BACKGROUND: The treatment of migraine is impeded by several difficulties, among 
which insufficient headache relief, side effects, and risk for developing 
medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs 
are currently being developed, among which the small molecule CGRP receptor 
antagonists, gepants, and the 5-HT1F receptor agonist lasmiditan. Whether 
treatment with these drugs carries the same risk for developing MOH is currently 
unknown.
MAIN BODY: Pathophysiological studies on MOH in animal models have suggested 
that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased 
calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor 
expression (lower 5-HT1B/D and higher 5-HT2A expression) may be involved in MOH. 
The decreased 5-HT may increase cortical spreading depression frequency and 
induce central sensitization in the cerebral cortex and caudal nucleus of the 
trigeminal tract. Additionally, low concentrations of 5-HT, a feature often 
observed in MOH patients, could increase CGRP expression. This provides a 
possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and 
gepants, respectively. Since lasmiditan is a 5-HT1F receptor agonist and gepants 
are CGRP receptor antagonists, they could have different risks for developing 
MOH because of the different (over) compensation mechanisms following prolonged 
agonist versus antagonist treatment.
CONCLUSION: The acute treatment of migraine will certainly improve with the 
advent of two novel classes of drugs, i.e., the 5-HT1F receptor agonists 
(lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on 
the effects of 5-HT1F receptor agonism in relation to MOH, as well as the 
effects of chronic CGRP receptor blockade, are awaited with interest.