Registered studies, protocols and reported results
Studies
Clinical study protocols and source-reported registry results, preserved locally.
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Registered studies, protocols and reported results
Clinical study protocols and source-reported registry results, preserved locally.
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Registered studies, protocols and reported results
Study registrations describe protocols. Results are shown only when the registry supplied a Results section; local links are not efficacy claims.
17 exact matches
Snapshot 14/09/2026In previous clinical trial work, the investigators observed lasting reductions in headache burden after limited dosing of psilocybin. This purpose of this study is to examine potential sources for this observed effect. This study will measure brain resting state functional connectivity (fMRI), central synaptic density (SV2A PET), peripheral markers of inflammation, circadian rhythm (actigraphy), and sleep (sleep EEG) in both migraine and healthy control participants before and one week after the administration of psilocybin or an active control agent.
Open study recordDepression and migraine are among the most prevalent conditions in the general population, and many research shows they are closely related. Migraine is one of the most common debilitating diseases, affecting over one billion people worldwide. Migraine is frequently comorbid with psychiatric conditions such as anxiety disorders and major depression, with a negative impact on quality of life (QoL) and disability. The knowledge of the pathophysiology of migraine involves changes in physiological processes, functional connectivity, and structural changes of the central nervous system (CNS) in patients with underlying genetic susceptibility. Upregulation of vasoactive and pro-inflammatory mediators such as calcitonin gene-related peptide (CGRP) and cytokines have been found in the trigeminal ganglia and the plasma, cerebrospinal fluid, saliva, and tears of these patients. Various classes of antidepressants - like Selective Serotonin Reuptake Inhibitors (SSRI), Selective Serotonin and Norepinephrine Inhibitors (SNRI), and Tricyclic Antidepressants (TCAs) - were investigated but in a low number of studies and with inconsistent results. Vortioxetine (VO) is a novel multimodal serotonergic antidepressant, approved in the last decade for the treatment of major depression. VO inhibits 5-HT transporter (SERT), like commonly used antidepressants, but different from them, it directly modulates the activity of 5-HT receptors. Vortioxetine also modifies the release of glutamate and gamma amino butyric acid (GABA), implicated in migraine pathogenesis. Recent experimental and clinical studies have shown that VO exerts antidepressant and pro-cognitive activities and is also effective in modulating pain hypersensitivity and could be effective in treating chronic pain syndromes.
This study will evaluate the efficacy and safety of cannabis for the treatment of chronic migraine headaches. Study subjects will be randomized to one of three groups: lower dose CBD, higher dose CBD or placebo. Migraine is a neurological disorder characterized by recurrent attacks of moderate to severe headache, often accompanied by sensory sensitivity and nausea. Migraine can be very disabling and often interferes with social and occupational functioning. Given the high prevalence of migraine and the significant burden it places on the individual and society, it is an important condition to study and manage optimally. This is especially true because current migraine treatments often result in only marginal improvement and are frequently associated with intolerable side effects. For this reason, there is a need for new migraine treatments. The endocannabinoid system is an important potential treatment target as it is involved in pain processing and overlaps with some mechanisms of migraine pathophysiology. Cannabis was legalized in Canada on October 17th, 2018. As a result, the consumption of cannabis products for migraine treatment may increase. However, at this time there is limited evidence for the safety and efficacy of cannabis for the treatment of migraine. As a result, there is a need for further study and research in this area. Thus, we propose a randomized, double-blind, placebo-controlled clinical trial to study cannabis (specifically cannabidiol) as a preventative therapy for patients with chronic migraine.
Open study recordThis pilot crossover study will evaluate 3 different potencies of inhaled cannabis (2.5%, 5%, and 10%) and inhaled placebo cannabis for the acute treatment of migraine. In this double-blind, randomized, crossover trial, subjects will treat 4 separate migraine attacks with 4 different treatments. Inhaled cannabis will be administered using a portable system. Subjects will self-administer inhaled cannabis as early as possible in the course of a migraine, taking 4 puffs of 1) THC 2.5%, 2) THC 5%, 3) THC 10%, or 4) placebo. Patients will treat each of the 4 distinct migraine attacks with a different cannabis sample. Outcomes measured will include pain freedom, most bothersome symptom (MBS), and pain relief as well as presence or absence of photophobia, phonophobia, and nausea at 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 24 hours, and 48 hours.
Open study record* This two-stage clinical trial will assess a novel combination therapy for acute migraine. In Stage 1 (factorial), participants will receive the combination, each individual component, or placebo. In Stage 2 (dose-finding), they will test three doses of the combination. Before both stages, participants will complete a run-in period, documenting a migraine attack without study medication. They will then treat one migraine attack in each stage. * 4 visits * Requirements: Migraine Diagnosis. BMI below 34. Read, write, and speak English. No opioids, marijuana, benzodiazepines, or excessive alcohol. This study evaluating naltrexone-acetaminophen in the acute treatment of migraine.
Open study recordCanvert-M (manufactured by Alasht Pharmed Co. Iran) is a topical roll-on formulation that contains cannabidiol, peppermint, lavender, rosemary, eucalyptus, wintergreen, basil oil, etc. This phase IV, single-arm, open-label clinical trial evaluated the efficacy and safety of Canvert-M in males and females aged 18 to 55 years diagnosed with migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), for the treatment of migraine attacks. The primary objective was to assess the reduction in headache intensity using a 4-point scale (0=no headache, 1=mild headache, 2=moderate headache, 3=severe headache). Secondary objectives included evaluating additional efficacy and safety outcomes of Canvert-M in managing migraine attacks. In this study, participants are asked to: * Apply an adequate amount of Canvert-M roll-on to the areas of the forehead, temporal, behind the ears, and base of the neck, at the onset of a migraine attack. (If the participant's headache persists after 30 minutes, a second dose can be used.) * Record the date when the headache occurred. * Record the severity of the headache at various time points (before using Canvert-M, and then at 30 minutes, 60 minutes, 120 minutes, 4 hours, and 24 hours after using the Canvert-M roll-on) based on the 4-point scale. * As much as possible, avoid using any other analgesics for two hours after applying Canvert-M. However, if the headache persists after two hours, the participant may use another medication and should record the name(s) of the drug(s) taken. * Record a general evaluation of the effectiveness of the investigational product using a simple Likert-type verbal scale.
