Abstract

While pharmacological, behavioral and psychosocial treatments are available for substance use disorders (SUDs), they are not always effective or well-tolerated. Neuromodulation (NM) methods, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) may address SUDs by targeting addiction neurocircuitry. We evaluated the efficacy of NM to improve behavioral outcomes in SUDs. A systematic literature search was performed on MEDLINE, PsychINFO, and PubMed databases and a list of search terms for four key concepts (SUD, rTMS, tDCS, DBS) was applied. Ninety-four studies were identified that examined the effects of rTMS, tDCS, and DBS on substance use outcomes (e.g., craving, consumption, and relapse) amongst individuals with SUDs including alcohol, tobacco, cannabis, stimulants, and opioids. Meta-analyses were performed for alcohol and tobacco studies using rTMS and tDCS. We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge’s g > 0.5). Results were most encouraging when multiple stimulation sessions were applied, and the left dorsolateral prefrontal cortex (DLPFC) was targeted. tDCS also produced medium effect sizes for drug use and craving, though they were highly variable and less robust than rTMS; right anodal DLPFC stimulation appeared to be most efficacious. DBS studies were typically small, uncontrolled studies, but showed promise in reducing misuse of multiple substances. NM may be promising for the treatment of SUDs. Future studies should determine underlying neural mechanisms of NM, and further evaluate extended treatment durations, accelerated administration protocols and long-term outcomes with biochemical verification of substance use.

Discussion

We systematically reviewed the cumulative literature on the efficacy of NM (rTMS, tDCS, DBS) for SUD treatment (Table 4). Findings were inconsistent across each stimulation methodology, and varied significantly with respect to SUD. This may be attributed to variations in treatment parameters, symptom severity across SUD participants, use of adjunctive treatment interventions and population heterogeneity, including the presence of comorbid psychiatric disorders, age, sex, and treatment history.

Nonetheless, findings from rTMS and tDCS studies demonstrated several commonalities. For rTMS, positive outcomes when treating tobacco, stimulant and opioid use disorders were observed, as indicated by post-treatment reductions in subjective and cue-induced substance craving and/or consumption when compared to sham treatment. Accordingly, effect sizes were clinically relevant (Hedge’s g > 0.5) but highly variable, consistent with heterogeneity of the published literature [9]. Furthermore, meta-analyses found that multi-session active versus sham rTMS was particularly effective in reducing tobacco consumption, but effects on tobacco craving were non-significant. Interestingly, effects of rTMS on AUD were less consistent, with 7/16 studies demonstrating significant improvements. Subsequent meta-analyses found that multi-session rTMS produced significantly greater reductions in alcohol craving and consumption. tDCS studies were promising in the treatment of tobacco, alcohol, stimulant, and opioid use disorders, as suggested by medium effect sizes (Table 2). However, meta-analyses of tDCS trials for AUD and TUD found that both single- and multi-session stimulation were not superior to sham stimulation in reducing craving or consumption, suggesting that rTMS may be superior to tDCS for these SUDs.

DBS produced reductions in craving, consumption and/or abstinence in alcohol, tobacco, and opioid use disorders. Available data is limited to case-series making it difficult to calculate effect sizes (Table 3), with the exception of one randomized sham-controlled study in AUD [145]. Sample sizes in DBS studies were low (ranging 2–12, averaging 6.9 ± 3.1 participants), suggesting the need for larger samples and randomized controlled trials.

Treatment parameters

Variability in treatment efficacy across NM studies may be attributed to differences in stimulation parameters (e.g., stimulation target, frequency, intensity, treatment duration and sample size/demographics). For both rTMS and tDCS studies, multi-session protocols are more effective than single-sessions protocols, as indicated by larger effect sizes and the number of positive outcome studies (see Tables 1–4). This is consistent with previous reports in the addictions neuromodulation literature [149]. However, total number of sessions needed to produce long-lasting effects is unclear and requires further investigation. For rTMS, the most commonly used paradigm across substances was 10–20 sessions once daily. In contrast, studies investigating TMS in depression suggest ≥30 sessions are needed for treatment durability [150]. While studies demonstrated persistent effects, including post-TMS reductions in 3-month alcohol [71] and cigarette consumption [82] after only 10 sessions of rTMS, durability of these effects remains uncertain as there is lack of long-term follow-up and biochemical verification beyond 1-month. Amiaz et al. [77] found that reductions in cigarette consumption after 10 sessions of rTMS were not maintained at 6-months. Similarly, number of tDCS sessions needed remains unclear due to lack of long-term follow-up. tDCS protocols were also considerably shorter, with all but two studies [129, 138] applying ≤10 sessions overall. Interestingly, Ghorbani Behnam et al. [129] applied 20 total sessions and found that when these sessions were distributed over a longer period of time (12 versus 4 weeks), tobacco abstinence was considerably higher at 6-month follow-up. Accordingly, session frequency may also play an important role. Moreover, potential effects of an accelerated stimulation paradigm (e.g. more than one session daily) should also be further investigated. Studies in depression have found that accelerated protocols are safe and well-tolerated, and perform comparably to standard once-daily rTMS [151,152,153]. Martinotti et al. [93] conducted the only randomized sham-controlled addictions study to adopt such an accelerated stimulation approach, but reported unfavourable cocaine use outcomes following twice daily stimulation. Nonetheless, Steele and colleagues [154] have found that three iTBS sessions/day for 10 days was tolerable and reduced cocaine consumption.

