10.1159/000343199
29. Luigjes J van den Brink W Feenstra M van den Munckhof P Schuurman PR Schippers R Deep brain stimulation in addiction: a review of potential brain targets Mol Psychiatry 2012 17 572 83 10.1038/mp.2011.114 21931318
Luigjes J, van den Brink W, Feenstra M, van den Munckhof P, Schuurman PR, Schippers R, et al. Deep brain stimulation in addiction: a review of potential brain targets. Mol Psychiatry. 2012;17:572–83.21931318 10.1038/mp.2011.114
30. Zhang C, Tao W, Zeljic K, Jin H, Zhan S, Li D, et al. Surgical treatment for refractory drug addiction. In: Elliot K, Peckham PH, Rezai A, editors. Neuromodulation: comprehensive textbook of principles, technologies, and therapies. Academic Press; 2018. pp.1089–97.
31. Coles AS Kozak K George TP A review of brain stimulation methods to treat substance use disorders Am J Addict 2018 27 71 91 10.1111/ajad.12674 29457674
Coles AS, Kozak K, George TP. A review of brain stimulation methods to treat substance use disorders. Am J Addict. 2018;27:71–91.29457674 10.1111/ajad.12674
32. Chakravarty MM Hamani C Martinez-Canabal A Ellegood J Laliberté C Nobrega JN Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature Neuroimage 2016 125 422 7 10.1016/j.neuroimage.2015.10.049 26525655
Chakravarty MM, Hamani C, Martinez-Canabal A, Ellegood J, Laliberté C, Nobrega JN, et al. Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature. Neuroimage. 2016;125:422–7.26525655 10.1016/j.neuroimage.2015.10.049
33. Fitzgerald PB Segrave RA Deep brain stimulation in mental health: review of evidence for clinical efficacy Aust N Z J Psychiatry 2015 49 979 93 10.1177/0004867415598011 26246408
Fitzgerald PB, Segrave RA. Deep brain stimulation in mental health: review of evidence for clinical efficacy. Aust N Z J Psychiatry. 2015;49:979–93.26246408 10.1177/0004867415598011
34. Caroni P Chowdhury A Lahr M Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits Trends Neurosci 2014 37 604 14 10.1016/j.tins.2014.08.011 25257207
Caroni P, Chowdhury A, Lahr M. Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits. Trends Neurosci. 2014;37:604–14.25257207 10.1016/j.tins.2014.08.011
35. Stephen JH Halpern CH Barrios CJ Balmuri U Pisapia JM Wolf JA Deep brain stimulation compared with methadone maintenance for the treatment of heroin dependence: a threshold and cost-effectiveness analysis Addiction 2012 107 624 34 10.1111/j.1360-0443.2011.03656.x 21919988
Stephen JH, Halpern CH, Barrios CJ, Balmuri U, Pisapia JM, Wolf JA, et al. Deep brain stimulation compared with methadone maintenance for the treatment of heroin dependence: a threshold and cost-effectiveness analysis. Addiction. 2012;107:624–34.21919988 10.1111/j.1360-0443.2011.03656.x
36. Münte TF Heinze HJ Visser-Vandewalle V Deep brain stimulation as a therapy for alcohol addiction Curr Top Behav Neurosci 2013 13 709 27 10.1007/978-3-642-28720-6_207 22678648
Münte TF, Heinze HJ, Visser-Vandewalle V. Deep brain stimulation as a therapy for alcohol addiction. Curr Top Behav Neurosci. 2013;13:709–27.22678648 10.1007/978-3-642-28720-6_207
37. Soyka M Mutschler J Treatment-refractory substance use disorder: focus on alcohol, opioids, and cocaine Prog Neuropsychopharmacol Biol Psychiatry 2016 70 148 61 10.1016/j.pnpbp.2015.11.003 26577297
Soyka M, Mutschler J. Treatment-refractory substance use disorder: focus on alcohol, opioids, and cocaine. Prog Neuropsychopharmacol Biol Psychiatry. 2016;70:148–61.26577297 10.1016/j.pnpbp.2015.11.003
