# Neuroplasticity and recovery of the brain affected by substance use disorder: multilevel mechanisms and new therapeutic strategies (2020–2025)

## TL;DR

This review explores how the brain recovers from substance use disorder by examining neuroplastic changes and new treatment strategies.

## Contribution

The paper identifies four core therapeutic domains for neuroplastic restoration in substance use disorder.

## Key findings

- Altered synaptic density and BDNF/TrkB signaling were consistently observed in substance use disorder.
- Neuromodulation and neurotrophic compounds showed potential in normalizing brain activity and reducing cravings.
- Personalized interventions targeting multiple levels of plasticity are emphasized for effective recovery.

## 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 was conducted in accordance with PRISMA 2020 guidelines and 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 findings revealed consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional neuroimaging changes in regions such as the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. 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.

Despite significant advances, important gaps remain, including methodological heterogeneity, 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-level plasticity, with growing emphasis on personalized approaches guided by neurobiological biomarkers.