The need for maintenance sessions following initial stimulation treatment should be further evaluated to increase durability [155]. Two studies incorporated weekly reminder sessions following 15 daily HF deep-TMS sessions, and found that reductions in alcohol consumption [68] and tobacco craving [37] persisted 3-months post-treatment. However, Amiaz et al. [77] found that improvements in tobacco use outcomes following 10 HF rTMS sessions and 8 maintenance sessions did not persist at 6-months; this may reflect the effects of the coil (Figure-8 vs. H-coil) or the number of initial sessions (10 versus 15).

Four rTMS studies [83, 84, 91, 104] compared the effects of LF (1 Hz) and HF (10 Hz) stimulation and found that 10 Hz rTMS significantly reduced substance craving and/or consumption, suggesting that HF rTMS stimulation parameters have greater therapeutic potential in comparison to LF stimulation. Accordingly, most rTMS studies used HF stimulation (e.g., ≥5 Hz) regardless of SUD. For tDCS studies, the effects of stimulation intensity (1 mA vs. 2 mA) were less clear. However, tDCS outcomes were more promising when stimulation sessions were of longer duration (>15 min).

Cue-exposure prior to rTMS may activate craving-related neurocircuitry, and subsequent stimulation could then disrupt drug-related memory consolidation [156]. Accordingly, Dinur-Klein et al. [84] incorporated smoking cue exposure prior to HF deep TMS and found that it reduced cigarette consumption. Amiaz et al. [77] evaluated differential effects of both neutral and smoking cues prior to HF rTMS, finding that smoking cues reduced cue-induced tobacco craving. This expands on previous findings in both PTSD [157] and OCD [158], wherein provocation using brief cue exposure prior to treatment alleviated symptoms compared to no cue provocation. Future studies should determine whether cue exposure should be utilized in all rTMS and tDCS protocols.

There were inconsistencies for rTMS in AUD treatment, with positive outcomes reported in 44% of studies. Nonetheless, deep TMS was effective when compared to rTMS using a Figure-8 coil, suggesting that the H-coil may be advantageous when treating AUD due to targeting of deep brain structures (e.g., insula, nucleus accumbens). Subsequent meta-analyses did find positive effects of multi-session rTMS on alcohol craving and consumption. However, given that there are several evidence-based treatments available for AUD [159], we suggest that neuromodulation treatment development should be focused on SUDs with a lack of evidence-based biological treatments, such as cannabis and stimulants.

Target brain region

Substance use outcomes with NM are influenced by targeted brain region, as well as the subsequent bilateral or unilateral stimulation of regions of interest. Most rTMS studies for SUDs have targeted the DLPFC (38/50 studies). rTMS targeting the left DLPFC produced predominantly positive effects and clinically relevant effect sizes when treating tobacco, stimulant and opioid use disorders, while those stimulating the right or bilateral DLPFC were less effective (Table 1). In contrast, studies in AUD were not responsive to left DLPFC rTMS, though right and bilateral DLPFC stimulation was effective when multiple sessions were conducted. Alternative regions were less commonly studied. Notably, the mPFC/frontal pole (with or without concurrent stimulation of ACC) emerged as a novel therapeutic target, particularly with a deep TMS protocol with H-coil technology, as indicated by studies with alcohol [63, 68] and cocaine [91]. Targeting bilateral PFC and insular cortex with deep TMS may also be effective in alcohol and tobacco treatment [37, 66, 84, 86].