Open study recordFor migraine patients experiencing at least four attack days per month and undergoing transcranial magnetic stimulation (TMS) treatment, a randomized, double-blind controlled trial is conducted, dividing participants into a traditional targeting group and an individualized targeting group. Patients in both groups are followed up before treatment and at 1, 2, and 3 months post-treatment, evaluating the following parameters: migraine diaries, the number of migraine days, rescue medication usage, headache intensity, the number of moderate-to-severe migraine days, and the proportion of patients achieving a ≥50% reduction in migraine days. Further assessments include changes in the Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), Migraine-Specific Quality of Life Questionnaire (MSQ), Pittsburgh Sleep Quality Index (PSQI), Patient Global Impression of Change (PGIC), 24-item Hamilton Depression Scale (HAMD-24), and 14-item Hamilton Anxiety Scale (HAMA-14). Biomarker and metabolic analyses include tryptophan and kynurenine metabolism, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P, endothelin-1, inflammatory cytokines (IL-1β, IL-6, TNF-α, TGF-β1), glutamate, endocannabinoids and related lipids, as well as gut microbiota composition. Additionally, changes in resting-state functional magnetic resonance imaging (rs-fMRI) before and after treatment are analyzed. This study aims to compare the efficacy of TMS treatment under different targeting strategies in migraine patients, providing theoretical support for clinical applications.
Open study recordChronic headaches are a major cause of disability among adolescents. Cannabis products have supported the management of headaches in adults and may play a role in pediatric chronic pain. We propose a multisite, open-label, tolerability study conducted across three centers in Canada of Cannabidiol-enriched Cannabis Herbal Extract in adolescents (ages 14 to 17 years old) with chronic headaches. The study includes a one month baseline assessment, four months of escalating treatment doses and a weaning period. Our primary outcome is tolerability defined as the number and severity of reported adverse events.
Open study recordThe investigators aim to assess and compare neurophysiological and biochemical changes induced by a 3-month treatment with atogepant (60 mg daily) in patients with high-frequency episodic migraine (8-14 monthly migraine days). Evaluations will include neurophysiological assessments (High-Density EEG, nociceptive reflexes, and visual evoked potentials) and biomolecular profiling (gene expression of endocannabinoid catabolizing enzymes, CGRP and PACAP plasma levels, and headache-specific microRNAs). Outputs will contribute to defining predictors of atogepant response, elucidating its effects on brain connectivity, excitability, and CGRP/endocannabinoid pathways, and identifying alternative therapeutic targets for non-responders. BACKGROUND: Migraine is a highly prevalent neurological disease associated to a severe burden for patients and society. Despite recent advances, the knowledge of the molecular and biochemical pathways that turn on and off a migraine attack and lead to an increased frequency of attacks is still limited. In addition, the lack of predictors of the therapeutic response is a barrier to access to care and to a personalized approach. In recent years, several migraine-specific drugs have become available for the preventive treatment of the disease, which is aimed at reducing the frequency and the intensity of the attacks. Among the drugs currently available for migraine treatment, there are molecules that directly interfere with the calcitonin gene-related peptide (CGRP) pathway. Gepants, oral drugs that are CGRP receptor antagonists, represent a recently available pharmacological class for the acute and preventive treatment of migraines due to their specific mechanism of action. The potential mechanism underlying the therapeutic benefit derived from drugs that block CGRP, as well as their impact on various biochemical and functional parameters associated with migraine pathophysiology, remains a topic of debate. The objective of the ATOM project is to characterize the neurophysiological and biomolecular mechanisms underlying the therapeutic action of Atogepant (ATO), a drug belonging to the new pharmacological class of gepants. ATO has been shown to be effective in the preventive treatment of both chronic and episodic migraine. However, preventive treatment with gepants is still ineffective (reducing the number of monthly migraine days by less than 50%) in 30% of patients. This finding suggests that other biological pathways independent of CGRP may play a role in migraine pathophysiology. Among these, the endocannabinoid system has gained increasing importance over the years. From a neurofunctional perspective, central sensitization is a significant aspect of migraine pathophysiology. Our group has demonstrated the utility of the nociceptive withdrawal reflex at the lower limb (RIII) in studying central sensitization. A subsequent study showed improvement in RIII reflex parameters in 30% of chronic migraine patients who responded to Erenumab after three months of treatment, suggesting a potential correlation between improved central sensitization and clinical benefit from anti-CGRP antibody treatment. Additionally, migraine patients exhibit altered responses following repeated cranial stimulation, specifically a deficit in habituation to such stimuli. It has been described that the habituation pattern follows a characteristic course throughout the migraine cycle. The habituation deficit has been demonstrated through various neurophysiological methods, such as the nociceptive blink reflex (nBR) and visual evoked potentials (VEPs). These assessments provide information about the modulation of relevant stations in the trigemino-vascular system, specifically the trigemino-cervical complex and the occipital cortex. Our study includes an evaluation of brain functional connectivity using High-Density Electroencephalography (HD-EEG). Recently, we analyzed potential variations in functional connectivity within the Resting State Network (RSN) in migraine patients undergoing six months of treatment with