Comparing synthetic and biological therapy for the treatment of cluster headache: what is needed and when?

INTRODUCTION: Cluster headache is an extremely painful and severely disabling primary headache disorder that, despite its profound impact on quality of life, remains underdiagnosed and undertreated. Effective management requires a structured approach across the cluster cycle, but practical, timeline-based guidance integrating established and emerging therapies is lacking. AREAS COVERED: The authors present a treatment framework organized by clinical timeline: inter-cycle period, cycle onset, active cycle, and resolution, addressing acute abortive, bridge, and prophylactic therapies with evidence quality, dosing, and monitoring. Both established synthetic agents and recently recognized biologic therapies are examined, with particular focus on anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and forward-looking targets such as PACAP and 5-HT2A. References were identified through searches of PubMed and clinical trial registries from inception to June 2026. EXPERT OPINION: Anti-CGRP monoclonal antibodies are a meaningful advance, best positioned as an adjunct to established prophylaxis rather than a replacement. PACAP-targeted therapy is a promising direction whose role in cluster headache remains to be defined. The serotonergic agent psilocybin warrants closer attention, as its early therapeutic signal merits rigorous investigation despite the legal and historical barriers constraining its study.