Both DLPFC and mPFC have emerged as leading rTMS targets; much remains unknown about the mechanism by which rTMS induces its therapeutic effects in SUDs. An understanding of rTMS-induced alterations in SUD-related brain circuitry is limited as very few studies have incorporated neuroimaging. Furthermore, there is much uncertainty surrounding optimal target locations, both for specific SUDs and individual patients, as there have been no direct head-to-head comparisons of different active rTMS targets. Consequently, it is possible that alternate targets may be required for distinct SUDs. Interestingly, there is evidence that the Default Mode Network may be a SCZ-specific network of tobacco dependence [160]. It is critical that rTMS clinical trials include brain-based measures (e.g., MRI, EEG) in order to elucidate mechanisms of action and identify optimal treatment targets.

With respect to tDCS, right anodal DLPFC stimulation appears to be most efficacious across all substances. However, right anodal DLPFC studies had considerably more stimulation sessions (≥5 sessions) than those applying left anodal DLPFC (≤5 sessions) stimulation. Thus, observed differences may be related to treatment duration, and future studies should explore longer durations of left anodal DLPFC tDCS.

Importantly, stimulation sites for rTMS and tDCS are conventionally identified using the 10–20 EEG system or by measuring distances from predefined external landmarks. While this one-size-fits-all approach produces approximate targeting of specified regions, it does not consider inter-individual differences in brain morphology and network architecture. Neuronavigation-guided NM with magnetic resonance imaging (MRI) may achieve greater precision with personalized targets. rTMS studies in depression have demonstrated the benefits of such an approach and found that clinical outcomes were significantly improved when patients were stimulated closer to fMRI-personalized targets [161]. Selected rTMS studies integrated MRI-neuronavigation [56,57,58, 60, 75, 81, 90], though the number of studies was insufficient to distinguish its effectiveness in comparison to non-personalized targeting. No tDCS studies were present. Consequently, future randomized control trials are warranted to assess the clinical potential of neuronavigation-guided personalized rTMS and tDCS. Most DBS studies targeted the NAc, and were consistently positive.

Alternate neuromodulation modalities

Other NM methods that are less frequently used and excluded from this review include Electroconvulsive Therapy (ECT) [162], Magnetic Seizure Therapy (MST) and Transcranial Alternating Current Stimulation (tACS) [163]. Studies examining their effects on SUDs are limited. We also excluded invasive ACC stimulation; ACC implants have shown positive effects, particularly for AUD, although adverse events have been reported [164].

Psychiatric comorbidities

Only a few studies have tested neuromodulation interventions in populations with comorbid psychiatric disorders. Notably, 3/4 of rTMS studies that examined TUD participants with co-occurring SCZ observed significant reductions in tobacco craving and consumption [78, 80, 85] (Table 1). Prevalence of tobacco use in SCZ is 60–80% and contributes to a 25-year decreased life expectancy in SCZ [165], emphasizing the therapeutic potential of rTMS for this comorbidity. Moreover, SCZ patients have high rates of cannabis misuse [166]. Kozak-Bidzinski et al. [88] studied rTMS in outpatients with SCZ and CUD (N = 19). Although the difference in cannabis use was not statistically significant, larger reductions (~60%) were observed in the active (n = 9) versus sham (n = 10) group, highlighting its treatment potential. Ultimately, these NM methods show promise in treating co-occurring SUD and psychiatric disorders, warranting further research in clinical trials with larger sample sizes.

Conclusions and future directions

There is considerable promise for the use of NM therapies in SUDs. Nonetheless, further research is required to determine clinical safety and efficacy. Future studies should focus on optimizing stimulation parameters and regimens for these NM methods, with emphasis on stimulation duration, number of treatment sessions needed to produce enduring effects, accelerated treatment paradigms, stimulation frequency and intensity and targeted brain region. Assessment of enduring effects of NM treatment using biochemical verification at extended time-points and the need for maintenance sessions following treatment cessation to optimize clinical outcomes should be emphasized. Neuroimaging data (fMRI) should be acquired prior to, during, and following treatment to elucidate the underlying neural mechanisms mediating treatment effects. Moreover, MRI-neuronavigation may address potential discordance between coil/electrode placement and region of interest, potentially improving treatment efficacy.

Finally, greater emphasis on co-occurring psychiatric disorders is needed. rTMS may be a promising intervention for patients with SCZ and concurrent SUDs, warranting larger randomized sham-controlled trials. Finally, the potential of adjunctive psychotherapeutic and/or pharmacological intervention should be determined, which may improve substance use outcomes [81]. While some studies have implemented concurrent pharmacological interventions [78], few have parsed the clinical impact of each therapy for augmentation of NM outcomes.

Source: Nature