Beyond total BDNF: The proBDNF/mBDNF balance in substance use disorders

Brain-derived neurotrophic factor (BDNF) is a central regulator of synaptic plasticity, neuronal survival, and reward circuitry, all of which have been implicated in substance use disorders (SUDs). While prior research has focused on total BDNF levels, emerging evidence highlights the importance of its two major isoforms, proBDNF and mature BDNF (mBDNF), which exert opposing effects through differential receptor activation. ProBDNF promotes synaptic weakening and neuronal apoptosis, while mBDNF supports synaptic strengthening and neuronal survival. Environmental exposures, such as substances of abuse, may shift the proBDNF/mBDNF balance and thereby influence addiction-related neuroplasticity. This review synthesizes evidence highlighting the need to resolve BDNF isoforms, suggesting that the proBDNF/mBDNF ratio may provide mechanistic insight beyond total BDNF alone in addiction neurobiology. We examine BDNF isoform changes following exposure to alcohol, stimulants, and opioids, integrating clinical and preclinical evidence across stages of addiction (acute exposure, chronic use, withdrawal, and abstinence) and brain regions. Collectively, the evidence supports a model in which the proBDNF/mBDNF balance reflects region-specific neurobiological adaptations across stages of addiction. Future isoform-resolved longitudinal clinical studies, together with mechanistic animal and cellular models, may clarify causal relationships and identify opportunities for therapeutic modulation of BDNF signaling in SUDs.