Systematic review reveals inconsistent but significant neurotransmitter and neuropeptide changes in cluster headache, highlighting key knowledge gaps and promising therapeutic targets.
Inconsistent results across studiesWhile multiple neurochemical changes have been reported in cluster headache, study results do not always agree, highlighting the need for standardized research
What the researchers found
Multiple neurotransmitter and neuropeptide changes have been identified in cluster headache, but study results are inconsistent, highlighting gaps in understanding the neurochemical basis of attacks.
Why it matters
Cluster headache remains poorly treated despite its severity. Identifying the specific neurochemical imbalances driving attacks could lead to more targeted and effective therapies.
The numbers in context
38 studies included. Searched PubMed, Embase, Scopus. Assessed neurotransmitters in plasma, saliva, CSF, and platelets. Histamine and sensory neuropeptides (CGRP, substance P) most consistently altered.
How the study worked
Systematic review of PubMed, Embase (Ovid), and Scopus for studies reporting quantitative neurotransmitter measurements in cluster headache patients.
Who was studied
People with cluster headache
What this study cannot tell us
Inconsistent findings across studies may reflect differences in methodology, sample timing, and patient populations. Small sample sizes in many individual studies.
How to read the evidence
Systematic review of observational studies — methodologically strong but limited by the inconsistency of the underlying evidence base.
When this study was published
Published in 2025, providing the most current synthesis of cluster headache neurochemistry.
The bigger picture
This review creates a roadmap for future cluster headache research by clearly identifying which neurochemical pathways have the strongest evidence and where more work is needed.
Questions still open
- Which specific neuropeptide pathways are most consistently altered during cluster headache attacks?
- Could targeting multiple neurotransmitter systems simultaneously improve cluster headache treatment?
Common questions
What causes cluster headache attacks?
Will this research lead to better cluster headache treatments?
Read the original research
Neurotransmitter Imbalance in Cluster Headache: A Systematic Review of Mechanisms and Therapeutic Targets.
Pain and therapy, 14(6), 1629-1645
Citation
Pellesi, Lanfranco; Mohammad, Anas; Wang, Wei; Martelletti, Paolo. (2025). Neurotransmitter Imbalance in Cluster Headache: A Systematic Review of Mechanisms and Therapeutic Targets.. Pain and therapy, 14(6), 1629-1645. https://doi.org/10.1007/s40122-025-00778-8