38. Fettes P Schulze L Downar J Cortico-striatal-thalamic loop circuits of the orbitofrontal cortex: promising therapeutic targets in psychiatric illness Front Syst Neurosci 2017 11 25 10.3389/fnsys.2017.00025 28496402
Fettes P, Schulze L, Downar J. Cortico-striatal-thalamic loop circuits of the orbitofrontal cortex: promising therapeutic targets in psychiatric illness. Front Syst Neurosci. 2017;11:25.28496402 10.3389/fnsys.2017.00025
39. Salling MC Martinez D Brain stimulation in addiction Neuropsychopharmacology 2016 41 2798 809 10.1038/npp.2016.80 27240657
Salling MC, Martinez D. Brain stimulation in addiction. Neuropsychopharmacology. 2016;41:2798–809.27240657 10.1038/npp.2016.80
40. Farrell SM Green A Aziz T The current state of deep brain stimulation for chronic pain and its context in other forms of neuromodulation Brain Sci 2018 8 158 10.3390/brainsci8080158 30127290
Farrell SM, Green A, Aziz T. The current state of deep brain stimulation for chronic pain and its context in other forms of neuromodulation. Brain Sci. 2018;8:158.30127290 10.3390/brainsci8080158
41. Falowski SM Deep brain stimulation for chronic pain Curr Pain Headache Rep 2015 19 27 10.1007/s11916-015-0504-1 26049773
Falowski SM. Deep brain stimulation for chronic pain. Curr Pain Headache Rep. 2015;19:27.26049773 10.1007/s11916-015-0504-1
42. Chen YS Shu K Kang HC Deep brain stimulation in alzheimer’s disease: targeting the nucleus basalis of meynert J Alzheimers Dis 2021 80 53 70 10.3233/JAD-201141 33492288
Chen YS, Shu K, Kang HC. Deep brain stimulation in alzheimer’s disease: targeting the nucleus basalis of meynert. J Alzheimers Dis. 2021;80:53–70.33492288 10.3233/JAD-201141
43. Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD The PRISMA 2020 statement: an updated guideline for reporting systematic reviews BMJ 2021 372 n71 10.1136/bmj.n71 33782057
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.33782057 10.1136/bmj.n71
44. Yang ZR Sun F Zhan SY Risk on bias assessment: (2) revised cochrane risk of bias tool for individually randomized, parallel group trials (RoB2.0) Zhonghua Liu Xing Bing Xue Za Zhi 2017 38 1285 91 28910948
Yang ZR, Sun F, Zhan SY. Risk on bias assessment: (2) revised cochrane risk of bias tool for individually randomized, parallel group trials (RoB2.0). Zhonghua Liu Xing Bing Xue Za Zhi. 2017;38:1285–91.28910948
45. Slim K Nini E Forestier D Kwiatkowski F Panis Y Chipponi J Methodological index for non-randomized studies (Minors): development and validation of a new instrument ANZ J Surg 2003 73 712 6 10.1046/j.1445-2197.2003.02748.x 12956787
Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (Minors): development and validation of a new instrument. ANZ J Surg. 2003;73:712–6.12956787 10.1046/j.1445-2197.2003.02748.x
46. Bach P Luderer M Müller UJ Jakobs M Baldermann JC Voges J Deep brain stimulation of the nucleus accumbens in treatment-resistant alcohol use disorder: a double-blind randomized controlled multi-center trial Transl Psychiatry 2023 13 49 10.1038/s41398-023-02337-1 36755017
Bach P, Luderer M, Müller UJ, Jakobs M, Baldermann JC, Voges J, et al. Deep brain stimulation of the nucleus accumbens in treatment-resistant alcohol use disorder: a double-blind randomized controlled multi-center trial. Transl Psychiatry. 2023;13:49.36755017 10.1038/s41398-023-02337-1
