Neuroplasticity and Recovery of the Brain Affected by Substance Use Disorder: Multilevel Mechanisms and New Therapeutic Strategies (2020–2025)

Abstract

Substance use disorder (SUD) is a complex neurobiological disorder characterized by the consolidation of maladaptive neuroplasticity affecting dopaminergic, glutamatergic, and neurotrophic systems, as well as cortical and subcortical networks critical for executive control, emotional regulation, and associative learning. This systematic review, conducted according to the PRISMA 2020 guidelines, integrated 57 studies published between 2020 and 2025 to analyze neuroplastic mechanisms involved in vulnerability to substance use disorder and brain recovery following chronic substance exposure. The results show consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional changes detected by neuroimaging in regions such as the prefrontal cortex, nucleus accumbens, and amygdala. Furthermore, four core therapeutic domains for neuroplastic restoration were identified: neuromodulation approaches (including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation), compounds that promote neuroplasticity via neurotrophic signaling, epigenetic and anti-inflammatory interventions, and psychological therapies based on memory reconsolidation processes. These strategies demonstrated the capacity to normalize prefrontal activity, modulate reward networks, strengthen emotional regulation, and reduce craving. However, significant gaps remain related to methodological heterogeneity, a scarcity of longitudinal studies, and limited clinical generalizability. Overall, the evidence suggests that recovery from substance use disorder requires multimodal interventions simultaneously targeting molecular, synaptic, and circuit plasticity, with a growing emphasis on personalized approaches guided by neurobiological biomarkers.