monoclonal antibodies targeting the CGRP pathway through serial HD-EEG evaluations (unpublished data). Our findings demonstrate that migraine patients, when compared to healthy controls, exhibit widespread hyperconnectivity in the theta and delta frequency bands, potentially attributable to dysfunction of the generators of these frequency bands, highlighting the importance of the thalamo-cortical dysrhythmia concept in migraine pathophysiology. Conversely, longitudinal comparisons revealed a trend towards normalization of connectivity in patients with a good clinical response to anti-CGRP monoclonal antibodies. From a biochemical standpoint, our group has demonstrated that the gene expression of endocannabinoid catabolizing enzymes - fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) - is altered in peripheral cells of patients with episodic and chronic migraine and is correlated with migraine severity. Similarly, various literature evidence supports the role of microRNAs in the mechanisms underlying migraines. Elevated expression levels of miR-382-5p and miR-34a-5p, combined with lower levels of miR-30a-5p expression, have been found in migraine patients compared to healthy controls, confirming an epigenetic alteration. In a previous study, we reported that peripheral levels of miR-382-5p and miR-34a-5p in migraine patients were correlated with disease severity, as they were increased in patients with chronic migraine and medication-overuse headache (CM-MOH) compared to episodic migraine (EM) patients, suggesting involvement in chronicization, while not excluding an influence of pharmacological migraine treatments . Elevated levels of miR-155, a microRNA known to modulate inflammation, have been found in peripheral cells of both EM and CM-MOH patients compared to healthy controls, with higher levels in chronic patients. The overarching aim of this project is the identification of specific neurophysiological and biomolecular signatures that differentiate subjects with migraine who benefit or do not benefit from atogepant treatment. This aim will be achieved via a thorough neurophysiological and biochemical profiling of subjects with high frequency episodic migraine treated with atogepant 60 mg for a period of 3 months. STUDY DESIGN: Patients will be enrolled from those attending the outpatient clinic of IRCCS Mondino Institute (Pavia). The investigators will enroll 30 patients with high-frequency episodic migraine (8-14 monthly migraine days) with clinical indications to start atogepant (ATO - 60 mg daily) according to the Italian regulations. The investigators will collect clinical data and perform biochemical and neurofunctional profiling of migraine patients at baseline (T0) and after three months of atogepant treatment (T1). METHODS: All patients will undergo at T0 and T1: 1. Biochemical profiling that will include analysis of: * eCBome system: FAAH, MAGL mRNA in PBMCs; * plasma levels of CGRP, PACAP, and VIP; * miR-382-5p, miR-34a and miR-155 in PBMCs. The investigators will collect biochemical sampling between 9 and 11 a.m. to avoid circadian rhythm influence. All evaluation will be performed in the interictal phase. The following collection methods will be adopted: • mRNA and microRNA analysis in PBMCs. Blood samples will be collected within ethylenediamine tetra-acetic acid tubes, the investigators will first isolate PBMCs and total RNA. Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs. • CGRP alpha, PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay. 2. Neurofunctional profiling that will include: * recording of the Nociceptive Withdrawal Reflex (RIII); * recording of the nociceptive Blink Reflex (nBR); * recording of High-Density EEG (HD-EEG); * recording of Visual Evoked Potentials (VEP). The following methods will be adopted: - Nociceptive Withdrawal Reflex (RIII reflex): The sural nerve will be stimulated via surface electrodes behind the right lateral malleolus. Reflex threshold (≥20 μV, \>10 msec) will be determined using the ladder method. Temporal summation threshold (TST) will be assessed by increasing stimulus intensity (5 stimuli at 2 Hz) until facilitation of the reflex response appears. (De Icco et al., 2020).- Nociceptive Blink Reflex (nBR): nBR R2 response will be recorded using a concentric electrode above the supraorbital nerve and surface electrodes at the orbicularis oculi muscle. Habituation will be evaluated with 25 stimuli at varying frequencies, with area under the curve (AUC) calculated for 5 averaged blocks. Habituation index (HI) will reflect percentage change in AUC from the last to the first block. (Perrotta et al., 2017). - Visual Evoked Potentials (VEP) recording: VEP will be recorded during monocular stimulation using black-and-white checkered patterns. Components (N70, P100, N145) will be analyzed, and habituation will be defined as the percentage change in P100 amplitude between the last and first block. (Ambrosini et al., 2017). High Density Electroencephalography recording (HD-EEG): Recordings (128 channels, high-pass: 0.5 Hz, low-pass: 100 Hz) will include four 6-minute resting-state sessions (2 with eyes open, 2 with eyes closed). Frequency bands (delta to gamma) will be analyzed using a validated custom pipeline to reconstruct cortical/subcortical neural sources. STATISTICAL ANALYSIS: Sample size calculation was performed for the primary outcome of ATOM project (namely compare the TST threshold of the RIII reflex between T0 and T1. From previous papers, preliminary data and experience of our research group, an expected difference between the means at T0 and T1 of 2 mA is inferred, with a standard deviation of 4 mA for both measurements. The comparison will be made by t test for paired data or corresponding nonparametric test (Wilcoxon Signed Rank Test), after performing a preliminary test on the normality of the data (Shapiro test). The investigators will consider a test power of β=0.8 and a 95% confidence. The suggested sample size is n=30. Regarding the co-primary outcome (Aim 2 - gene expression of MAGLs in PBMCs) a power analysis was performed, considering a significant difference between T0 and T1 of 5 RQ (standard deviation 4 and 10 respectively). Assuming a sample size of 30, the expected power is more than 80%.
