title: A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex(®), a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex(®) and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (p = 0.286), cognitive (p = 0.824), behavioral (p = 1.0) and functional (p = 0.581) scores were detected during treatment with Sativex(®) as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex(®) is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations.Clincaltrals.gov identifier: NCT01502046.
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain. joselopezsendon@hotmail.com.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. joselopezsendon@hotmail.com.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. joselopezsendon@hotmail.com.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: López-Sendón Moreno
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: García Caldentey
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Trigo Cubillo
authors.affiliation: Neurobiology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ruiz Romero
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García Ribas
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain.
authors.forename: M A Alonso
authors.initials: MA
authors.lastname: Alonso Arias
authors.affiliation: Instituto de Salud Músculoesquelética, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: García de Yébenes
authors.affiliation: Fundación Hospital de Alcorcón, Madrid, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Tolón
authors.affiliation: Department of Biochemistry and Molecular Biology I, Faculty of Biology, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology III, Faculty of Medicine, Complutense University, Madrid, Spain.
authors.forename: Onintza
authors.initials: O
authors.lastname: Sagredo
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology III, Faculty of Medicine, Complutense University, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Valdeolivas
authors.affiliation: Department of Biochemistry and Molecular Biology I, Faculty of Biology, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Resel
authors.affiliation: Department of Organic Chemistry I, Faculty of Chemistry, Complutense University, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutierrez
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: María Laura
authors.initials: ML
authors.lastname: García-Bermejo
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.|Department of Biochemistry and Molecular Biology III, Faculty of Medicine, Complutense University, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández Ruiz
authors.affiliation: Department of Biochemistry and Molecular Biology I, Faculty of Biology, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.affiliation: Neurology Department, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Justo
authors.initials: J
authors.lastname: García de Yébenes Prous
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid; D002185:Cannabidiol; D018592:Cross-Over Studies; D013759:Dronabinol; D004338:Drug Combinations; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D008297:Male; D008609:Mental Status Schedule; D035683:MicroRNAs / Q000097:blood; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010865:Pilot Projects; D010936:Plant Extracts / Q000627:therapeutic use*; D018514:Plant Structures; D012720:Severity of Illness Index; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides; D015306:Biogenic Monoamines; D004338:Drug Combinations; D063388:Endocannabinoids; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D010446:Peptide Fragments; D010936:Plant Extracts; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols
keywords: Cannabinoid; Clinical trial; Huntington’s disease; Sativex