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

Samantha L Anema; Marcelo M Melo; Sarah L Ferri; Serena B Gumusoglu; Kim T Blackwell; Susan Q Shen

doi:10.1016/j.nbd.2026.107531

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

Journal article

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

Samantha L Anema, Marcelo M Melo, Sarah L Ferri, Serena B Gumusoglu, Kim T Blackwell and Susan Q Shen

Neurobiology of disease, Vol.227, 107531

09/2026

DOI: 10.1016/j.nbd.2026.107531

PMID: 42442618

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Abstract

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.

Substance use disorders

mBDNF

proBDNF

Brain-derived neurotrophic factor

Addiction

Details

Title: Subtitle: Beyond total BDNF: The proBDNF/mBDNF balance in substance use disorders
Creators: Samantha L Anema - University of Iowa
Marcelo M Melo - University of Iowa, Psychiatry
Sarah L Ferri - University of Iowa
Serena B Gumusoglu - University of Iowa
Kim T Blackwell - University of Iowa
Susan Q Shen - University of Iowa
Resource Type: Journal article
Publication Details: Neurobiology of disease, Vol.227, 107531
DOI: 10.1016/j.nbd.2026.107531
PMID: 42442618
NLM abbreviation: Neurobiol Dis
ISSN: 1095-953X
eISSN: 1095-953X
Publisher: Elsevier; AMSTERDAM
Grant note: National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA): DP1DA063504 National Institute of Neurological Disorders and Stroke (NINDS): T32NS007421
Acknowledgement This work was supported by the National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) DP1DA063504 (to SQS and MMM) and the National Institute of Neurological Disorders and Stroke (NINDS) T32NS007421 (to SLA) .
Language: English
Electronic publication date: 07/13/2026
Date published: 09/2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Obstetrics and Gynecology; Developmental and Behavioral Pediatrics; Neuroscience and Pharmacology
Record Identifier: 9985182396102771

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