Open study recordTo evaluate the effect of the cannabidiol (CBD) + cannabigerol (CBG) + tetrahydrocannabinol (THC) up to 133/66/4mg daily versus placebo as adjuvant treatment in chronic migraine (CM) patients under preventive treatment at a stable dose for at least 3 months who present at least 5 headaches day a month. CM patients of both sexes, between 25 and 65 years old, who have not had CBD and/or THC as a migraine treatment. Patients may be having migraine preventive treatment such as propranolol, atenolol, topiramate, valproic acid/sodium valproate, levetiracetam, gabapentin, lamotrigine, pre-gabaline, flunarizine, amitriptyline, nortriptyline, clomipramine, candesartan, galcanezumab, erenumab, fremanezumab, botulinum toxin type A. Acute treatment will follow patients doctor's prescription. Exclusion criteria: active liver disease or elevated liver transaminases\> 3 times than the normal values, pregnancy, fertile age women without contraceptive treatment or who intend to get pregnant, patients without migraine preventive treatment or that changed the preventive treatment less than 3 months from the study start, substance abuse or addiction, use of medical cannabis or products with CBD or THC in the last 30 days or during study period, history of allergy or adverse reactions with the use of CBD or related products, substance users of liver enzymes inducers such as rifampicin, ketoconazole, theophylline, carbamazepine, phenytoin, phenobarbital and St. John's wort, clobazam, macrolides, verapamil, fluoxetine, amiodarone and tacrolimus. Patients on vitamin K anticoagulant medicines, as warfarin. Randomization using a computacional system will stratify participants in each group by gender (F/M), age (25-34/35-44/45-54/55-65yo), headache days presented in the baseline month (5-10/11-15/16-20/21-25/26-30), overuse medication (yes or no). After randomization patients will be divided into two groups of 55 participants, who will receive CBD + CBG + THC up to a maximum daily dose of 133/66/4 mg or placebo for 12 weeks (V0 screening, V1 allocation, V4 final visit). The main outcome is the reduction in frequency of headache days per 4 weeks between V1 and V4 compared to placebo. Secondary outcomes will be a reduction in duration and intensity of migraine attacks, amount of painkillers used and percentage of patients with a reduction greater than 50% on migraine days, 50% reduction in the other variables as MIDAS scores, HIT-6 scores, Beck's Anxiety and Depression Scales, Epworth Sleepiness Scales, and the scores at The Severity of Dependence Scale used as an indicator of overuse medication in this sample. Clinical data will be registered on a personalized headache diary developed to this study using MyCap, from RedCap System, as an APP for daily entries using smartphones, androids or IOS system. The clinical and laboratory data obtained in this study will comply with the objectives elaborated in the evaluation of the primary and secondary endpoints, the proposal of which is to publish the data regardless of the results obtained.
Open study recordAim of the study was to assess a potential dysfunction of the endocannabidiome system (eCBome) in migraine patients. Migraine patients who will undergo preventive therapy with monoclonal antibodies directed against the calcitonin gene related peptide (mAbs) will be evaluated through a deep phenotyping of peripheral neurochemical biomarkers (eCBome, neuropeptides, cytokines and kynurenine levels, and microRNAs expression). Primary aim is to assess baseline differences among those patients who achieved a reduction of monthly migraine days \>/= 50% after three months of tretament (namely Responders) and those who did not (namely Non-responders). Previous evidence showed that endocannabidiome system (eCBome) is altered in migraine patients demonstrating: i) altered gene expression of catabolizing enzymes (MAGL and FAAH) in patients with episodic and chronic migraine compared to healthy controls; ii) altered peripheral levels of the endocannabinoid-like lipid palmitoylethanolamide (PEA) with evidence of increased PEA levels during the acute migraine phase. Despite the high effectiveness and tolerability of mAbs monoclonal antibodies directed against the Calcitonin gene related peptide (mAbs), evidence from RCTs and real-life studies demonstrates that mAbs fail in 40% of patients. These patients may bear a non CGRP- dependent phenotype, potentially linked to eCBome dysfunction. Primary aim is to perform a deep phenotyping of the whole cohort of migraine patients comparing the subgroups of those patients who will be Responders to mAbs treatment (namely those patients who achieved a reduction of monthly migraine days \>/= 50%) compared to the Non-Respoder group (namely those patients who achieved a reduction of monthly migraine days \< 50%) . Neuropeptides, microRNAs, inflammatory cytokines, and kynurenine metabolites will be evaluated. These findings will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments and potentially unveiling other molecular targets. STUDY DESIGN: This study is part of the SPHERA project with funding from the Italian Ministry of Health (GR-2021-12372429). Patients will be enrolled from those attending the outpatient clinic of IRCCS Mondino Institute (Pavia) and Neurology Department of the University of L'Aquila (Avezzano). Data will be collected before mAbs starting (baseline-T0) and after three months (T1) of mAbs treatment. First, Repsonder and Non-responder groups will be identified, then a biochemical profiling of the two subgroups will be performed at T0 and T1. METHODS: All patients will undergo a biochemical profiling that will include analysis of: * eCBome system: mRNS levels of FAAH, MAGL, DAGL, NAPE, NAAA in peripheral blood mononuclear cells, * plasma levels of AEA, 2-AG, PEA and OEA; CGRP, PACAP, and VIP; IL-1beta, TNF-alpha, IL-4, and IL-10; kynurenic and quinolinic acids; * miR-382-5p, miR-34a, miR-30a, and miR-155 in peripheral blood mononuclear cells, * shotgun analysis of microbiota in patients' faeces. Biochemical sampling will be collected between 9 and 11 a.m. to avoid circadian rhythm influence. All evaluation will be performed in migraine interictal phase. The following collection methods will be adopted: * mRNA and microRNA analysis in PBMCs. Blood samples will be collected within ethylenediamine tetra-acetic acid tubes, with a first isolation of PBMCs and total RNA. Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs. * kynurenic acid and quinolinic acid, AEA, PEA, 2-AG and OEA will be determined according to Gao published method (Gao, 2020). Kinurenine metabolite levels will be measured according to the method described by Fuertig (Fuertig, 2016). * CGRP alpha, PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay * IL-1beta, TNF-alpha, IL-4, IL-10 cytokine will be measured by the Ella Automated Immunoassay System with a Simple Plex assay panel. * Microbiome analysis: after correct collection and preservation of stool specimens, they will be delivered to the Translational Neurovascular Research Unit (IRCCS Mondino Foundation) for DNA extraction. STATISTICAL ANALYSIS Sample size calculation is defined for primary outcome (MAGL expression), while a power analysis is performed for the co-primary outcome (FAAH expression). According to preliminary data from the work of Greco 2021 suggesting a ratio between Non-responders and Responders: 2:3 and MAGL gene expression: 8±10 RQ in Non-responders and 3±4 RQ in Responders, the minimum sample size is of 88 migraine patients (53 Responders and 35 NON-Responders) in order to have a confidence interval 95% and power of 80%. Normality analysis will be performed to evaluate parametric or non-parametric methods. A univariate analysis will be performed to search for differences in demographic, clinical and biochemical parameters between Non-Responder and Responder groups at T0. Main statistical analysis will include a multivariate approach to control for confounders. The level of significance will be set at alpha = 0.05 considering correction for multiple comparisons where appropriate.