47. Gonçalves-Ferreira A do Couto FS Rainha Campos A Lucas Neto LP Gonçalves-Ferreira D Teixeira J Deep brain stimulation for refractory cocaine dependence Biol Psychiatry 2016 79 e87 89 10.1016/j.biopsych.2015.06.023 26235303
Gonçalves-Ferreira A, do Couto FS, Rainha Campos A, Lucas Neto LP, Gonçalves-Ferreira D, Teixeira J. Deep brain stimulation for refractory cocaine dependence. Biol Psychiatry. 2016;79:e87–89.26235303 10.1016/j.biopsych.2015.06.023
48. Vorspan F Domenech P Grabli D Yelnik J Delavest M Dauré C A single case report of STN-DBS for severe crack-cocaine dependence: double-blind ON vs. SHAM randomized controlled assessment Front Psychiatry 2023 14 1146492 10.3389/fpsyt.2023.1146492 37304434
Vorspan F, Domenech P, Grabli D, Yelnik J, Delavest M, Dauré C, et al. A single case report of STN-DBS for severe crack-cocaine dependence: double-blind ON vs. SHAM randomized controlled assessment. Front Psychiatry. 2023;14:1146492.37304434 10.3389/fpsyt.2023.1146492
49. Kuhn J Bauer R Pohl S Lenartz D Huff W Kim EH Observations on unaided smoking cessation after deep brain stimulation of the nucleus accumbens Eur Addict Res 2009 15 196 201 10.1159/000228930 19622886
Kuhn J, Bauer R, Pohl S, Lenartz D, Huff W, Kim EH, et al. Observations on unaided smoking cessation after deep brain stimulation of the nucleus accumbens. Eur Addict Res. 2009;15:196–201.19622886 10.1159/000228930
50. Mantione M van de Brink W Schuurman PR Denys D Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report Neurosurgery 2010 66 E218 10.1227/01.NEU.0000360570.40339.64 20023526
Mantione M, van de Brink W, Schuurman PR, Denys D. Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report. Neurosurgery. 2010;66:E218. discussion E21820023526 10.1227/01.NEU.0000360570.40339.64
51. Zhang C Wei H Zhang Y Du J Liu W Zhan S Increased dopamine transporter levels following nucleus accumbens deep brain stimulation in methamphetamine use disorder: a case report Brain Stimul 2019 12 1055 7 10.1016/j.brs.2019.02.023 30853339
Zhang C, Wei H, Zhang Y, Du J, Liu W, Zhan S, et al. Increased dopamine transporter levels following nucleus accumbens deep brain stimulation in methamphetamine use disorder: a case report. Brain Stimul. 2019;12:1055–7.30853339 10.1016/j.brs.2019.02.023
52. Ge S Chen Y Li N Qu L Li Y Jing J Deep brain stimulation of nucleus accumbens for methamphetamine addiction: two case reports World Neurosurg 2019 122 512 7 10.1016/j.wneu.2018.11.056 30448569
Ge S, Chen Y, Li N, Qu L, Li Y, Jing J, et al. Deep brain stimulation of nucleus accumbens for methamphetamine addiction: two case reports. World Neurosurg. 2019;122:512–7.30448569 10.1016/j.wneu.2018.11.056
53. Kuhn J Lenartz D Huff W Lee S Koulousakis A Klosterkoetter J Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry 2007 78 1152 3 10.1136/jnnp.2006.113092 17878197
Kuhn J, Lenartz D, Huff W, Lee S, Koulousakis A, Klosterkoetter J, et al. Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry. 2007;78:1152–3.17878197 10.1136/jnnp.2006.113092
54. Xu J, Wang G. Therapeutic effect of deep brain stimulation of the nucleus accumbens on refractory drug addiction: a case report. https://www.neuromodulation.com/assets/documents/2007-ins-nans-conference-exhibitors-guide_100.pdf. Accessed 9-12 December 2007
