Introduction: Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT_1B/1D, 5-HT_1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission. Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. β-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT_1F receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.

5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT₁, 5-HT₅) or activation (5-HT₄, 5-HT₆, 5-HT₇) of adenylate cyclase, as well as activation (5-HT₂) of phospholipase C; and (ii) ionotropic receptor (5-HT₃), a ligand-gated Na⁺/K⁺ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.