Open study recordPrimary working hypothesis is that NON-responders to mAbs bear a dysfunction of the endocannabidiome system (eCBome), as suggested by pre-clinical and clinical data by our group. They will be identified as patients showing a reduction of monthly migraine days \< 50% after three months of treatment. The clinical, biochemical and neurofunctional impact of novel therapeutic approaches expected to interfere with eCBome will be evaluated in NON-responder patients Monoclonal antibodies directed against the calcitonin gene related peptide pathway (mAbs) have recently become available as the first targeted-therapy for migraine prevention. Despite their revolution in migraine therapy, clinical evidence demonstrated that nearly one-third of patients do not respond to mAbs. Even among Responders (namely those with a reduction in monthly migraine days - MMDs, of at least 50%), almost half still suffers from 8 residual MMDs or more. There is therefore room for improvement, and understanding the pathophysiological mechanisms involved in these processes is mandatory to develop novel therapies and optimize treatment outcome. Among several non-CGRP pathways, the eCBome may play a major role in migraine as it interacts with multiple pathways to modulate inflammation and pain. Previous evidence showed that genes expression of eCBome system is altered in migraine patients. Interestingly, it seems possible to normalize eCBome dysfunction in migraineurs, as demonstrated by the decrease of FAAH levels in chronic migraineurs with medication overuse who underwent a successful detoxification. From a therapeutic point of view, a potential role for PEA in the termination of experimentally-induced migraine attack in humans and in the acute treatment of spontaneous attacks were published. Polyunsaturated fatty acids (PUFAs) are other eCBome precursors involved in neuronal processes and anti-inflammatory properties. Data supports an interconnection between dietary n-3 PUFAs intake, also showing a protective action of high PUFAs intake in inflammation and neurodegenerative disease. Another therapeutic weapon is represented by the ketogenic diet (KD), a "fat" diet that induces an increase in PUFAs. In migraine, KD reduced the frequency of migraine attacks when compared to a standard mediterranean diet in episodic migraine. It may interfere with the eCBome at multiple levels (gut and brain) and via multiple mechanisms: i) increase in substrate availability; ii) improvement of cortical metabolism and hyperexcitability enhancing glutamate clearing from astrocytes; ii) modulation of neuro-inflammation. Preliminary evidence also support a role for KD in treatment-resistant migraine, and in a small number of CM patients resistant to approved therapies, with preliminary data suggest a positive response. Its efficacy in patients who failed mAbs treatment is yet to be elucidated, though. As intriguing data suggests the possibility to interfere with the eCBome via multiple modalities, ranging from PEA administration to dietary adaptations, it seems extremely interesting to identify an eCBome-dependent migraine phenotype and to test its performance in proof-of-concept therapeutic challenges. The investigators intend to act on the alteration of microbiota through the ketogenic diet (KD) and on the alteration in endocannabinoids related lipids with PEA or PUFA supplementation. These therapeutic modalities are already available for clinical use and have a highly safe profile, easily ready to be used for improving health in a group of highly disabled patients. The investigators will also try a concomitant therapy (mAbs + PEA / PUFA) in order to provide insights on the effect of a concomitant dual modulation (CGRP and eCBome system) in patients undergoing mAbs treatment. Furthermore, a comprehensive biochemical set of potential biomarkers will be evaluated, including neuropeptides, microRNAs, inflammatory cytokines, kynurenine metabolites and brain cortical connectivity trough recording of HD- EEG and rs-fMRI. The biochemical and functional phenotyping will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments, potentially associated to the clinical response to treatments that targets different pathways. Study design: Patients will be enrolled among those receiving treatment with monoclonal antibodies against the calcitonin gene receptor peptide pathway (mAbs) at the clinic of IRCCS Mondino Institute (Pavia) and Neurology Department of the University of L'Aquila (Avezzano). The following groups will be identified: * NON-responder group: patients who show a reduction \< 50% of MMDs after 3 to 6 months of mAbs treatment compared to baseline * Partial Responder: patients who show a reduction \> / = 50% of MMDs after 3 to 6 months of treatment compared to baseline, but still having at least 5 MMDs NON-responders will stop mAbs treatment and will receive one of the following: * PEA supplementation (600mg twice a day for three months) * ketogenic diet (KD) for three months (characterized by the following percentages of macronutrients: 65% fat, 27% protein and 8% carbohydrates) Partial responders will be assigned to add-on to mAbs: \- PEA (600mg twice a day for three months) Clinical data will be collected and biochemical and neurofunctional profiling of migraine patients will be performed before starting novel treatment (PEA or KD) (V0) and after three months of treatment (V1). Clinical data will be collected up to 6 months from treatment starting (V2). Methods: BIOCHEMICAL PROFILING All patients will undergo a biochemical profiling that will include analysis of: * eCBome system: FAAH, MAGL, DAGL, NAPE, NAAA mRNA in PBMCs; * plasma levels of AEA, 2-AG, PEA and OEA; CGRP, PACAP, and VIP; IL-1beta, TNF-alpha, IL-4, and IL-10; kynurenic and quinolinic acids; * miR-382-5p, miR-34a, miR-30a, and miR-155 in PBMCs; * shotgun analysis of microbiota in patients' faeces. Biochemical sampling will be collected between 9 and 11 a.m. to avoid circadian rhythm influence. All evaluation will be performed in the interictal phase. All samples will be pre-processed within 30 minutes from blood sampling, and immediately stored at -80° C. The final processing will be performed within 3 months. The following collection methods will be adopted: * mRNA of eCBome enzymes and microRNA analysis in PBMCs. Blood samples will be collected within ethylenediamine tetra-acetic acid tubes, with isolation of PBMCs and total RNA. Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs. * Endocannabinoids and related lipids extraction; kynurenic acid and quinolinic acid, AEA, PEA, 2-AG and OEA will be determined according to the method published by Gao and collaborators with minor modifications(Gao, 2020). Measurement of kinurenine metabolite levels will be performed according to the method described by Fuertig et al. with minor modifications (Fuertig, 2016). * Plasma samples will be prepared by centrifugation of blood samples. CGRP alpha, PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay; while IL-1beta, TNF-alpha, IL-4, IL-10 cytokine will be measured by the Ella Automated Immunoassay System with a Simple Plex assay panel. * Microbiome analysis: patients will be instructed for the correct collection and preservation of stool specimens; these will be delivered to the Translational Neurovascular Research Unit (IRCCS Mondino Foundation) for DNA extraction. DNA samples will be stored at -80°C until shotgun microbiome analysis. NEUROFUNCTIONAL PROFILING All patients will undergo high density-EEG and subset of 40 patients will also be studied in parallel with resting state- functional MRI at T0. \- HD-EEG: the investigators will randomly acquire 4 recordings (6 minutes each) in resting-state condition, 2 with opened eyes, and 2 with closed eyes. The following frequency bands will be considered: delta (1-4 Hz), theta (4-8 Hz), alfa (8-13 Hz), beta (13-30 Hz), gamma (30-80 Hz). Acquisition parameters will be: High-Pass: 0.5 Hz; Low-Pass: 100 Hz; Notch: 50 Hz. For analysis of HD-EEG data, a previously developed and validated tailored analysis pipe-line will be used to reconstruct neural sources from cortical/subcortical gray matter. EEG signals will be band-pass filtered (1-80 Hz) and down-sampled at 250 Hz. Biological artifacts will be rejected using Independent Component Analysis (ICA). EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique (REST). A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources. Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography (eLORETA) algorithm Statistical analysis As a pilot study, sample size is not calculated and our data will provide the fundament for further confirmatory randomized controlled studies. The investigators will separately evaluate the clinical effects of Ketogenic Diet and PEA supplementation in NON-responders and PEA supplementation in partial responders. As statistical test, ANOVA for repeated measure test, with a within-subject TIME factor (T0 vs. T3 vs. T6) will be used. The primary outcome will be the reduction in MMDs at T3 compared with baseline. As secondary outcome the investigators will analyze: modification of monthly headache days, monthly days of acute drug intake, monthly doses of acute drugs, percentage of patients with a 30-50% reduction of MMDs, migraine related disability (MIDAS, HIT-6), and quality of life (MSQ).
Open study recordThis crossover study will evaluate 3 different treatments of vaporized cannabis (THC, THC/CBD mix, and CBD) and vaporized placebo cannabis for the acute treatment of migraine. In this double-blind, randomized, crossover trial, subjects will treat 4 separate migraine attacks with 4 different treatments. Inhaled cannabis will be administered using a portable vaporization system (Mighty Medic; Storz \& Bickel) based on a validated Storz \& Bickel system and using a standardized inhalation approach. Subjects will self-administer inhaled cannabis as early as possible in the course of a migraine (see Procedure), taking 4 puffs of 1) THC, 2) THC/CBD mix, 3) CBD, or 4) placebo. Patients will treat each of the 4 distinct migraine attacks with a different cannabis sample. Outcomes measured will include pain freedom and pain relief as well as presence or absence of photophobia, phonophobia, and nausea at 1 hour, 2 hours (primary outcome), 24 hours, and 48 hours.