55. Müller UJ Sturm V Voges J Heinze H-J Galazky I Heldmann M Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases Pharmacopsychiatry 2009 42 288 91 10.1055/s-0029-1233489 19924591
Müller UJ, Sturm V, Voges J, Heinze H-J, Galazky I, Heldmann M, et al. Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry. 2009;42:288–91.19924591 10.1055/s-0029-1233489
56. Zhou H Xu J Jiang J Deep brain stimulation of nucleus accumbens on heroin-seeking behaviors: a case report Biol Psychiatry 2011 69 e41 42 10.1016/j.biopsych.2011.02.012 21489407
Zhou H, Xu J, Jiang J. Deep brain stimulation of nucleus accumbens on heroin-seeking behaviors: a case report. Biol Psychiatry. 2011;69:e41–42.21489407 10.1016/j.biopsych.2011.02.012
57. Kuhn J Gründler TOJ Bauer R Huff W Fischer AG Lenartz D Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring Addict Biol 2011 16 620 3 10.1111/j.1369-1600.2011.00337.x 21762290
Kuhn J, Gründler TOJ, Bauer R, Huff W, Fischer AG, Lenartz D, et al. Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring. Addict Biol. 2011;16:620–3.21762290 10.1111/j.1369-1600.2011.00337.x
58. Valencia-Alfonso CE Luigjes J Smolders R Cohen MX Levar N Mazaheri A Effective deep brain stimulation in heroin addiction: a case report with complementary intracranial electroencephalogram Biol Psychiatry 2012 71 e35 37 10.1016/j.biopsych.2011.12.013 22281120
Valencia-Alfonso CE, Luigjes J, Smolders R, Cohen MX, Levar N, Mazaheri A, et al. Effective deep brain stimulation in heroin addiction: a case report with complementary intracranial electroencephalogram. Biol Psychiatry. 2012;71:e35–37.22281120 10.1016/j.biopsych.2011.12.013
59. Heldmann M Berding G Voges J Bogerts B Galazky I Müller U Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing PLoS One 2012 7 e36572 10.1371/journal.pone.0036572 22629317
Heldmann M, Berding G, Voges J, Bogerts B, Galazky I, Müller U, et al. Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing. PLoS One. 2012;7:e36572.22629317 10.1371/journal.pone.0036572
60. Voges J Müller U Bogerts B Münte T Heinze HJ Deep brain stimulation surgery for alcohol addiction World Neurosurg 2013 80 S28.e21 31 10.1016/j.wneu.2012.07.011 22824557
Voges J, Müller U, Bogerts B, Münte T, Heinze HJ. Deep brain stimulation surgery for alcohol addiction. World Neurosurg. 2013;80:S28.e21–31.22824557 10.1016/j.wneu.2012.07.011
61. Kuhn J Möller M Treppmann JF Bartsch C Lenartz D Gruendler TOJ Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction Mol Psychiatry 2014 19 145 6 10.1038/mp.2012.196 23337942
Kuhn J, Möller M, Treppmann JF, Bartsch C, Lenartz D, Gruendler TOJ, et al. Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction. Mol Psychiatry. 2014;19:145–6.23337942 10.1038/mp.2012.196
62. Müller UJ Sturm V Voges J Heinze H-J Galazky I Büntjen L Nucleus accumbens deep brain stimulation for alcohol addiction - safety and clinical long-term results of a pilot trial Pharmacopsychiatry 2016 49 170 3 10.1055/s-0042-104507 27145161
Müller UJ, Sturm V, Voges J, Heinze H-J, Galazky I, Büntjen L, et al. Nucleus accumbens deep brain stimulation for alcohol addiction - safety and clinical long-term results of a pilot trial. Pharmacopsychiatry. 2016;49:170–3.27145161 10.1055/s-0042-104507
63. Ge S Geng X Wang X Li N Chen L Zhang X Oscillatory local field potentials of the nucleus accumbens and the anterior limb of the internal capsule in heroin addicts Clin Neurophysiol 2018 129 1242 53 10.1016/j.clinph.2018.03.008 29674090
