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<jats:p>Migraine and stroke are the most common neurovascular disorders affecting adults. Migraine, particularly with aura, is associated with increased stroke risk both during and between attacks; as such, migraine may be viewed as a potentially modifiable risk factor for stroke. The exact mechanism by which migraine can predispose to stroke remains uncertain.</jats:p>

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>In this narrative review, we summarize experimental and clinical evidence demonstrating mechanistic connections between POTS and migraine.</jats:p></jats:sec><jats:sec><jats:title>Background</jats:title><jats:p>Migraine is the most common comorbidity in patients with POTS, a heterogenous disorder of the autonomic nervous system characterized by orthostatic intolerance and positional tachycardia. POTS is a debilitating illness with few effective treatments. We aim for this narrative review to increase awareness of the mechanistic connections between POTS and migraine providing foundational information that optimizes clinical care and advances the development of pathophysiologic‐based treatments.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used the PubMed and Medline databases in November 2021 to perform a literature review and searched for the following keywords: “postural orthostatic tachycardia syndrome,” “POTS,” “autonomic nervous system,” AND “migraine,” “headache.”</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The high prevalence of migraine in patients with POTS may be explained by common pathologic mechanisms. There is evidence that dysregulation of the sympathetic nervous system, alterations in central and peripheral hemodynamics, and central sensitization increase vulnerability to both POTS and migraine. Non‐pharmacologic and pharmacologic treatments that target these shared mechanisms may provide significant benefit for the patient with POTS and migraine.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Identification of common affected pathways may provide important insight that advances our understanding and treatment of both migraine and POTS.</jats:p></jats:sec>

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Using a patient‐informed regimen, we conducted an exploratory randomized, double‐blind, placebo‐controlled study to systematically investigate the effects of psilocybin in cluster headache.</jats:p></jats:sec><jats:sec><jats:title>Background</jats:title><jats:p>Sustained reductions in cluster headache burden after limited quantities of psilocybin‐containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] −2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and −3.2 (95% CI −8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; <jats:italic>p</jats:italic> = 0.251). Group difference in change from baseline had a moderate effect size (<jats:italic>d</jats:italic> = 0.69). The effect size was small in episodic participants (<jats:italic>d</jats:italic> = 0.35) but large in chronic participants (<jats:italic>d</jats:italic> = 1.25), which remained over the entire 8‐week period measured (<jats:italic>d</jats:italic> = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well‐tolerated without any unexpected or serious adverse events.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.</jats:p></jats:sec>