Migraine is a highly disabling neurovascular disorder characterized by a severe 
headache (associated with nausea, photophobia and/or phonophobia), and 
trigeminovascular system activation involving the release of calcitonin-gene 
related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through 
either stimulation of 5-HT1F receptors on trigeminovascular nerves (resulting in 
inhibition of CGRP release) or direct blockade of CGRP or its receptor. 
Lasmiditan is a highly selective 5-HT1F receptor agonist and, unlike the 
triptans, is devoid of vasoconstrictive properties, allowing its use in patients 
with cardiovascular risk. Since lasmiditan can actively penetrate the 
blood-brain barrier, central therapeutic as well as side effects mediated by 
5-HT1F receptor activation should be further investigated. Other novel 
anti-migraine drugs target CGRP signaling directly. This neuropeptide can be 
targeted by the monoclonal antibodies eptinezumab, fremanezumab and 
galcanezumab, or by CGRP-neutralizing L-aptamers called Spiegelmers. The CGRP 
receptor can be targeted by the monoclonal antibody erenumab, or by 
small-molecule antagonists called gepants. Currently, rimegepant and ubrogepant 
have been developed for acute migraine treatment, while atogepant is studied for 
migraine prophylaxis. Of these drugs targeting CGRP signaling directly, 
eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant 
have been approved for clinical use, while atogepant is in the last stage before 
approval. Although all of these drugs seem highly promising for migraine 
treatment, their safety should be investigated in the long-term. Moreover, the 
exact mechanism(s) of action of these drugs need to be elucidated further, to 
increase both safety and efficacy and to increase the number of responders to 
the different treatments, so that all migraine patients can satisfactorily be 
treated.