Neurobiological Mechanisms of Action of Transcranial Direct Current Stimulation (tDCS) in the Treatment of Substance Use Disorders (SUDs)-A Review.

Introduction: Substance use disorders (SUDs) pose a significant public health challenge, with current treatments often exhibiting limited effectiveness and high relapse rates. Transcranial direct current stimulation (tDCS), a noninvasive neuromodulation technique that delivers low-intensity direct current via scalp electrodes, has shown promise in various psychiatric and neurological conditions. In SUDs, tDCS may help to modulate key neurocircuits involved in craving, executive control, and reward processing, potentially mitigating compulsive drug use. However, the precise neurobiological mechanisms by which tDCS exerts its therapeutic effects in SUDs remain only partly understood. This review addresses that gap by synthesizing evidence from clinical studies that used neuroimaging (fMRI, fNIRS, EEG) and blood-based biomarkers to elucidate tDCS's mechanisms in treating SUDs. Methods: A targeted literature search identified articles published between 2008 and 2024 investigating tDCS interventions in alcohol, nicotine, opioid, and stimulant use disorders, focusing specifically on physiological and neurobiological assessments rather than purely behavioral outcomes. Studies were included if they employed either neuroimaging (fMRI, fNIRS, EEG) or blood tests (neurotrophic and neuroinflammatory markers) to investigate changes induced by single- or multi-session tDCS. Two reviewers screened titles/abstracts, conducted full-text assessments, and extracted key data on participant characteristics, tDCS protocols, neurobiological measures, and clinical outcomes. Results: Twenty-seven studies met the inclusion criteria. Across fMRI studies, tDCS-especially targeting the dorsolateral prefrontal cortex-consistently modulated large-scale network activity and connectivity in the default mode, salience, and executive control networks. Many of these changes correlated with subjective craving, attentional bias, or extended time to relapse. EEG-based investigations found that tDCS can alter event-related potentials (e.g., P3, N2, LPP) linked to inhibitory control and salience processing, often preceding or accompanying changes in craving. One fNIRS study revealed enhanced connectivity in prefrontal regions under active tDCS. At the same time, two blood-based investigations reported the partial normalization of neurotrophic (BDNF) and proinflammatory markers (TNF-α, IL-6) in participants receiving tDCS. Multi-session protocols were more apt to drive clinically meaningful neuroplastic changes than single-session interventions. Conclusions: Although significant questions remain regarding optimal stimulation parameters, sample heterogeneity, and the translation of acute neural shifts into lasting behavioral benefits, this research confirms that tDCS can induce detectable neurobiological effects in SUD populations. By reshaping activity across prefrontal and reward-related circuits, modulating electrophysiological indices, and altering relevant biomarkers, tDCS holds promise as a viable, mechanism-based adjunctive therapy for SUDs. Rigorous, large-scale studies with longer follow-up durations and attention to individual differences will be essential to establish how best to harness these neuromodulatory effects for durable clinical outcomes.