Open study recordThe term "refractory" migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against Calcitonin Gene Related Peptide (CGRP). Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study on the efficacy of a CGRP-targeting monoclonal antibody in Chronic Migraine (CM) patients with at least 3 failures to previous preventive treatments, the investigators showed a higher prevalence of psychological disturbances in those who did respond to the monoclonal antibody compared with the responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological evaluations are available to explain how psychological comorbidities may contribute to treatment refractoriness. Isolated clinical evidence and growing pre-clinical evidence suggests a role for the endocannabinoid system in migraine. Hence, the present study aims to identify psychological and biological factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP. Migraine is a common and highly disabling condition, representing the second-leading cause of disability in the global ranking of most disabling diseases . In the majority of individuals, the disease manifests as episodic (EM), with attacks recurring weekly or monthly. In a smaller (2-3% of the general population), but still significant portion of patients, migraine becomes chronic, i.e., occurring on at least 15 days per month (CM). Previous studies have shown that CM patients are characterized by the presence of multiple psychiatric comorbidities compared with subjects with episodic migraine and healthy controls. In recent years, it has also been shown that among the neurobiological systems involved in the genesis and development of mental disorders, the endocannabinoid system (ES) appears to play an active role. In particular, patients with these disorders are characterized, at the level of peripheral cells, by a gene alteration of cannabinoid receptors. Several studies reported the involvement of SE in immune responses, psychological processes, transduction of neurobiological signals and pain, including migraine pain. Recently it has been shown that the peripheral gene expression of enzymes involved in the metabolism of anandamide (AEA) and 2-aciglycerol (2-AG), the two best known endocannabinoids, is altered in migraine patients, but more markedly in the chronic subtype, suggesting a role for these lipid molecules not only in the pathophysiology of the disease, but also in its exacerbation. The role of CGRP in the pathophysiology of migraine has now been demonstrated, although the mechanism of action at both peripheral and central levels and its possible interactions with other pathways are not completely known. The term "refractory" migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against CGRP (Consensus document of the European Headache Federation). Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study regarding the efficacy of monoclonal antibody targeting CGRP in CM patients refractory to at least three preventive therapies,the investigators showed a higher prevalence of personality disorders (77% vs 37%) in those who were not responding to treatment at 1 year (non-responders: reduction in migraine days \<50%), compared with those who were responding (responders: reduction in migraine days ≥50%). Non-responders were also characterized by a higher prevalence of anxiety spectrum disorders and more stressful events than responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological data are available to explain how psychological comorbidities may contribute to treatment refractoriness. In this frame, the present study aims to identify psychological and potential biochemical/molecular factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP. There will be a screening phase of one month in which patients will complete a daily headache diary in which they will note the occurrence, intensity and duration of attacks, as well as the use of symptomatic drugs. At baseline patients will undergo the psychological and biochemical/molecular evaluation. Subjects will then be treated with one of the three commercially available monoclonal antibodies targeting CGRP and will continue to record the characteristics of attacks and the use of symptomatic drugs in their headache diary. Follow-up visits are foreseen after 3 and 6 months of treatment. At 6 months, patients will be divided into 2 groups (responder or not responder to the treatment) depending on the reduction of monthly migraine days in the previous 3 months (\>50% and \<50%, respectively). The patients who failed to respond to the treatment will be considered refractory. Psychological evaluation: All patients will be evaluated by psychological interview and by adopting the DSM-V criteria for personality disturbances, anxiety and mood disorders. All patients will also be administered the Hospital Anxiety and Depression Scale (HADS) the Toronto Alexithymia Scale 20 (TAS-20), severity of dependence questionnaires (Severity Dependence Scale - SDS - and Leeds Dependence Questionnaire - LDQ), questionnaires related to Childhood trauma and Stressful life events.
Open study recordPreclinical and clinical evidence suggests a role for the dysregulation of endocannabinoid system (ES) in migraine pain, particularly in subjects with chronic migraine. The gene expression of ES components were assayed in peripheral blood mononuclear cells (PBMCs) of patients with episodic migraine (EM), chronic migraine with medication overuse (CM-MO) and age-matched healthy controls (CT). It was evaluated the protein expression of cannabinoid receptors (CB) 1 and 2 as well as DNA methylation changes in genes involved in ES components. Migraine is a neurovascular disease whose pathophysiology is far from being completely clarified. This is mainly due to the complex mechanisms that underlie migraine attack as well as its recurrence. The endocannabinoid system (ES) is a complex signalling system involved in different biological processes (e.g. neuronal activity, pain sensation and immune functions) and it plays a crucial role in the maintenance of body homeostasis. The ES components include the endogenous lipids, the most studied ones being N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), their metabolic enzymes and at least two cannabinoid receptors (CB1 and CB2). The biosynthesis of AEA mainly occurs by N-acylphosphatidylethanolamide-phospholipase D (NAPE-PLD), whereas 2-AG is produced through the action of diacylglycerol lipase (DAGL). AEA is metabolized by fatty acid amide hydrolase (FAAH) and 2-AG mainly by monoacylglycerol lipase (MAGL). Alterations in gene expression of ES components may involve various cell types, multiple catabolic pathways and the generation of active metabolites via epigenetic mechanisms, under both physiological and pathological conditions. CB genes, for instance, may interact with different transcriptional factors, many of which are related to DNA methylation and histone post-translational modifications. A dysfunctional ES has been associated to numerous disorders including migraine. The ES, indeed, modulates multiple activities and neuromodulators/neurotransmitters that play a crucial role in migraine pathogenesis. ES is also implicated in the descending