Ge S, Geng X, Wang X, Li N, Chen L, Zhang X, et al. Oscillatory local field potentials of the nucleus accumbens and the anterior limb of the internal capsule in heroin addicts. Clin Neurophysiol. 2018;129:1242–53.29674090 10.1016/j.clinph.2018.03.008
64. Zhang C Huang Y Zheng F Zeljic K Pan J Sun B Death from opioid overdose after deep brain stimulation: a case report Biol Psychiatry 2018 83 e9 e10 10.1016/j.biopsych.2017.07.018 28882316
Zhang C, Huang Y, Zheng F, Zeljic K, Pan J, Sun B. Death from opioid overdose after deep brain stimulation: a case report. Biol Psychiatry. 2018;83:e9–e10.28882316 10.1016/j.biopsych.2017.07.018
65. Chen L Li N Ge S Lozano AM Lee DJ Yang C Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: an open-label pilot study Brain Stimul 2019 12 175 83 10.1016/j.brs.2018.09.006 30245163
Chen L, Li N, Ge S, Lozano AM, Lee DJ, Yang C, et al. Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: an open-label pilot study. Brain Stimul. 2019;12:175–83.30245163 10.1016/j.brs.2018.09.006
66. Zhang C Li J Li D Sun B Deep brain stimulation removal after successful treatment for heroin addiction Aust N Z J Psychiatry 2020 54 543 4 10.1177/0004867419890671 31782321
Zhang C, Li J, Li D, Sun B. Deep brain stimulation removal after successful treatment for heroin addiction. Aust N Z J Psychiatry. 2020;54:543–4.31782321 10.1177/0004867419890671
67. Zhu R Zhang Y Wang T Wei H Zhang C Li D Deep brain stimulation of nucleus accumbens with anterior capsulotomy for drug addiction: a case report Stereotact Funct Neurosurg 2020 98 345 9 10.1159/000509313 32846423
Zhu R, Zhang Y, Wang T, Wei H, Zhang C, Li D, et al. Deep brain stimulation of nucleus accumbens with anterior capsulotomy for drug addiction: a case report. Stereotact Funct Neurosurg. 2020;98:345–9.32846423 10.1159/000509313
68. Leong SL Glue P Manning P Vanneste S Lim LJ Mohan A Anterior cingulate cortex implants for alcohol addiction: a feasibility study Neurotherapeutics 2020 17 1287 99 10.1007/s13311-020-00851-4 32323203
Leong SL, Glue P, Manning P, Vanneste S, Lim LJ, Mohan A, et al. Anterior cingulate cortex implants for alcohol addiction: a feasibility study. Neurotherapeutics. 2020;17:1287–99.32323203 10.1007/s13311-020-00851-4
69. Mahoney JJ Haut MW Hodder SL Zheng W Lander LR Berry JH Deep brain stimulation of the nucleus accumbens/ventral capsule for severe and intractable opioid and benzodiazepine use disorder Exp Clin Psychopharmacol 2021 29 210 5 10.1037/pha0000453 34043402
Mahoney JJ, Haut MW, Hodder SL, Zheng W, Lander LR, Berry JH, et al. Deep brain stimulation of the nucleus accumbens/ventral capsule for severe and intractable opioid and benzodiazepine use disorder. Exp Clin Psychopharmacol. 2021;29:210–5.34043402 10.1037/pha0000453
70. Davidson B Giacobbe P George TP Nestor SM Rabin JS Goubran M Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial Mol Psychiatry 2022 27 3992 4000 10.1038/s41380-022-01677-6 35858989
Davidson B, Giacobbe P, George TP, Nestor SM, Rabin JS, Goubran M, et al. Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial. Mol Psychiatry. 2022;27:3992–4000.35858989 10.1038/s41380-022-01677-6
71. Rezai AR, Mahoney JJ, Ranjan M, Haut MW, Zheng W, Lander LR, et al. Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder. J Neurosurg. 2023;140:1–9.
72. Witbrodt J Kaskutas LA Grella CE How do recovery definitions distinguish recovering individuals? five typologies Drug Alcohol Depend 2015 148 109 17 10.1016/j.drugalcdep.2014.12.036 25630961
Witbrodt J, Kaskutas LA, Grella CE. How do recovery definitions distinguish recovering individuals? five typologies. Drug Alcohol Depend. 2015;148:109–17.25630961 10.1016/j.drugalcdep.2014.12.036
73. Borkman TJ Stunz A Kaskutas LA Developing an experiential definition of recovery: participatory research with recovering substance abusers from multiple pathways Subst Use Misuse 2016 51 1116 29 10.3109/10826084.2016.1160119 27159851
Borkman TJ, Stunz A, Kaskutas LA. Developing an experiential definition of recovery: participatory research with recovering substance abusers from multiple pathways. Subst Use Misuse. 2016;51:1116–29.27159851 10.3109/10826084.2016.1160119
74. Zrinzo L Foltynie T Limousin P Hariz MI Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review: clinical article J. Neurosurg 2012 116 84 94 10.3171/2011.8.JNS101407 21905798
Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review: clinical article. J. Neurosurg. 2012;116:84–94.21905798 10.3171/2011.8.JNS101407
75. Sarica C Iorio-Morin C Aguirre-Padilla DH Najjar A Paff M Fomenko A Implantable pulse generators for deep brain stimulation: challenges, complications, and strategies for practicality and longevity Front Hum Neurosci 2021 15 708481 10.3389/fnhum.2021.708481 34512295
Sarica C, Iorio-Morin C, Aguirre-Padilla DH, Najjar A, Paff M, Fomenko A, et al. Implantable pulse generators for deep brain stimulation: challenges, complications, and strategies for practicality and longevity. Front Hum Neurosci. 2021;15:708481.34512295 10.3389/fnhum.2021.708481
76. Di Chiara G Nucleus accumbens shell and core dopamine: differential role in behavior and addiction Behav Brain Res 2002 137 75 114 10.1016/S0166-4328(02)00286-3 12445717
Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res. 2002;137:75–114.12445717 10.1016/S0166-4328(02)00286-3
77. Salgado S Kaplitt MG The nucleus accumbens: a comprehensive review Stereotact Funct Neurosurg 2015 93 75 93 10.1159/000368279 25720819
Salgado S, Kaplitt MG. The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg. 2015;93:75–93.25720819 10.1159/000368279
78. Heinze H-J Heldmann M Voges J Hinrichs H Marco-Pallares J Hopf J-M Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: clinical and basic science aspects Front Hum Neurosci 2009 3 22 10.3389/neuro.09.022.2009 19750197
Heinze H-J, Heldmann M, Voges J, Hinrichs H, Marco-Pallares J, Hopf J-M, et al. Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: clinical and basic science aspects. Front Hum Neurosci. 2009;3:22.19750197 10.3389/neuro.09.022.2009
79. Koob GF Neurocircuitry of alcohol addiction: synthesis from animal models Handb Clin Neurol 2014 125 33 54 10.1016/B978-0-444-62619-6.00003-3 25307567
Koob GF. Neurocircuitry of alcohol addiction: synthesis from animal models. Handb Clin Neurol. 2014;125:33–54.25307567 10.1016/B978-0-444-62619-6.00003-3
80. Herrington TM Cheng JJ Eskandar EN Mechanisms of deep brain stimulation J Neurophysiol 2016 115 19 38 10.1152/jn.00281.2015 26510756
Herrington TM, Cheng JJ, Eskandar EN. Mechanisms of deep brain stimulation. J Neurophysiol. 2016;115:19–38.26510756 10.1152/jn.00281.2015
81. Creed MC Toward a targeted treatment for addiction Science 2017 357 464 5 10.1126/science.aao1197 28774920
Creed MC. Toward a targeted treatment for addiction. Science. 2017;357:464–5.28774920 10.1126/science.aao1197
82. Spix TA Nanivadekar S Toong N Kaplow IM Isett BR Goksen Y Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation Science 2021 374 201 6 10.1126/science.abi7852 34618556
Spix TA, Nanivadekar S, Toong N, Kaplow IM, Isett BR, Goksen Y, et al. Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation. Science. 2021;374:201–6.34618556 10.1126/science.abi7852
83. Williamson L Creating an ethical culture to support recovery from substance use disorders J Med Ethics 2020 47 e9 10.1136/medethics-2020-106661 33177147
Williamson L. Creating an ethical culture to support recovery from substance use disorders. J Med Ethics. 2020;47:e9.33177147 10.1136/medethics-2020-106661
84. Publication and related biases: a review. Health technology assessment. 2000. https://www.who.int/health-topics/health-technology-assessment#tab=tab_1.
85. Easterbrook PJ Berlin JA Gopalan R Matthews DR Publication bias in clinical research Lancet 1991 337 867 72 10.1016/0140-6736(91)90201-Y 1672966
Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337:867–72.1672966 10.1016/0140-6736(91)90201-Y