modulation of the trigeminovascular nociceptive transmission from the brainstem afferents. Previous studies from the Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, IRCCS Mondino Foundation, Pavia (Italy), using the migraine-specific animal model based on nitroglycerin administration in rat, demonstrated the existence of interactions between the ES and pain mediation. In particular, the investigators showed a key role for AEA and for FAAH-regulated AEA activity in the processing of trigeminal nociceptive signals. AEA inhibits neurogenic dural vasodilatation, as well as calcitonin gene-related peptide-induced and nitric oxide-induced dural vessel dilation, an activity that is reversed by CB1 antagonism. The interaction between the ES and migraine pain is also suggested by clinical observations. FAAH activity was higher in platelets of women with episodic migraine (EM) to suggest a more marked degradation of AEA. Subjects with chronic migraine (CM) and medication overuse (MO) showed an altered endocannabinoid metabolism not only in platelets, but also in the CSF. Although the above clinical findings are scattered and replicated, their re-consideration in the light of more recent data from the increasing pre-clinical evidence prompt the need to investigate in more depth the role of ES in migraine pathophysiology. Several studies suggest that changes in ES components detected in peripheral blood mononuclear cells (PBMCs) are reliable indicators of a central dysfunction of the ES in different neurological diseases. For instance, in patients with Parkinson disease or multiple sclerosis, increased CSF levels of AEA were associated with a reduction in the activity and protein content of FAAH in PBMCs, which is indicative of an increased AEA tone. AEA levels were elevated in the CSF and in the blood of schizophrenic subjects, with a significant drop in AEA blood levels and in mRNA transcripts of CB2 and FAAH in PBMCs following clinical remission. The aim of this study, was the identification of specific functional patterns of ES activity in subjects with migraine. To this end, the investigators performed a thorough evaluation of multiple peripheral components of the ES (gene expression, protein expression and DNA methylation) in PBMCs of representative samples of subjects with EM without aura, CM-MO and in healthy controls (CT). Twenty-five subjects with EM, 26 with CM-MO and 24 CT were enrolled in the headache center of the IRCCS Mondino Foundation of Pavia (Italy). The study was approved by the local Ethics Committee and all subjects enrolled signed a written informed consent. Blood samples (20ml) were collected within ethylenediamine tetra-acetic acid (EDTA) containing tubes from participants. Blood samples were diluted in 1:1 ratio with phosphate buffer saline 1X (PBS 1X) (Sigma). Diluted blood samples were slowly loaded onto Ficoll separating solution (15ml) (Sigma) and centrifuged at 800 g without brake for 30 min at room temperature. PBMCs accumulated as the middle white monolayer, were washed twice in sterile PBS 1X and centrifuged at 300 g for 15 min. For each sample, a batch of PBMCs was used for RNA or DNA extraction and another one for flow-cytometer analysis. In the PBMCs isolated from the subjects in the 3 study groups the investigators assayed: * CB1 and CB2 protein expression; * expression of the following genes: CB receptors, FAAH, NAPE-PLD, MAGL and DAGL * DNA methylation of ES components. To determine the relative level of CB1 and CB2 protein expression in PBMCs, the investigators used flow-cytometry with a FACS Canto flow-cytometer (Becton-Dickenson). After isolation, cells (100000 per reaction) were stained using antibodies against CD45 (BD Biosciences, 1:50), CB1 (R\&D system, 1:50) and CB2 receptors (Cayman Chemical, 1:30); a total of 10000 events were counted in windows gated for the intersection of CD45 staining with CB1 and CB2. Total RNA from PBMCs was isolated using standard procedure (Zymo Research) and RNA quality was assessed using a nanodrop spectrophotometer (Nanodrop™ Thermo Fisher Scientific); cDNA was generated using the iScript cDNA Synthesis kit (Biorad) following the supplier's instructions. Gene expression of CB receptors, FAAH, NAPE-PLD, MAGL and DAGL was analyzed using the Fast Eva Green supermix (BIO-RAD). Ubiquitin (UBC), whose expression remained constant in all experimental groups, was used as housekeeping gene. The amplification was performed with a light Cycler 480 Instrument rt-PCR Detection System (Roche) following the supplier's instructions. All samples were assayed in triplicate and gene expression levels were calculated according to 2-∆Ct = 2- (Ct gene - Ct housekeeping gene) formula by using Ct values. Since PBMCs contain the full complement of epigenetic enzymes found in most tissues, including neurons and peripheral nucleated cells, the investigators evaluated the role of DNA methylation in the regulation of ES gene transcription in all the enrolled subjects. DNA was extracted from whole blood using QIAmp DNA Blood Mini Kit (Qiagen) and its concentration was determined by NanoDrop quantification (NanoDrop Techologies, Thermofisher). Arrays preparation and data analysis were performed by Genomix4Life srl (Baronissi, Italy). High-quality DNA (500 ng) was bisulfite converted using EZ DNA methylation kit (Zymo Research, Irvine, CA, USA). Bisulfite converted DNA (200ng) was used for analysis of whole-genome methylation, using the HumanMethylation 450 K BeadChip (Illumina, San Diego, CA, USA), which contains 485 577 probes covering 21 231 (99%) RefSeq genes. In brief, bisulfite converted DNA was whole-genome amplified for 20 h followed by end-point fragmentation. Fragmented DNA was precipitated, denatured and hybridised to the BeadChips for 20 h at 48 °C. The BeadChips were washed and the hybridised primers were extended and labelled before scanning the BeadChips using the Illumina iScan system. GenomeStudio software (version 2011.1; Illumina Inc.) was used for the extraction of DNA methylation signals from scanned arrays. The methylation level for each cytosine was expressed as a beta value calculated as the fluorescence intensity ratio of the methylated to unmethylated versions of the probes: beta values ranged between 0 (unmethylated) and 1 (methylated). The annotation relating to CGIs uses the following categorisation: 'shore', each of the 2-kb sequences flanking a CGI; 'shelf', each of the 2-kb sequences next to a shore; 'open sea', DNA not included in any of the previous sequences or in CGIs 4. TSS200 and TSS1500 indicate the region between position -200 bp and -1500 bp from the TSS, respectively. The significant methylation difference between two given loci is indicated by a delta-beta value and determined with GenomeStudio Methylation Module using Illumina custom algorithm for calculating DiffScores (DiffScore⩽-30.0 (≈ pval \<0.001)=hypo-methylation; DiffScore⩾30.0 (≈ p val\<0.001)=hyper-methylation).
Open study recordSublingual Tablets With Cannabinoid Combinations for the Treatment of Dysmenorrhea
Open study recordThe primary objective of this study is to evaluate the efficacy and safety of dronabinol MDI for the acute treatment of moderate to severe migraine headache.
Open study record